Carlo Enrique Marcucci

Patrick Schoettker Editors

Perioperative
Hemostasis

Coagulation for
Anesthesiologists

123
Perioperative Hemostasis
Carlo Enrique Marcucci • Patrick Schoettker
Editors

Perioperative Hemostasis
Coagulation for Anesthesiologists
Editors
Carlo Enrique Marcucci Patrick Schoettker
Department of Anesthesiology Department of Anesthesiology
University Hospital of Lausanne University Hospital of Lausanne
Lausanne Lausanne
Switzerland Switzerland

ISBN 978-3-642-55003-4 ISBN 978-3-642-55004-1 (eBook)

DOI 10.1007/978-3-642-55004-1
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To Carine, Ella, Catherine, Sophie and Zoé, our girls
Acknowledgement

English language editing by Darren Hart.

vii
 SIZE OF TREATMENT EFFECT

CLASS I CLASS IIa CLASS IIb CLASS III

Benefit >>> Risk Benefit >> Risk Benefit ≥ Risk Risk ≥ Benefit

Procedure/Treatment Additional studies with Additional studies with broad Procedure/Treatment should
SHOULD be performed/ focused objectives needed objectives needed; additional NOT be performed/adminis-
administered registry data would be helpful tered SINCE IT IS NOT HELP-
IT IS REASONABLE to per- FUL AND MAY BE HARMFUL
form procedure/administer Procedure/Tretment
treatment MAY BE CONSIDERED

LEVEL A Recommendation that Recommendation in favor Recommendation’s Recommendation that

Multiple populations procedure or treatment of treatment or procedure usefulness/efficacy less procedure or treatment is
evaluated* is useful/effective being useful/effective well established not useful/effective and
may be harmful
Data derived from multiple Sufficient evidence from Some conflicting evidence Greater conflicting
randomized clinical trials multiple randomized trials from multiple randomized evidence from multiple Sufficient evidence from
or meta-analyses or meta-analyses trails or meta-analyses randomized trails or multiple randomized trials
meta-analyses or meta-analyses

LEVEL B Recommendation that Recommendation in favor Recommendation’s Recommendation that

Limited populations procedure or treatment of treatment or procedure usefulness/efficacy less procedure or treatment is
evaluated* is useful/effective being useful/effective well established not useful/effective and
may be harmful
Data derived from a Evidence from single Some conflicting Greater conflicting
single randomized trial randomized trial or evidence from single evidence from single Evidence from single
or nonrandomized studies nonrandomized studies randomized trial or randomized trail or randomized trial or
nonrandomized studies nonrandomized studies nonrandomized studies

LEVEL C Recommendation that Recommendation in favor Recommendation’s Recommendation that

Very limited populations procedure or treatment is of treatment or procedure useful/efficacy less procedure or treatment is
evaluated* useful/effective being useful/effective well established not useful/effective and
may be harmful
Only consensus opinion Only expert opinion, case Only diverging expert Only diverging expert
of experts, case studies, studies, or standard of care opinion, case studies, opinion, case studies, or Only expert opinion, case
or standard of care or standard of care standard of care studies, or standard of care

ESTIMATE OF CERTAINTY (PRECISION) OF TREATMENT EFFECT

Suggested phrases for Should Is reasonable May/might be considered is not recommended
writing recommendations* is recommended can be useful/effective/ may/might be reasonable is not indicated
is indicated beneficial is probably usefulness/effectiveness is should not
is useful/effective/beneficial recommended unknown/unclear/uncertain is not usefull/effective/
or indicated or not well established beneficial may be harmful

Reproduced, with permission, from: Jacobs AK, Kushner FG, Ettinger SM et al. (2013) ACCF/AHA Clinical practice guideline methodology summit report: a
report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation 127:268–310
Abbreviations

%CIn percent of clotting inhibition

AA arachidonic acid
Ab antibodies
ACCP American College of Chest Physicians
ACoTS acute coagulopathy of trauma shock
ACP American College of Physicians
ACS acute coronary syndrome
ACT activated clotting time
ADP adenosine diphosphate
ALI acute lung injury
AP antiplatelet
APC agonist platelet count
APC activated protein C
aPTT activated partial thromboplastin time
ARU aspirin reactions units
ASA American Society of Anesthesiologists
ASA acetylsalicylic acid
ASRA American Society of Regional Anesthesia and Pain Medicine
AT antithrombin
AT III antithrombin III
ATC acute traumatic coagulopathy
ATE arterial thromboembolism
ATP adenosine triphosphate
AU aggregation units
AUC area under the curve
AVK anti-vitamin K anticoagulants
AvWD acquired von Willebrand disease
AvWS acquired von Willebrand syndrome
BD base deficit
BMS bare-metal stents
BNP brain natriuretic peptide
BPC baseline platelet count
BT bleeding time
C4bBP C4b-binding protein

xi
xii Abbreviations

CA5 clot amplitude at 5 min

CABG coronary artery bypass graft
cAMP cyclic adenosine monophosphate
CATS continuous autotransfusion system
CBC complete blood count
CERA continuous erythropoiesis receptor activators
CFT clot formation time
CHF chronic heart failure
CLD chronic liver disease
COPD chronic obstructive pulmonary disease
COX cyclooxygenase
COX-1 cyclooxygenase-1
CPB cardiopulmonary bypass
CPM continuous passive motion
CrCl creatinine clearance
CRF chronic renal failure
CRP C-reactive protein
CT coagulation time
CT closure time
DATS discontinuous autotransfusion system
DCR damage control resuscitation
DCS damage control surgery
DDAVP deamino-D-arginine vasopressin
DES drug-eluting stents
DIC disseminated intravascular coagulation
DVT deep vein thrombosis
EAC endogenous acute coagulopathy
ECA endothelial cell activation
ECG electrocardiogram
ECMO extracorporeal membrane oxygenation
ECS elastic compressive stockings
ECT ecarin clotting time assay
EIAs enzyme immunoassays
ELISA enzyme-linked immunosorbent assay
EMA European Medicines Agency
EPCR endothelial protein C receptor
EPI epinephrine
EPO erythropoietin
ESA erythropoiesis-stimulating agents
ESA European Society of Anaesthesiology
ET essential thrombocythemia
ETP endogenous thrombin potential
FBN fibrinogen
FEIBA factor eight inhibitor bypassing agent
FFP fresh frozen plasma
Abbreviations xiii

FI factor I
FNHTR febrile nonhemolytic transfusion reactions
FVIII factor VIII
FX factor X
FXa activated factor X
FXIII factor XIII
GP glycoprotein
GPIb glycoprotein Ib
HA human albumin
HAES/HES hydroxyethyl starch
HAV hepatitis A virus
HCR hemostatic control resuscitation
HEA Hypotensive epidural anesthesia
HELLP syndrome hemolysis, elevated liver enzymes, and
low platelets syndrome
HEV hepatitis E virus
HF hyperfibrinolysis
HHS hypertonic–hyperoncotic solutions
HIT heparin-induced thrombocytopenia
HIV human immunodeficiency virus
HLA human leukocyte antigen
HMWK high-molecular-weight kininogen
HNA human neutrophil antigen
HR hemostatic resuscitation
HUS hemolytic uremic syndrome
IBD inflammatory bowel disease
i-CFC isolated coagulation factor concentrate
ICH intracerebral hemorrhage
ICU intensive care unit
IL-6 interleukin 6
INR international normalized ratio
IPC intermittent pneumatic compression
ISS injury severity score
ISTH International Society on Thrombosis and Haemostasis
ITP immune thrombocytopenia
ITP idiopathic thombocytopenic purpura
JW Jehovah’s Witness
LMWH low-molecular-weight heparin
LPR low on-treatment platelet reactivity
MA maximum amplitude
MB methylene blue
MCF maximum clot firmness
MI myocardial infarction
MPS myeloproliferative syndrome
MTP massive transfusion protocol
xiv Abbreviations

MUF modified ultrafiltration

MW molecular weight
NHL non-Hodgkin lymphoma
NICE National Institute for Health and Clinical Excellence
NOAC novel oral anticoagulant
NS normal saline
NSAID nonsteroidal anti-inflammatory drug
NT N-terminal
OAC oral anticoagulant
ONTraC Ontario Nurse Transfusion Coordinators
P pasteurization
PAI plasminogen activator inhibitor
PAI-1 plasminogen activator inhibitor 1
PAI-2 plasminogen activator inhibitor 2
PAR4 protease-activated receptor 4
PAS platelet additive solution
PAU platelet aggregation units
PBM patient blood management
PC platelet count
PC platelet concentrate
PCC prothrombin complex concentrate
PCT photochemically treated
PE pulmonary embolism
PF4 platelet factor 4
PFA platelet function analyzer
PGE1 prostaglandin E1
PK prekallikrein
PLT platelets
POC point of care
PPH postpartum hemorrhage
PRBC packed red blood cells
PRU P2Y12 reaction units
PT prothrombin time
PV polycythemia vera
RBC red blood cell
r-CFC recombinant coagulation factor concentrate
RCT randomized control trial
rFVIIa recombinant activated factor VII
RIPA ristocetin-induced platelet aggregation
RL Ringer’s lactate
ROTEM rotational thromboelastometry
RPFA rapid platelet function assay
rTPA recombinant tissue plasminogen activator
SCA Society of Cardiovascular Anesthesiologists
SD solvent detergent
Abbreviations xv

SIGN Scottish Intercollegiate Guideline Network

SOPs standard operating procedures
SSNRI selective serotonin norepinephrine reuptake inhibitors
SSRI selective serotonin reuptake inhibitors
ST stent thrombosis
STS Society of Thoracic Surgeons
TACO transfusion-associated circulatory overload
TAFI thrombin-activatable fibrinolysis inhibitor
TAT thrombin-antithrombin complex
TBI traumatic brain injury
TEG thromboelastography
TEM thromboelastometry
TF tissue factor
TFPI tissue factor pathway inhibitor
TG thrombin generation
THA total hip arthroplasty
TIC trauma-induced coagulopathy
TKA total knee arthroplasty
TM thrombomodulin
tPA tissue plasminogen activator
t-PA tissue-type plasminogen activator
TRALI transfusion-related acute lung injury
TRAP thrombin receptor activating peptide
TRIM transfusion-related immunomodulation
TT thrombin time
TTP thrombotic thrombocytopenic purpura
TXA tranexamic acid
TXA2 thromboxane A2
U units
UFH unfractionated heparin
u-PA urokinase-type plasminogen activator
VH or T vapor and/or heat
VHA viscoelastic hemostatic assay
VKA vitamin K antagonist
VTE venous thromboembolism
vWD von Willebrand disease
vWF von Willebrand factor
vWS von Willebrand syndrome
WHO World Health Organization
α2-PI α2-plasmin inhibitor
Contents

Part I Pre-operative Hemostasis

1 The Cell-Based Coagulation Model . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Christoph Sucker and Rainer B. Zotz
2 Laboratory Testing of Hemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Fanny Bonhomme and Pierre Fontana
3 Viscoelastic Tests of Hemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Catherine Heim and Patrick Schoettker
4 Point-of-Care Platelet Function Tests . . . . . . . . . . . . . . . . . . . . . . . . . 45
Gabriele Casso, Fabio Lanzi, and Carlo E. Marcucci
5 Hemostasis Assessment and Evaluation. . . . . . . . . . . . . . . . . . . . . . . . 65
Christoph Sucker and Rainer B. Zotz
6 Congenital Bleeding Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Maria Martinez, Lukas Graf, and Dimitrios A. Tsakiris
7 Acquired Hemostatic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Stefano Barelli, Sabine Blum, and Anne Angelillo-Scherrer
8 Antiplatelet Therapy and Anticoagulation . . . . . . . . . . . . . . . . . . . . . 109
Pierre-Guy Chassot, Stefano Barelli, Sabine Blum,
Anne Angelillo-Scherrer, and Carlo E. Marcucci
9 Intravenous Fluids and Coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Herbert Schöchl, Christoph Schlimp, and Wolfgang Voelckel
10 Split Blood Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Theresa M. Boyd, Evelyn Lockhart, and Ian Welsby
11 Coagulation Factor Concentrates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Lars M. Asmis
12 Procoagulant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Rainer B. Zotz, Nikola Zotz, and Christoph Sucker

xvii
xviii Contents

13 Patient Blood Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Oliver M. Theusinger, Stephanie L. Kind, and Donat R. Spahn

Part II Per-operative Hemostasis

14 Perioperative Coagulation in Cardiovascular Surgery . . . . . . . . . . . 243

Fabrizio Gronchi and Marco Ranucci
15 Perioperative Hemostasis in Hepatic Surgery. . . . . . . . . . . . . . . . . . . 267
Klaus Görlinger, Eva Schaden, and Fuat H. Saner
16 Perioperative Hemostasis in Pediatric Surgery. . . . . . . . . . . . . . . . . . 285
Thorsten Haas
17 Perioperative Hemostasis in Obstetrics . . . . . . . . . . . . . . . . . . . . . . . . 299
Albrice Levrat, Christian Kern, and Cyril Huissoud
18 Perioperative Hemostasis in Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Catherine Heim and Karim Brohi
19 Perioperative Hemostasis in Neurosurgery . . . . . . . . . . . . . . . . . . . . . 331
Julien Picard, Pierre Bouzat, Gilles Francony, Jean-François Payen,
and Patrick Schoettker
20 Bleeding Management in Elective Orthopedic Surgery . . . . . . . . . . . 351
Oliver M. Theusinger
21 Perioperative Coagulation in Neuraxial
and Peripheral Nerve Blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Kyle Kirkham and Eric Albrecht

Part III Post-operative Hemostasis

22 Coagulation Disorders in Intensive Care Patients . . . . . . . . . . . . . . . 377

Marcel Levi
23 Perioperative Thromboprophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Marc Aldenkortt and Marc Licker

Part IV Economic Aspects and Organization

24 Economic Aspects and Organization . . . . . . . . . . . . . . . . . . . . . . . . . . 421

Klaus Görlinger and Sibylle A. Kozek-Langenecker

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
 Part I
Pre-operative Hemostasis
The Cell-Based Coagulation Model
1
Christoph Sucker and Rainer B. Zotz

1.1 Introduction

The term “hemostasis” summarizes a variety of physiological processes that lead

to a cessation of bleeding in case of vascular injury. Hemostasis keeps blood
within damaged blood vessels and is therefore a life-saving mechanism.
Furthermore, adequate hemostasis is a prerequisite for effective wound healing
following injury.
The process of hemostasis is complex. In the initial phase, constriction of injured
blood vessels leads to a reduction of blood flow. Then a plug forms, consisting of
adhering and aggregating platelets and fibrin; this leads to a complete control of
blood loss and allows for the repair of the vascular and tissue defect.
Since antiquity, physicians have been developing and extending theories to
explain the process of coagulation. Some of the most important steps on this jour-
ney were the description of fibrin as the main content of blood clots, by Johannes
Mueller (1801–1858); the description of its precursor, fibrinogen, by Rudolf Virchow
(1821–1902); and its isolation by Prosper Sylvain Denis (1799–1863). Alexander
Schmidt (1831–1894) and Rudolf Virchow were the first to suggest that the forma-
tion of fibrin from fibrinogen is an enzymatic process. Alexander Schmidt termed
the fibrinogen-converting enzyme “thrombin” and its precursor “prothrombin”
(Schmidt 1872, 1892). In 1890, calcium was found to be essential for coagulation

C. Sucker
LaboMed Gerinnungszentrum Berlin, Tauentzienstrasse 7 b/c,
Berlin 10789, Germany
e-mail: [email protected]
R.B. Zotz (*)
Centrum für Blutgerinnungsstörungen und Transfusionsmedizin (CBT),
Immermannstrasse 65 a, Düsseldorf 40210, Germany
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 3

DOI 10.1007/978-3-642-55004-1_1, © Springer-Verlag Berlin Heidelberg 2015
4 C. Sucker and R.B. Zotz

(Arthus and Pagès 1890). Platelets were discovered in 1865 and described further in
the following years (Brewer 2006).
Paul Morawitz (1879–1936) published his classic theory of plasmatic hemostasis
just over 100 years ago. According to his model, prothrombin is converted to throm-
bin by tissue-derived thrombokinase; thrombin then converts fibrinogen to fibrin –
the most important step of coagulation (Morawitz 1905). This first concept of
hemostasis was modified and extended over the following years. In particular, more
coagulation factors were discovered, allowing for the development of more detailed
concepts of the hemostatic process (Wright 1962; Douglas 1999). This resulted in
the publication of the “Cascade Model” by MacFarlane and the “Waterfall Sequence
Model” of plasmatic hemostasis by Davie and Ratnoff (MacFarlane 1964; Davie
and Ratnoff 1964).
In the following sections, we illustrate the process of primary hemostasis, defined
as all aspects of platelet adhesion and platelet aggregation, and secondary hemosta-
sis, defined as the process of fibrin formation and fibrin stabilization. In the final
section, we briefly review the most important antithrombotic mechanisms: the fibri-
nolytic system, protein C/S system, and antithrombin.

1.2 Primary Hemostasis

The term “primary hemostasis” encompasses all aspects of platelet adhesion and
aggregation. Apart from platelets, components of the vessel wall – subendothelial
matrix components in particular – and von Willebrand factor (vWF) are involved in
this process (Riddel et al. 2007). The whole process is depicted in Fig. 1.1.
A healthy endothelium provides a physiological barrier, preventing initiation of
hemostasis by subendothelial matrix components, and has specific antithrombotic
properties, e.g., the secretion of antithrombotic agents such as nitric oxide and pros-
taglandins. In the case of vascular injury, a transient local vasoconstriction slows
down the blood flow and reduces extravascular blood loss. Hemostasis is initiated
when the rupture of this physiological barrier exposes the subendothelium to the
blood. VWF is a large multimeric glycoprotein which plays a crucial role in the
initial adhesion of platelets, particularly in vascular regions with high shear rates.
When subendothelial collagen is exposed to blood due to a vascular injury, vWF
quickly binds to it, leading to conformational changes of its binding areas for plate-
lets. This allows platelets to bind to vWF, mediated by their vWF receptors, the
glycoprotein (GP) Ib/V/IX complex. This process leads to an approximation of
platelets to the endothelial lesion and an initial adhesion. The adhesion is then fur-
ther stabilized by direct interaction of platelet receptors with subendothelial matrix
components, such as contact of platelet collagen receptors GP Ia/IIa and VI with
subendothelial collagen. Platelet adhesion to the injured vessel wall and the release
of a variety of inductors lead to platelet activation, and through several processes a
shape change occurs. The shape change increases the surfaces of the reactive plate-
lets by conversion from a discoid to a globular shape. The excretion of the content of
the platelets’ α- and δ-granules leads to the release of a variety of components (e.g.,
1 The Cell-Based Coagulation Model 5

Platelet

GP IIb-IIIa

GP IIb-IIIa

Platelet

GP Ib-V-IX

GP VI GP Ia-IIa
vWF
Endothelial cell Endothelial cell

Subendothelial collagen matrix

Fig. 1.1 Schematic view of platelet adhesion and aggregation. Following endothelial injury,
platelets adhere to collagen by interaction of the receptor glycoprotein (GP) Ib/V/IX with von
Willebrand factor which is bound to collagen. This adhesion is stabilized by direct interaction of
platelet collagen receptors GP Ia/IIa and GP VI with collagen. Following activation of the aggrega-
tion receptors GP IIb/IIIa, platelets aggregate, mediated by von Willebrand factor or fibrinogen

coagulation factors, calcium, ADP) and modulators of hemostasis, such as throm-

boxane A2 (TXA2) and platelet-activating factor, both of which are potent platelet
activators and promote vasoconstriction. Upon activation, platelets also exhibit a
more thrombogenic surface by exposing a negatively charged phospholipid layer,
providing the catalytic surface for the binding of coagulation factors and, thus, the
process of fibrin formation and stabilization (see Chap. 2).
Furthermore, externalization, clustering, and activation of receptors on the plate-
lets’ surface occur, allowing for a complex and intense interaction of platelets with
matrix proteins and other platelets. In this process, platelets aggregate by cross-
linking the highly expressed GP IIb/IIIa aggregation receptors on the platelet
surfaces via vWF or fibrinogen.
As a result of primary hemostasis, a primary platelet plug forms on the injured
endothelium, mainly consisting of platelets and vWF. This platelet clot is further
modified and stabilized by cross-linking of fibrin.

1.3 Secondary Hemostasis: Fibrin Formation

and Stabilization

In addition to primary hemostasis as the process of platelet adhesion and aggrega-

tion, fibrin formation and stabilization is crucial. The secondary hemostasis process
involves multiple enzymatic steps, resulting in the conversion of fibrinogen to fibrin
by thrombin and the cross-linking of fibrin by activated coagulation factor XIII. The
main proteins needed for plasmatic hemostasis and the process of fibrin generation
6 C. Sucker and R.B. Zotz

Table 1.1 Characteristics of coagulation factors (factor XII is not regarded as an essential coagulation
factor according to the current hemostasis model and is, therefore, not shown in the table)
Molecular Plasma
Coagulation factor Function weight (mg/l) half-life (h)
I Fibrinogen Substrate 3,000 90
II Prothrombin Serine protease 100 65
V Proaccelerin Cofactor 10 15
VII Proconvertin Serine protease 0.5 5
VIII Antihemophilic factor Cofactor 0.1 10
IX Christmas factor Serine protease 5 25
X Stuart-Prower factor Serine protease 10 40
XI Plasma thromboplastin Serine protease 5 45
antecedent
XIII Fibrin-stabilizing factor Transglutaminase 30 200

and stabilization are summarized in Table 1.1. These “coagulation factors” include
enzymes of the serine protease family and cofactors that have no enzymatic activity
of their own but enhance the reactions of the coagulation enzymes. Some factors,
such as tissue factor (formerly factor III) and calcium (formerly factor IV) are no
longer regarded as coagulation factors today. Unless activated coagulation factors
have an individual name, such as thrombin (factor IIa), they are labeled with the
number of the factor and the suffix “a.”
In Morawitz’s first model of plasmatic hemostasis, prothrombin converted to
thrombin in the presence of tissue-derived thromboplastin and calcium, and throm-
bin then converted fibrinogen to fibrin (Morawitz 1905). In subsequent years, more
coagulation factors were detected and characterized, which led to an extension and
adaptation of the Morawitz model. However, despite the description of ever more
components of hemostasis, the complete interaction of these coagulation factors
and the way in which they convert prothrombin to thrombin remained unclear for
decades (Riddel et al. 2007). In 1964, two groups of researchers independently
reported a model of hemostasis in which the activation of one coagulation factor
resulted in the activation of another in a cascade or waterfall sequence, finally
resulting in the generation of thrombin. The “Cascade Model” was published by
MacFarlane in Nature (MacFarlane 1964), shortly followed by an independent
publication of the “Waterfall Model,” reported in Science by Davie and Ratnoff
(Davie and Ratnoff 1964). In these closely related models, each coagulation factor
was activated by another in cascade sequences, resulting in thrombin generation
from prothrombin and conversion of fibrinogen to fibrin. Both models described
two different ways in which thrombin formation was induced: firstly there was the
intrinsic pathway, for which all the required components were regarded as being
present in the blood, and secondly there was the extrinsic pathway, which required
an initiation by extravascular, subendothelially localized, and membrane-bound
tissue factor (TF) which is identical to the “thromboplastin” reported by Morawitz
in 1905. Both models concluded with a final common pathway in which factor X
was activated by either the intrinsic or extrinsic pathway, leading to the conversion
1 The Cell-Based Coagulation Model 7

Fig. 1.2 Cascade or XII VII

Waterfall Model of hemosta-
sis: hemostasis is initiated via
activation of the intrinsic or Intrinsic Extrinsic
extrinsic pathway of XI
pathway pathway
coagulation. In a common
final pathway, activated factor
X
X (Xa) together with its IX+VIII
cofactor, factor Va, induces
thrombin generation from
prothrombin, resulting in the Xa + Va
conversion of fibrinogen to
fibrin Common
pathway Prothrombin Thrombin

Fibrinogen Fibrin

of prothrombin to thrombin and, consequently, to the formation of fibrin from

fibrinogen. This classic Cascade or Waterfall Model of plasmatic hemostasis is
depicted in Fig. 1.2.

1.3.1 The Current Concept: The Cell-Based Model of Hemostasis

The cascade-type model of hemostasis remained accepted for a long time. However,
certain observations led to criticism of this model as it became clear that it was not
able to describe the real hemostatic process in vivo. Critical failings in the earlier
coagulation models led to further research and the development of a cell-based
model of hemostasis by Monroe and Hoffman in 2001. Today this model is widely
accepted and regarded as the best description of the process of hemostasis (Hoffman
and Monroe 2001; Roberts et al. 2006; Monroe and Hofman 2006).
The cell-based coagulation model distinguishes three distinct overlapping
phases of the hemostatic process. According to this concept, initiation of coagula-
tion occurs when blood is exposed to TF, expressed on TF-bearing cells. TF then
binds to factor VII which leads to activation of factor VII to factor VIIa. If the stimu-
lus is strong enough, further coagulation factors are activated, which results in the
formation of small amounts of thrombin generated by the enzymatic cleavage of
prothrombin (Fig. 1.3a). The small amounts of thrombin formed in this step, how-
ever, are not sufficient for the conversion of fibrinogen to fibrin and for the stabiliza-
tion of the fibrin clot by means of coagulation factor XIII. In the second phase of the
coagulation process, the amplification, thrombin activates platelets which then pres-
ent their thrombogenic surface of negatively charged phospholipids. Here, the coag-
ulation process is catalyzed and thus intensified (Fig. 1.3b). Thrombin activates
further coagulation factors, which bind to the activated platelet surfaces and mas-
sively increase the thrombin generation in the propagation phase of the coagulation
process (Fig. 1.3c). The “thrombin burst” generated by these mechanisms leads to
8 C. Sucker and R.B. Zotz

IX
a

VII X
IXa
II

Xa
VII TF IIa
VIIa TF

Tissue-factor (TF) Tissue-factor (TF) Tissue-factor (TF)

bearing cell bearing cell bearing cell

vWF/VIII VIIIa
b
Platelet activation
II

Xa
IIa IIa
Va Platelet

Tissue-factor (TF)
bearing cell V Va
XI XIa

c
X II

VIIIa + IXa Xa Va IIa

Platelet

IIa
Fibrinogen Fibrin
1 The Cell-Based Coagulation Model 9

an extensive stimulation of hemostasis and is sufficient to convert fibrinogen to

fibrin and to activate factor XIII to XIIIa, which cross-links the fibrin fibers and
stabilizes the fibrin clot. In contrast to the previous models, the most recent findings
suggest that coagulation factor XII is not needed for the formation of fibrin and not
relevant for normal hemostasis.

1.4 Antithrombotic Mechanisms

As a complement to the mechanisms of blood coagulation, antithrombotic mecha-

nisms are required to restrict the process of coagulation, thus preventing throm-
botic events. Among these antithrombotic mechanisms, the most important are the
fibrinolytic system or fibrinolysis, protein C/S system, and antithrombin. Defects in
these mechanisms lead to an impaired function of the antithrombotic mechanism
and predispose for thrombotic events (Esmon 2006).

1.4.1 Fibrinolytic System

The fibrinolytic system allows for the lysis of a fibrin clot (fibrinolysis). The main
fibrinolytic enzyme, plasmin, is derived from its precursor plasminogen upon acti-
vation by tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen
activator (u-PA), which is mainly present in the urine. Plasmin itself cleaves fibrin,
producing fibrin degradation products. The fibrinolytic system is strictly regulated.
The most important inhibitors are plasminogen activator inhibitor (PAI), which
inactivates the plasminogen activators t-PA and u-PA; plasmin inhibitor (previously
termed α2-antiplasmin), which inactivates plasmin; and thrombin-activatable fibri-
nolysis inhibitor (TAFI), which inhibits the action of plasmin on the fibrin clot. The
process of fibrinolysis is depicted in Fig. 1.4. Notably, fibrinolytic capacity differs
significantly among different tissues, with high activities in the genitourinary tract
and the oral mucosa. This tissue-dependent variability of fibrinolytic capacity pro-
vides an explanation of the bleeding pattern in patients with pathologically enhanced
fibrinolysis (hyperfibrinolysis).

Fig. 1.3 (a) Initiation phase of the cell-based model of hemostasis: the complex of tissue factor
(TF) and factor VII activates factor VII to factor VIIa. The complex of TF and factor VIIa activates
factors IX and X, resulting in the generation of thrombin (IIa) by means of the complex of factor
Xa and its cofactor, factor Va (activated by factor Xa). (b) Amplification phase of the cell-based
model of hemostasis: thrombin activates platelets, which then present a thrombogenic surface. On
this catalytic surface, other coagulation factors such as V and XI are activated, and factor VIII is
released by its carrier, von Willebrand factor. Factor XIa activates factor IX. Activated platelets bind
factors Va, VIIIa, and IXa on their surface. (c) Propagation phase of the cell-based model of hemo-
stasis: factor VIIIa/IXa complex activates factor X on the catalytic platelet surfaces, and factors Xa/
Va activate prothrombin (factor II), resulting in a massive generation of thrombin (factor IIa) – a
“thrombin burst.” This burst is able to convert fibrinogen to fibrin and, in addition, to activate factor
XIII to XIIIa, which cross-links the fibrin fibers and stabilizes the fibrin clot
10 C. Sucker and R.B. Zotz

PAI

Plasminogen

Plasminogen activators
(t-PA; u-PA)

Antiplasmin Plasmin

TAFI

Fibrin Fibrin
degradation products

Fig. 1.4 Fibrinolytic system. Plasminogen is converted to plasmin by plasminogen activators,

mainly tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA).
Plasmin cleaves fibrin to fibrin degradation products. The system is strictly regulated by inhibitors
such as antiplasmin, plasminogen activator inhibitor (PAI), and thrombin-activatable fibrinolysis
inhibitor (TAFI)

1.4.2 Protein C/S System

The protein C/S system is the main system to terminate an activated clotting process
(Esmon 2006). When large quantities of thrombin are generated in the process of
plasmatic hemostasis, binding of thrombin to its endothelial receptor thrombomodulin
(TM), supported by additional binding of the endothelial protein C receptor
(EPCR), initiates the breakdown of plasmatic hemostasis. The complex of throm-
bin and TM activates protein C. Together with its cofactor, protein S, activated
protein C (aPC) cleaves the activated coagulation factors Va and VIIIa, which leads
to a breakdown of thrombin formation and, thus, to a cessation of fibrin formation.
Deficiencies of protein C and protein S as well as a frequent mutation in the factor
V gene that prevents its cleavage by activated protein C, called factor V Leiden, are
important inherited risk factors predisposing to thrombotic events. These throm-
botic risk factors impair the physiological inactivation of the hemostatic process by
aPC, leading to a prolonged and increased thrombin formation and thus an elevated
thrombotic risk.

1.4.3 Antithrombin

Antithrombin is an important protein required to localize the coagulation process to

the site of vascular injury. In the absence of functional active antithrombin, throm-
bin and other activated clotting factors would be carried away with the bloodstream
and induce clot formation in areas distant from the injured vessel wall. Antithrombin
inactivates circulating thrombin by forming enzymatically inactive thrombin-
antithrombin complexes. In addition, other activated clotting factors are also
1 The Cell-Based Coagulation Model 11

inactivated by antithrombin. Antithrombin deficiency leads to thrombinemia and

the presence of activated clotting factors in the blood, potentially inducing blood
coagulation regardless of blood vessel injury and thus leading to thrombotic events.

References
Arthus M, Pagès C (1890) Nouvelle theorie chimique de la coagulation du sang. Arch Physiol
Norm Pathol 5:739–746
Brewer DB (2006) Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br
J Haematol 133:251–258
Davie EW, Ratnoff OD (1964) Waterfall sequence of intrinsic blood clotting. Science
145:1310–1312
Douglas AS (1999) Historical review: coagulation history, Oxford 1951–1953. Br J Haematol
107:22–32
Esmon CT (2006) Inflammation and the activated protein C anticoagulant pathway. Semin Thromb
Haemost 32:49–60
Hoffman M, Monroe DM 3rd (2001) A cell-based model of hemostasis. Thromb Haemost
85:958–965
MacFarlane RG (1964) An enzyme cascade in the blood clotting mechanism, and its function as a
biologic amplifier. Nature 202:498–499
Monroe DM, Hofman M (2006) What does it take to make the perfect clot? Arterioscler Thromb
Vasc Biol 26:41–48
Morawitz P (1905) Die Chemie der Blutgerinnung. Ergebn Physiol 4:307–422
Riddel JP, Bradley EA, Miaskowski C, Lillicrap DP (2007) Theories of blood coagulation. J Pediatr
Oncol Nurs 24:123–131
Roberts HR, Hoffman M, Monroe DM (2006) A cell-based model of thrombin generation. Semin
Thromb Hemost 32(Suppl 1):32–38
Schmidt A (1872) Neue Untersuchungen über die Faserstoffesgerinnung. Pflügers Arch für die
gesamte Physiol 6:413–538
Schmidt A (1892) Zur Blutlehre. Vogel, Leipzig
Wright IS (1962) The nomenclature of blood clotting factors. Can Med Assoc J 86:373–374
Laboratory Testing of Hemostasis
2
Fanny Bonhomme and Pierre Fontana

2.1 Introduction

Hemostasis laboratories can carry out large numbers of assays either to obtain accu-
rate and comprehensive diagnoses of hemostatic abnormalities or to monitor anti-
thrombotic treatment. Activated partial thromboplastin time (aPTT) and prothrombin
time (PT) are the most prescribed routine tests.
The evaluation of a patient’s history, symptoms and clinical signs are essential to
assess their bleeding tendency and to determine which laboratory test to use.
Moreover, in order to interpret laboratory test results, it is important to understand
how the assays are performed and to be aware of their limitations.
A normal range (reference range) is defined as the interval into which 95 % of
the values of a reference population fall; thus, 2.5 % of values are inferior to the
lower limit, and 2.5 % are superior to the upper limit (Fig. 2.1). Applied to hemo-
static testing, this means, for example, that 2.5 % of healthy individuals have a
prolonged aPTT (longer than the upper limit).

2.2 Importance of Sample Collection, Processing,

and Storage

Pre-analytical variables strongly influence hemostasis test results, and particular

attention should be paid to blood collection, sample transportation, and storage. The
accuracy of hemostasis tests depends on the sample quality (Lippi et al. 2012).

F. Bonhomme (*)
Division of Anesthesiology, Geneva University Hospitals,
Geneva, Switzerland
e-mail: [email protected]
P. Fontana
Division of Angiology and Hemostasis, Geneva University Hospital
and Faculty of Medicine, Geneva, Switzerland

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 13

DOI 10.1007/978-3-642-55004-1_2, © Springer-Verlag Berlin Heidelberg 2015
14 F. Bonhomme and P. Fontana

Fig. 2.1 Normal range Normal range

definition. When values of
the reference population are
normally distributed, the
reference range is defined as
the interval containing 95 %
of the values

95 %

2.5 % 2.5 %

Blood collection must be as thorough as possible in order to obtain reliable results:

samples should be obtained from a peripheral vein using an atraumatic puncture,
away from any intravenous perfusion line. Tubes containing 3.2 % (0.109 M)
sodium citrate are recommended as other anticoagulants may yield invalid results.
These tubes must be carefully filled to predetermined levels in order to respect the
blood-to-anticoagulant ratio and then gently inverted five times to mix them
together. The first few milliliters of blood collected after the puncture should be
discarded.

2.3 Coagulation Testing

2.3.1 Coagulation Cascade

The cell-based coagulation model focuses on the successive steps of thrombin

generation. These are initiation, propagation, and a burst of thrombin generation
that occurs in the close vicinity of cell membranes (i.e., platelets) that provide the
phospholipids required for the coagulation reaction (see Chap. 1). Depending on
how coagulation is initiated, the classic coagulation cascade describes two some-
what artificial activation pathways that lead to fibrin formation: the intrinsic and
extrinsic pathways (Fig. 2.2). The two pathways link up to form a common pathway.
This model relates closely to the in vitro coagulation assays usually performed to
evaluate the coagulation potency of plasma: aPTT explores the intrinsic pathway,
whereas PT explores the extrinsic pathway (Hoffman and Monroe 2005).

2.3.2 Activated Partial Thromboplastin Time (aPTT)

Activated partial thromboplastin time is a clotting assay that measures the intrin-
sic pathway and is dependent on the concentrations of contact-phase factors
(high-molecular-weight-kininogen (HMWK), prekallikrein (PK), factor XII),
intrinsic factors VIII, IX, and XI, and on the common pathway factors (II, V, X,
and fibrinogen).
2 Laboratory Testing of Hemostasis 15

Fig. 2.2 Coagulation Intrinsic pathway

cascade model
PK, HMWK
Extrinsic pathway

XII XIIa

Trauma
XI XIa

IX IXa VIIa VII

aPTT VIIIa TF PT
X Xa X

Va
II IIa

Fibrinogen Fibrin

Common pathway

aPPT PT

Activator Thromboplastin
phospholipids calcium
calcium

Time : s Time : s
PT converted to % (calibration with thivolle straight line)
INR = (PT patient / PT control)ISI
ISI = international sensitivity index

Fig. 2.3 aPTT and PT principles. aPTT is the time it takes to form a clot after adjunction of calcium
and a surface-activating agent into plasma. PT is the time it takes to form a clot after adjunction of
calcium and thromboplastin into plasma

After blood centrifugation, calcium and a surface-activating agent are added to

plasma. The time it takes to form a clot, expressed in seconds, is aPTT (Fig. 2.3).
The normal range is specific to each laboratory and depends on the reagents and
device used for the coagulation assay. Generally, aPTT is used as a screening test
for a deficiency of more than 50 % in factors VIII, IX, and XI, depending on the
reagents used – it is less useful for the detection of deficiencies of common factors.
The sensitivity of the test depends on the activators used. The causes of shortened
(Lippi et al. 2010) or prolonged aPTT (Olson 1999) are listed in Table 2.1.
16 F. Bonhomme and P. Fontana

Table 2.1 Causes of aPTT abnormalities

Shortened aPTT
Traumatic/difficult blood puncture
Pre-analytical problem: handling, storage
Physical activity
Obesity
Pregnancy, postpartum
Estrogen treatment
Neoplasia
Postoperative period
Venous thromboembolic disease
Asthma, respiratory failure
Diabetes
Hyperthyroidism
Isolated prolonged aPTT
Anticoagulant treatment (unfractionated heparin) Increased hemorrhagic risk
Factor VIII, IX, and XI deficiencies
Inhibitors of intrinsic pathway factors VIII, IX, and XI
Factor XII, PK, HMWK deficiencies No increased hemorrhagic risk
Pre-analytic errors
Newborns, young infants
Circulating lupus anticoagulant Thrombotic risk
Prolonged aPTT and prolonged PT
Common factor deficiencies (I, II, V, X) or factor inhibitors Possible increased
Vitamin K deficiency, malabsorption, VKA treatment hemorrhagic risk
Liver disease
Some direct thrombin inhibitors Increased hemorrhagic risk
Disseminated intravascular coagulation
Dilutional coagulopathy
Hemorrhage
Pre-analytic errors No increased hemorrhagic risk

2.3.3 Prothrombin Time (PT)

Prothrombin time, or Quick time, measures the extrinsic pathway. It assesses the
function of factor VII and of the common factors II, V, and X, and fibrinogen. PT is
the time it takes for a clot to form after having added calcium and thromboplastin to
the plasma. Expressed in seconds, PT is very short in normal individuals (12–13 s).
In some countries, PT is expressed as a percentage of the PT of control plasma. For
monitoring the treatment of vitamin K antagonist (VKA), PT is standardized accord-
ing to the characteristics of the thromboplastin and calibrators used and is expressed
as an international normalized ratio (INR).
An isolated prolonged PT may rarely reflect an inherited factor VII deficiency (1 in
500,000 of the general population). More commonly it reflects a moderate deficiency
in vitamin K-dependent factors.
Prolonged PT, associated with prolonged aPTT, can be due to (Kamal et al.
2007):
• Deficiencies in factors II, V, and X or fibrinogen
• Presence of factor inhibitors
2 Laboratory Testing of Hemostasis 17

• VKA treatment
• Direct thrombin inhibitor
• Vitamin K deficiency, malabsorption
• Liver disease
• Disseminated intravascular coagulation
• Dilutional coagulopathy
• Hemorrhage

2.3.4 Fibrinogen

Fibrinogen is the most abundant clotting protein in plasma (2–4 g/l). Fibrinogen
abnormalities can be either qualitative (dysfibrinogenemia) or quantitative (total
lack, afibrinogenemia, or partial deficiency, hypofibrinogenemia).
Fibrinogen measurement is usually performed using a functional qualitative
method (von Clauss chronometric assay); when a high concentration of thrombin is
added to diluted plasma, the clotting time is proportional to the level of clottable
fibrinogen. Fibrinogen activity levels can also be estimated using a prothrombin
time-based kinetic assay, which is a rapid, inexpensive, automated assay, although
less specific of fibrinogen activity.
Immunoassays for fibrinogen antigen quantification are also available, but are
not used for screening tests. These immunological assays measure the protein con-
centration rather than the functional activity of fibrinogen.
Fibrinogen measurement is indicated in cases of apparent bleeding symptoms or
in cases of suspicion of disseminated intravascular coagulation, hepatic insuffi-
ciency, or hyperfibrinolysis (Table 2.2).

2.3.5 Specialized Testing

A combination of tests for PT and aPTT is usually the first step of a coagulation
assessment. Then, according to the results, further assays may be performed (Sié
and Steib 2006).

2.3.5.1 Mixing Studies

A mixing study mixes patient plasma with control plasma. It is able to distinguish
between a prolonged clotting time due to a factor deficiency and one due to an

Table 2.2 Causes of abnormal fibrinogen levels

Reduced fibrinogen levels Increased fibrinogen levels
Disseminated intravascular coagulation Age
Dilutional coagulopathy Pregnancy, oral contraception,
postmenopausal
Liver disease with decreased synthesis Inflammatory syndrome
Inherited deficiencies Malignancy
Thrombolytic therapy
High doses of corticosteroids
18 F. Bonhomme and P. Fontana

Fig. 2.4 Factor assays Deficient plasma in factor Deficient plasma in factor
principles. Specific factor VIII, or IX, or XI or XII II, or V, or VII, or X
assays are based on the
ability of the patient’s diluted
plasma to change the clotting
times of specific factor- Activator Thromboplastin
deficient plasmas, measured phospholipids calcium
by aPTT or PT calcium
Patient plasma

aPPT PT

Time : s

inhibitor. The control plasma contains the coagulation factors that could be deficient
in patient plasma. When the mixture corrects the clotting time, it is indicative of one
or more factor deficiencies. When the mixture fails to correct the clotting time, it is
indicative of an inhibitor (specific factor inhibitor or lupus anticoagulant).

2.3.5.2 Clotting Factor Assays

Except for the measurement of factor XIII, specific factor assays are based on the abil-
ity of patient’s diluted plasma to change the clotting time of specific factor-deficient
plasmas, measured by PT (for factors II, V, VII, and X) or by aPTT (for factors VIII,
IX, XI, and XII). Clotting time is therefore directly proportional to the activity of the
factor tested (Fig. 2.4). The result is usually expressed as a percentage of factor
activity in control plasma but can also be expressed in IU/dl; one unit of activity
being present in 1 ml of normal plasma with 100 % activity, 100 % corresponds to
100 IU/dl. The measurement of factor activity is an essential step in determining the
etiology of a prolonged PT or aPTT.

2.3.5.3 Thrombin Time

Thrombin time is the clotting time of plasma in the presence of exogenous throm-
bin, expressed in seconds. This test looks solely at the conversion of fibrinogen to
fibrin. Thrombin time is prolonged in cases of inherited or acquired dysfibrinogen-
emias or hypo-/afibrinogenemias or in the presence of thrombin inhibitors (heparin,
hirudin, dabigatran, elevated levels of fibrin degradation products, some parapro-
teins, or thrombin antibodies).

2.3.5.4 The Reptilase Test

This test is equivalent to the thrombin time test, but is not sensitive to heparin. It
measures the conversion of fibrinogen to fibrin by a thrombin-like enzyme (repti-
lase). Reptilase is not inhibited by heparin, hirudin, antithrombin antibodies, or anti-
fibrinolytics. The test is used to exclude the presence of dysfibrinogenemia in cases
with a prolonged aPTT.
2 Laboratory Testing of Hemostasis 19

2.3.5.5 D-Dimer Assay

d-dimers are specific breakdown fragments of cross-linked fibrin; they are not pro-
duced when non-cross-linked fibrin or fibrinogen are degraded. Increased d-dimer
levels reflect the formation of fibrin and subsequent in vivo lysis. There are several
methods of measuring d-dimers.
d-dimer levels are elevated in case of thromboembolism (pulmonary embolism,
venous thrombosis, arterial thrombosis), malignancy, pregnancy, sepsis, cirrhosis,
disseminated intravascular coagulation, and in the postoperative period.
d-dimer levels are widely used to rule out a venous thromboembolic event since
a normal result has a high negative predictive value (95–98 %).

2.3.5.6 Thrombin Generation Test

The thrombin generation test measures the quantity of thrombin produced in
response to a calibrated stimulus. It is performed on plasma, with or without plate-
lets. The amount of thrombin reflects the overall functioning of the hemostatic sys-
tem (activators and inhibitors), without assessing fibrinolysis. The main parameters
of the thrombogram are (Dieri et al. 2012; Hemker et al. 2006):
• Lag time (= clotting time)
• Peak (= maximal concentration of thrombin)
• Time to peak
• Area under the curve (endogenous thrombin potential = total amount of
thrombin)
The thrombin generation test has numerous drawbacks – including the lack of a
standardized procedure – which restrict its use mainly to research programs.

2.3.5.7 Thrombophilia Testing

Laboratory testing can help understand recurrent thromboembolic venous or arterial
diseases, due to inherited or acquired abnormalities of hemostasis. Thrombophilia
can be linked to:
• Anticoagulant protein deficiency: antithrombin, protein C, protein S
• Genetic mutation of factor V (including the Leiden mutation), responsible for
activated protein C resistance
• Genetic mutation of factor II (mutation G20210A)
• Presence of antiphospholipid antibodies (anticardiolipin, anti-β2GPI, lupus
anticoagulant)
Both functional and antigenic assays are available for antithrombin, protein C,
and protein S.

2.4 Primary Hemostasis Testing

Primary hemostasis involves the vessel wall, endothelial cells, platelets, and some
serine proteins (von Willebrand factor (vWF), thrombin, and fibrinogen).
Many assays are available for platelet function testing; however, no laboratory
test can explore vessel walls or endothelial cells. Platelet function assays are time-
consuming, difficult, and very sensitive to pre-analytical variables (drugs, food,
20 F. Bonhomme and P. Fontana

platelet count, temperature, pH, fibrinogen level, quality of sample, storage,

transport).

2.4.1 Platelet Count

Platelet count is measured using an automated counter, on blood drawn in EDTA-

anticoagulated samples. In cases of thrombocytopenia (<150 G/l), platelet clumps
have to be considered; if clumps are identified, platelet count should be assessed on
blood collected in citrate-anticoagulated tubes.
The normal platelet count range for adults is 150–400 G/l. Platelet count, of
course, does not evaluate their qualitative performance.

2.4.2 Bleeding Time

Bleeding time is supposed to provide an overall picture of primary hemostasis

in vivo. It is determined mainly using the Ivy method (normal Ivy incision bleed-
ing time <10 min). The Duke method (earlobe incision) is no longer used.
Bleeding time is prolonged in cases of severe thrombocytopenia (platelets
<50 G/l), thrombopathy, deep hypofibrinogenemia, afibrinogenemia, dysfibrino-
genemia, von Willebrand disease (vWD), severe anemia (hematocrit <30 %), or
treatment interfering with platelet function. However, a normal bleeding time
does not exclude platelet dysfunction or vWD. The bleeding time procedure is
delicate, requiring experienced operators, which partly explains why this method
has fallen out of use.

2.4.3 Platelet Function Analyzer (PFA-100® and PFA-200®,

Siemens)

The platelet function analyzer is a Food and Drug Administration-approved device

used to evaluate acquired or congenital platelet dysfunction and, most importantly,
to screen for vWD. This device measures the time (closure time) required for plate-
lets to plug an aperture in a membrane after platelet activation by collagen and
epinephrine or by collagen and adenosine diphosphate. This closure time is some-
times referred as the “in vitro bleeding time” and is performed using whole blood
(Harrison 2005). Closure time is prolonged in cases of anemia or thrombocytope-
nia or following the intake of drugs that alter platelet function by inducing acquired
thrombopathy.

2.4.4 Light Transmission Platelet Aggregometry

Platelet aggregation assays are indicated for the investigation of inherited or

acquired qualitative platelet disorders (Dawood et al. 2012).
2 Laboratory Testing of Hemostasis 21

These tests are useful in patients suspected with disease of primary hemostasis
(purpura, cutaneo-mucous bleeding) with a normal platelet count. After centrifuga-
tion, the platelet-rich plasma is incubated with various aggregation activators.
Activators commonly used for exploring the different activation pathways of plate-
lets are arachidonic acid, ADP, collagen, TRAP (thrombin receptor agonist pep-
tide), epinephrine, and ristocetin. The modification of light transmission due to
platelet aggregation induced by the agonist is then studied. Platelet secretion may
also be studied after platelet activation with several agonists. Light transmission
platelet aggregometry is usually performed in qualified laboratories.

2.4.5 Diagnosis of von Willebrand Disease

vWD is the most frequent inherited bleeding disorder. The diagnosis is based on
bleeding symptoms associated with qualitative or quantitative defects of vWF.
The patient’s bleeding history, in particular, the family history, is of most importance
for the diagnosis of vWD. A panel of assays are available (Favaloro 2009):
• vWF antigen measures the amount of vWF; plasma vWF levels vary with blood
group; O blood group patients usually have lower vWF levels (up to 40 %) than
individuals of other blood groups.
• Factor VIII coagulant activity measures the functional activity of factor VIII.
• vWF ristocetin cofactor activity and vWF collagen-binding activity measure the
functional activity of vWF.
Further assays are necessary for the diagnosis of subtypes:
• Factor VIII binding assay measures the affinity of vWF for factor VIII (useful in
type 2 N vW disease).
• vWF multimer analysis shows how the vWF monomer is multimerized (joined
into chains).
• Ristocetin-induced platelet agglutination measures the sensitivity of vWF to ris-
tocetin (useful in type 2B vW disease).

2.5 Monitoring of Antithrombotic Treatment

Several tests are routinely available for assessing the action of anticoagulants such
as heparins or vitamin K antagonist. New direct oral anticoagulants (specific inhibi-
tors of thrombin or factor Xa) cannot be monitored using standard coagulation
assays and require specific tests. If necessary with regard to antiplatelet therapy, a
number of specialized assays are available to assess platelet inhibition, but their util-
ity in clinical and routine practice remains to be determined.

2.5.1 Heparin Monitoring

Since the pharmacodynamic profile of unfractionated heparin (UFH) is poorly pre-

dictable, monitoring its anticoagulant effect is essential. The pharmacodynamic
22 F. Bonhomme and P. Fontana

profile of low molecular weight heparins (LMWH) is more predictable, and moni-
toring should be considered only in selected cases (e.g., mild renal insufficiency or
extremely high or low body weight).

2.5.1.1 Unfractionated Heparin (UFH)

aPTT is widely used for monitoring UFH. The target time range is two or three
times longer than the basal aPTT value. It must be stressed that the aPTT clotting
assay depends on several coagulation factors. Thus, in some instances, aPTT can
under- or overestimate the degree of anticoagulation conferred by UFH. This may
occur in the case of an important inflammatory syndrome with a very short basal
aPTT or in cases of factor deficiency or lupus anticoagulant with longer basal
aPTT, for example. In such situations, the use of a specific chromogenic assay that
measures the activity of factor Xa provides a more reliable assessment of the anti-
coagulant effect. Anti-Xa activity measurement requires calibration: a standard
curve is constructed using different plasma samples with different concentrations
of heparin. After adding known quantities of factor Xa, any residual Xa activity is
inversely proportional to the concentration of heparin in the sample. The result can
be reported either in international units of heparin per ml (IU/ml) or in anti-Xa
units per ml (anti-Xa U/ml).

2.5.1.2 Low Molecular Weight Heparin (LMWH)

LMWHs have a poor antithrombin effect and do not usually affect aPTT. The
anti-Xa assay is thus required for monitoring with specific calibrators. Anti-Xa
levels are usually measured 3–5 h after a dose of LMWH, when its concentration
in the blood is expected to be at its highest level (peak level). Residual anti-Xa
tests may also be carried out when accumulation is suspected (e.g., in renal
failure).

2.5.2 Fondaparinux and Danaparoid Monitoring

Fondaparinux is a synthetic direct Xa-inhibitor that does not usually require

monitoring. In some cases, anti-Xa measurement may be prescribed when there
are concerns that fondaparinux may be accumulating. A fondaparinux standard
curve is required for reporting fondaparinux levels when using an anti-Xa
assay.
Danaparoid is a heparinoid containing heparan sulfate, dermatan sulfate, and
chondroitin sulfate. Its activity should be monitored using an anti-Xa assay with
danaparoid calibrators.

2.5.3 Vitamin K Antagonist Treatment

See Sect. 2.3.3.

2 Laboratory Testing of Hemostasis 23

2.5.4 Novel Direct Oral Anticoagulants (NOACs)

Direct oral inhibitors of thrombin (dabigatran) or of factor Xa (rivaroxaban, apixa-

ban) cannot be monitored using simple standardized laboratory assays. At pharma-
cological doses, these drugs may interfere on different ways with aPTT and PT
(depending of the reagents), but aPTT and PT are poorly correlated with NOAC
blood concentrations. It should be noted that the standard INR refers to VKA treat-
ment and cannot evaluate the effectiveness of NOACs: the therapeutic ranges of
INR used to monitor VKA do not apply to NOACs.
Specific assays for the measurement of NOAC plasma concentrations are avail-
able in specialized laboratories and should be ordered in case of hemorrhagic events
or emergent surgeries (Sié et al. 2011; Pernod et al. 2013).

2.6 Standard Tests and Predicting Perioperative

Bleeding Risk

The goal of preoperative screening for congenital or acquired hemostatic disorders

is to prevent perioperative hemorrhagic complications by using appropriate medical
and surgical management. When prescribing hemostatic tests prior to invasive pro-
cedures, the objective should be to identify those patients with an increased risk of
perioperative bleeding. Unfortunately, the standard tests (PT, aPTT, platelet count)
have very low positive predictive values for bleeding risk in the general population
(Chee et al. 2008; Segal et al. 2005).
The percentage of abnormal test results depends on the indication (systematic
testing or clinically indicated), on the reference values, and on the types of patients
(Kitchens 2005):
• In selected patients (hemostasis assessment clinically indicated), the percentage
of abnormalities may be up to 40 %.
• In patients not selected on the basis of history and clinical examination, standard
hemostatic testing revealed 0.5–16.0 % abnormalities.
The performance of systematically prescribed standard hemostatic tests in pre-
dicting the bleeding risk during surgery or other invasive procedure is very poor
since normal results do not preclude the possibility of hemostatic disease or periop-
erative hemorrhage.

References
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prior to surgery or invasive procedures. British Committee for Standards in Haematology. Br J
Haematol 140:496–504
Dawood BB, Lowe GC, Lordkipanidze M et al (2012) Evaluation of participants with suspected
heritable platelet function disorders including recommendation and validation of a streamlined
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24 F. Bonhomme and P. Fontana

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Viscoelastic Tests of Hemostasis
3
Catherine Heim and Patrick Schoettker

3.1 Introduction

Traditional plasma-based coagulation tests, such as prothrombin time (PT) and acti-
vated partial thromboplastin time (aPTT), have proved their utility in detecting abnor-
malities in the clotting factor cascade. However, these tests evaluate only the initiation
of the clotting process and correspond to artificially created segments of hemostasis.
They are therefore of limited value in the assessment of the in vivo clotting process.
Further, long turnaround times make them poorly suited to the management of acute
perioperative bleeding.
In a setting of massive bleeding, the absence of real-time assessment of a patients’
capacity for coagulation and his evolving requirements for blood products can be a
major issue, leading to empirical treatment and the potential for inappropriate
administration of blood products.
The need for a rapid, comprehensive, physiological assessment of the entire
process of coagulation, as well as the patient’s overall hemostatic capacity, has led to
the development of ‘global hemostasis assays’; these include viscoelastic tests which
allow for a rapid bedside analysis of the patient’s in vivo hemostatic condition.

3.2 Viscoelastic Tests

Viscoelastic tests measure the continuous process of clotting in whole blood and its
effects on changes in viscosity, elasticity and stability, thus providing global infor-
mation on the dynamics of a clot’s development, its stabilization and ultimately its
dissolution (Nair et al. 2010). To date, these tests are the only ones available allow-
ing for a rapid identification of hyperfibrinolysis, a common pattern in massive

C. Heim (*) • P. Schoettker

Service d’Anesthésie, Centre Hospitalier Universitaire Vaudois CHUV,
Lausanne Suisse CH-1011, Switzerland
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 25

DOI 10.1007/978-3-642-55004-1_3, © Springer-Verlag Berlin Heidelberg 2015
26 C. Heim and P. Schoettker

bleeding, especially following major trauma. Today, commercially available visco-

elastic tests can be carried out at the bedside and provide the first results within
5 min. There is growing evidence that they may identify early coagulation deficits
and thereby facilitate timely goal-directed blood component therapy. Although
there is a lack of standardization and evidence-based guidelines for interpretation,
these tests are in widespread use in complex surgery and perioperative trauma care.
They have also been shown to be valid predictors of transfusion needs (Davenport
et al. 2011; Kashuk et al. 2012), to limit the use of blood component therapy and,
ultimately, to lead to improved patient outcomes in cardiac surgery, liver transplan-
tation and massive trauma (Ak et al. 2009; Brohi 2009; Johansson 2009; Westbrook
et al. 2009; Afshari et al. 2011; Holcomb et al. 2012; Kashuk et al. 2012; Johansson
et al. 2013; Tapia et al. 2013). Further, economic analyses have indicated that bleed-
ing management guided by the viscoelastic tests currently available can result in
cost savings (Spalding et al. 2007; Gorlinger et al. 2011).

3.3 Technology

Thromboelastography was developed by Dr. Hellmut Hartert in 1948 to describe the

viscoelastic changes seen in a sample by using fibrin polymerization (Hartert 1948).
Recent innovations adding computer technology have improved its utility for clini-
cal and perioperative assessment and the management of clotting disorders.
There are currently two types of viscoelastometric point-of-care apparatus avail-
able on the market: a thromboelastography (TEG) device, the TEG® Hemostasis
Analyzer (Haemonetics Corp., Braintree, MA, USA), and a rotational thromboelas-
tometry device, the ROTEM® (Tem International GmbH, Munich, Germany), which
evolved from TEG technology. The TEG system has been available for many years
in the United States, whereas the US Food and Drug Administration only approved
the ROTEM system for clinical use in 2010 (www.fda.gov).
These point-of-care devices are used to assess viscoelastic changes in clotting
whole blood under low-shear conditions after the addition of a specific coagulation
activator. TEG® and ROTEM® measure the dynamic interaction of coagulation fac-
tors, inhibitors and the cellular components of blood during the phases of clotting
and subsequent lysis (Solomon et al. 2012; Romlin et al. 2013) (Fig. 3.1). The test
procedures are based on a motion sensor which detects clot formation in whole
blood in a sample cup. Hartert’s original experiment (Hartert 1948) used a metal pin
suspended by a torsion wire and immersed in the non-anticoagulated whole blood
in a metal sample cup. In TEG®, it is the sample cup that rotates around an immersed
fixed pin; in ROTEM®, it is the immersed pin which rotates in a fixed sample cup.
Modifications in the rotation as clotting progresses are recorded electronically and
expressed both numerically and graphically. TEG® and ROTEM® are static mea-
surement techniques that do not take into account flow-related influences on coagu-
lation capacity. The basic principle of both devices involves the incubation of around
300 μl of citrated whole blood in a cylindrical plastic sample cup which is heated to
37 °C. Adding CaCl2 leads to the recalcification necessary for clot initiation. Then,
as the cup and the pin begin to oscillate relative to each other, the sample is activated
with a test-specific reagent (Table 3.1). With the start of thrombin generation,
3 Viscoelastic Tests of Hemostasis 27

Picture 3.1 TEG® and ROTEM® device

Table 3.1 Technical characteristics of TEG® and ROTEM®

Characteristics TEG® 5000 ROTEM® delta
Pipetting Manual Automated
Measuring technique Shear elasticity of a Shear elasticity of a coagulation
coagulation sample sample by motion of the pin
by motion of the cup
Pin motion Fixed Moving
Angle of rotation/oscillation 4°45′/5 s 4°75′/6 s
time
Detection system Pin transduction Impedance of rotation
Type of detection Electronic Optical
Signal transducer Electrical-mechanical Optical 4 CCD chips
transducer
Measuring channels 2 4
Temperature control (°C) 20–40 30–40
Temperature regulation Heated cup Heated metal block
Cup interior and material Smooth cryolite Rigid polymethylmethacrylate
Sample volume 360 μl 300 μl
Total reaction volume 360–380 μl 320–340 μl
Operable to height above 3,048 m (10,000 ft) 2,000 m (6,560 ft)
sea level

platelets are activated, expressing glycoprotein (GP) IIb/IIIa receptors, and fibrin is
formed and subsequently polymerized. The interactions between the GP IIb/IIIa
receptors and the polymerized fibrin increase the sample’s viscoelasticity which in
turn increases the torque between the sample cup and the pin. The suspended pin is
connected to a detector system, either a torsion wire (TEG®) or an optical detector
via the reflection of light onto a small mirror (ROTEM®). As the sample clotting
process progresses, fibrin strands form between the cup and the pin, further imped-
ing rotational movements. These changes are also detected, either mechanically or
28 C. Heim and P. Schoettker

Fig. 3.1 (a) Technology

a Torsion wire
for TEG® 5000 (Adapted
from www.haemonetics.
com). (b) Technology for
ROTEM® (Adapted from Pin
www.rotem.de) Cup
.36 ml whole blood
Heating element, (clotted)
sensor and controller

4°45

b 1
3

2 5
10 11

7 6

9 8

1 Oscillating axis 7 Cuvette with blood sample

2 Counterforce spring 8 Fibrin strands and platelet aggregates
3 Light beam from LED 9 Heated cuvette holder
4 Mirror 10 Ball bearing
5 Detector (electr. camera) 11 Data processing unit
6 Sensor pin

optically, then transmitted electronically and transformed into numerical and graph-
ical read-outs (Figs. 3.1a, b). When no clotting takes place in a ROTEM® assay, for
example, the pin’s movement is not obstructed, whereas if a clot does form, it
attaches to the pin and cup surfaces, impairing pin movement. An amplitude of
0 mm means unobstructed oscillation (no clot), whilst an amplitude of 100 mm can
be regarded as total firmness—the pin is completely blocked by the clot.

3.4 Tests and Agents

Whilst TEG® originally used non-anticoagulated whole blood, today this method is
essentially only used in research settings. For clinical use, both systems now employ
citrated whole blood which is recalcified to initiate coagulation. This allows longer
sample storage: in the case of ROTEM®, up to 120 min (Theusinger et al. 2010b).
It must be noted that blood sampling using sodium citrate tubes dilutes the blood
3 Viscoelastic Tests of Hemostasis 29

samples by approximately 10 %. In addition, citrate may affect platelet GP IIb/IIIa

receptors and therefore influence thromboelastographic measurements (Camenzind
et al. 2000; Zambruni et al. 2004).
To initiate the sample clotting process in a standardized way, the use of an activator
is recommended. Originally, TEG® used celite as a contact activator, but this has
been replaced by kaolin (kaoTEG), kaolin + tissue factor (RapidTEG), kaolin + hep-
arinase or abciximab. There are multiple liquid reagents available for ROTEM®,
such as ellagic acid and phospholipids (INTEM), tissue factor (EXTEM) and lyoph-
ilized heparinase, aprotinin or cytochalasin D as standard activators (Table 3.2). A
single-use reagent exists for all ROTEM® tests, thus allowing easier test compari-
sons, with good correlations to the classic reagents (Rahe-Meyer et al. 2009).
Tissue factor activation enables the clot to reach its maximum amplitude within 10
min. TEG® offers a rapid variant for emergency settings: the rapid (R)-TEG®. R-TEG®
differs from standard TEG® via an addition of tissue factor which enhances (RapidTEG)
clotting speed; this produces a visualization of the initial clotting phase within seconds
and is therefore increasingly used. However, the information on coagulation and clot
formation it provides is very limited due to a significant shortening of the reaction time
(R value), and this could potentially lead to loss of valuable information about this
period of clotting. Platelets and fibrinogen are essential components of a clot.
Running several tests in parallel allows a comparative analysis. Comparison of
EXTEM and FIBTEM is suited to distinguishing hypofibrinogenaemia from throm-
bocytopenia. Antifibrinolytic agents (aprotinin) are used to detect fibrinolysis by
comparing APTEM to EXTEM. The presence of a heparin effect can be detected by
comparing HEPTEM with INTEM (ROTEM®), by using the kaolin clotting time
test with or without addition of heparinase (TEG®), respectively. The independent
contributions of fibrinogen and platelets can be analysed by adding platelet inhibi-
tors such as abciximab in TEG® or cytochalasin D in ROTEM®.

Table 3.2 Activators for different tests in TEG® and ROTEM®

Activator Test
TEG® ROTEM® TEG® ROTEM® Interpretation
Kaolin Ellagic acid/ Kaolin INTEM Contact activation
phospholipid Similar information
to aPTT
Kaolin + Tissue factor Rapid TEG EXTEM Similar information
tissue factor to ACT (R-TEG)
and PT (ROTEM)
Kaolin + Lyophilized heparinase Heparinase HEPTEM Detection of heparin
heparinase effect
Aprotinin APTEM Detection of
fibrinolysis
Abciximab Cytochalasin D TEG FIBTEM Analysis of
functional fibrinogen
component of clot
Ecarin ECATEM Detection of
presence of direct
thrombin inhibitors
30 C. Heim and P. Schoettker

The determination of activated clotting time (ACT) is another piece of informa-

tion that existing test methods can provide through the incorporation of tissue factor
and kaolin into a TEG® sample cup.
Viscoelastic tests may also be helpful in screening for hypercoagulable states.
TEG® and ROTEM® analyses of patients with a history of thromboembolic compli-
cations showed shorter R values and accelerated clot propagation when compared to
healthy reference subjects. An increased maximal amplitude (MA) may be a useful
indicator of the risk of postoperative thromboembolic events. However, further
studies are needed to determine the clinical value of viscoelastic tests for screening
for thromboembolic complications (Wilson et al. 2001; McCrath et al. 2005).

3.5 Parameters Measured by TEG® and ROTEM® (Fig. 3.2)

The main goal of TEG® and ROTEM® is the determination of viscoelasticity as

expressed by clot amplitude and clot firmness. The dynamic evolution of clot for-
mation over timescale allows a clinical understanding of clot formation. The two
systems are a closely related, but due to technical differences, their results are not
completely interchangeable. The different materials of the surfaces of the pin and
cup exert their forces on procoagulant activity to different extents. Data from older
studies using TEG® with metal cups and native whole blood cannot be compared
directly with more recent studies using plastic cups and recalcified whole blood
(Ganter and Hofer 2008). Reference values are also different between plasma and
native or recalcified citrated blood. Nevertheless, the most significant reason for
different clot formation variables is the use of different activators at various

A30 A60
TEG analysis
K

R MA
CL
Clot firmness

α
CT MCF LY

CFT
ROTEM analysis
A5 A10 A20 A30 A60

Time

Fig. 3.2 TEG® and ROTEM ® output demonstrating clot initiation, propagation, stabilization and
lysis. TEG® parameters: R reaction time, K kinetics, α alpha angle, MA maximum amplitude, CL
clot lysis, A amplitude at set time in min (30 and 60). ROTEM® parameters: CT clotting time, CFT
clot formation time, α alpha angle, MCF maximum clot firmness, A amplitude at set time in min
(5, 10, 20 and 30), LY clot lysis
3 Viscoelastic Tests of Hemostasis 31

concentrations. Clinical reference values differ between the two systems and must
be interpreted accordingly. Reference values for TEG® are based on unspecified
surgical patient samples of limited size (Haemoscope Corporation 2007), whilst
those established for ROTEM® were determined in a multicenter study of patients
and healthy volunteers (Lang et al. 2005).
There are also differences in nomenclature between the devices and other minor
details exist (Table 3.3 and Fig. 3.2).

3.5.1 TEG®-Derived Parameters

R ‘Reaction time’ (seconds). Time from the start of the test to initial fibrin
formation; corresponding to a clot amplitude of 2 mm. This represents the
enzymatic portion of the coagulation process.
Simplified: R represents coagulation factors.
K ‘Kinetics’ (seconds). Time necessary to achieve a given clot strength of an
amplitude of 20 mm.
Simplified: K represents thrombin.
α Alpha angle. The slope between R and K. Corresponds to the speed of fibrin
build-up and cross-linking/clot strengthening. Dependent on fibrinogen levels.
Simplified: α represents the speed of clot formation.

Table 3.3 Summary of the variables measured

Correlation to
Variable TEG® ROTEM® Process conventional tests
Time from Reaction Clotting Interval between the PT, INR, ACT
start to 2 time R time CT start of the test and (for R-TEG)
mm above appearance of the first
baseline clot. Initiation of
thrombin generation
and clot polymerization.
Expression of
coagulation factor
activity
Time from K Clot Rate of clot formation, aPTT, fibrinogen
start of formation fibrin polymerization concentration
clotting to time (CFT) and cross-linking with
amplitude platelet interaction
of 20 mm
Alpha α (slope α (angle of Rate of clot formation, Fibrinogen
angle α between R tangent at 2 fibrin polymerization concentration,
and K) mm and cross-linking with platelet count
amplitude) platelet interaction
Maximum Maximum Maximum Stabilization of clot by Platelet count
strength amplitude clot firmness platelets and factor XIII
(MA) (MCF)
Clot lysis CL30, CL60 LY30, LY45, Degree of fibrinolysis
at specific LY60 after a given amount of
time (min) time
32 C. Heim and P. Schoettker

MA Maximum amplitude (millimetres). Represents the ultimate strength of the

fibrin clot and therefore the interaction of fibrin, platelets and factor XIII.
It is related to the maximum dynamic properties of fibrin and platelet
bonding via GP IIb/IIIa. It is affected by changes in fibrinogen, platelet
count, function and aggregation.
Simplified: MA represents platelet function, fibrinogen and factor XIII.
A30 Amplitude reached at 30 min after R-time.
CL30 Percentage of decrease in clot amplitude at 30 min after MA. Expresses the
degree and speed of fibrinolysis as the relationship between amplitude at
30 min and MA

3.5.2 ROTEM®-Derived Parameters

CT Clotting time. Time from the start of measurement to the initiation of

clotting.
Simplified: depends on thrombin formation.
CFT Clot formation time. Time from the initiation of clotting to the achievement of
clot firmness at 20 mm. Represents the initial rate of fibrin polymerization.
Simplified: depends on fibrin polymerization, platelets and FXIII (acting as
clot stabilizer).
α angle Indicates the speed at which a solid clot forms.
Simplified: depending on platelet function and to lesser extent to fibrino-
gen and coagulation factors.
MCF Maximum clot firmness and viscoelastic strength.
Simplified: clot strength depends mainly on polymerized fibrin, platelets
and FXIII.
A10 Amplitude 10 min after CT. Early indicator of achievable MCF.
ML Maximum lysis. Indicates the decrease of clot firmness after MCF. An ML
>15 % is a diagnostic for a premature breakdown of the clot
(hyperfibrinolysis).

3.6 Differences Between TEG® and ROTEM®

TEG® and ROTEM® basically provide similar informations on the kinetics and
strengths of clot formation and have been shown to produce comparable results
when samples were activated with the same exogenous activator (Zambruni et al.
2004). However, differences in operating characteristics when different activators
are used render their results non-interchangeable (Nielsen et al. 2005; Nielsen 2007;
Venema et al. 2010). The use of different nomenclature for identical parameters also
makes comparison difficult.
Depending on the activator used, clotting speed can vary significantly. INTEM-
activated plasma (ROTEM®), for example, generates a time to clot initiation three
times faster than kaolin-activated plasma, as used in TEG® (Nielsen 2007).
3 Viscoelastic Tests of Hemostasis 33

Further, viscoelastic test results are also dependent on the concentration of activa-
tor in the sample as this particularly affects clot initiation and propagation by influenc-
ing thrombin generation (Nielsen et al. 2005). Differences in the composition of the
plastic polymer sample cups, which could generate greater surface charges, could
potentially contribute an additional source of differences in results (Roche et al. 2006).
It has been demonstrated that the plastic tube in which citrated blood is collected may
provide additional inference in the activation of coagulation (Roche et al. 2006).
However, it seems unlikely that these would affect clinical decision making (Nielsen
2007), and relative trends within one method are still expected to be comparable.
These specificities explain part of the differences in the reference ranges shown
in Table 3.4. The manufacturer of TEG® recommends that each institution should
determine its own normal values.
Another difference is the speed of result acquisition, with ROTEM® having a
faster turnaround time (5–10 min) than TEG® (15–20 min). The main reason for this
is that ellagic acid (ROTEM®) activates coagulation faster than kaolin (TEG®).
The two methods have been the subjects of numerous claims about their equiva-
lency or superiority, but neither has actually been proven superior. One study compar-
ing the diagnostic performances of TEG® and ROTEM® in the detection of dilutional
coagulopathy, thrombocytopenia, hyperfibrinolysis and the presence of heparin sug-
gested that ROTEM® not only readily distinguishes all the types of coagulopathy cited
but also provides faster diagnosis; TEG®, however, failed to distinguish dilutional
coagulopathy from thrombocytopenia (Larsen et al. 2011). On the other hand,

Table 3.4 Reference ranges for TEG® (from ‘User manual TEG® 5000 Thromboelastograph
Hemostasis System’) and EXTEM (ROTEM®) (Lang et al. 2005)
Angle MA Sample
Sample type R (min) K (min) (degree) (mm) G (kd/sc) sizea
Celite/kaolin 4–8 0–4 47–74 54–72 6.0–13.2 132
Sodium citrate celite/kaolin 2–8 1–3 55–78 51–69 4.6–10.9 98
Native 12–26 3–13 14–46 42–63 3.2–7.1 132
Sodium citrate native 9–27 2–9 22–58 44–64 3.6–8.5 132
Tissue factor 1–3 1–3 57–78 55–75 6.0–13.0 178
Sodium citrate plus TF 0–2 0–5 52–82 46–72 2.7–12.5 41
Tissue factor kaolin 17–38 30–118 66–82 54–72 5.3–12.4 86
Citrated tissue factor kaolin 22–44 34–138 64–80 52–71 5.0–11.6 89
Tissue factor plus functional – – – 9–29 0–2.0 72
fibrinogen
Citrated tissue factor plus – – – 10–25 0.5–1.7 72
functional fibrinogen
Test Normal range (median)
CT (s) 42–74 (55)
CFT (s) 46–148 (95)
A10 (mm) 43–65 (53)
MCF (mm) 49–71 (60)
ML (%) 0–18 (4)
a
Sample sizes range from 41 to 78 depending on the participating hospitals
34 C. Heim and P. Schoettker

ROTEM® has a lower sensitivity to the effect of aspirin on platelets and is, unlike
TEG®, unable to detect the effect of low molecular weight heparin (LMWH). TEG®
has the advantage of offering a specific test of platelet function, the TEG® Platelet
Mapping™ assay. This test analyses platelet function by measuring clot strength and
maximum amplitude, reflecting maximum platelet function and detecting reduction
in platelet function, represented as percentage of inhibition (see Chap. 4).
Whilst the ROTEM® FIBTEM assay has been validated as an accurate estimate
of the fibrinogen contribution to clot strength independent of platelets, the TEG®
Functional Fibrinogen assay requires further validation (Solomon et al. 2012).
Neither test is a suitable substitute for the traditional plasma-based determination of
fibrinogen levels using the Clauss method. Furthermore, the correlation between
FIBTEM MCF and the plasmatic concentration of fibrinogen worsens after exoge-
nous fibrinogen administration (Solomon et al. 2011).
Based on these differences, caution is warranted when interpreting comparative
data generated by TEG® and ROTEM®. TEG®-based treatment algorithms should
not be used thoughtlessly for ROTEM®-based sample analysis and vice versa.
Therefore, whilst these two devices can, under similar circumstances, generate sim-
ilar data, their processes, involving different activator agents, are not equivalent and
must be well understood.

3.7 Examples of Interpretation and Special Conditions

The assessments made by TEG® and ROTEM® are illustrated graphically along
the horizontal time axis (left to right). The shapes of these representations are
often as useful as the results of individual values. The types of activators used need
to be taken into account when interpreting reference ranges (Figs. 3.3 and 3.4).
Examples from ROTEM traces with permission from (www.rotem.de)

3.7.1 Normal Patient: Fig. 3.5a

3.7.2 Platelet Deficiency: Fig. 3.5b

3.7.3 Fibrinogen Deficiency: Fig. 3.5c

An abnormal clot formation is indicated by a prolonged clot formation time (CFT)

and/or a reduced maximum clot firmness (MCF). The CFT is thereby influenced
more strongly by a clot polymerization disorder than the MCF. A prolonged CFT
associated with a normal MCF primarily indicates a polymerization disorder,
whereas a reduced MCF associated with a normal CFT indicates a deficiency of the
clotting substrate such as fibrinogen and/or platelets.
3 Viscoelastic Tests of Hemostasis 35

Normal
R; K; MA; Angle = Normal

Anticoagulants/hemophilia
Factor Deficiency
R; K = Prolonged;
MA; Angle = Decreased

Platelet Blockers
Thrombocytopenia/
Thrombocytopathy
R ~ Normal; K = Prolonged;
MA = Decreased

Fibrinolysis (UK, SK, or t-PA)

Presence of t-PA
R ~ Normal;
MA = Continuous decrease
LY30 > 7.5 %; WBCLI30 < 97.5 %;
Ly60 > 15.0 %; WBCLI60 < 85 %

Hypercoagulation
R; K = Decreased;
MA; Angle = Increased

D.I.C
Stage 1
Hypercoagulable state with
secondary fibrinolisis

Stage 2
Hypocoagulable state

Fig. 3.3 TEG output in various clinical situations (From ‘User manual TEG® 5000
Thromboelastograph Hemostasis System’)
36 C. Heim and P. Schoettker

Fig. 3.4 Example of a TEG trace before and after treatment

a Normal patient:

EXTEM INTEM
CT: 67s CFT: 87s a: 73° CT: 200s CFT: 67s a: 77°

CFR: 54mm MCF: 57mm ML: −% CFR: 54mm MCF: 61mm ML: −%

FIBTEM APTEM
CT: 66s CFT: −s a: 57° CT: 74s CFT: 89s a: 72°

CFR: 9mm MCF: 10mm ML: −% CFR: 53mm MCF: 61mm ML: −%

Fig. 3.5a With permission from www.rotem.de

3 Viscoelastic Tests of Hemostasis 37

b Platelet deficiency:

EXTEM INTEM
CT: 57s CFT: 444s a: 80° CT: 200s CFT: 449s a: 72°

A10: 23mm MCF: 35mm ML: −% A10: 23mm MCF: 32mm ML: −%

FIBTEM APTEM
CT: 67s CFT: −s a: −° CT: 52s CFT: 398s a: 80°

A10: 15mm MCF: 16mm ML: −% A10: 25mm MCF: 35mm ML: −%

Fig. 3.5b With permission from www.rotem.de

3.7.4 Hyperfibrinolysis: Fig. 3.5d

Fibrinolysis is detected by the lysis of the clot. This is defined as an ML value

>15 % or by the discovery of better clot formation in APTEM than in EXTEM.
This is expressed as an overall shorter CFT and a greater MCF in APTEM than
in EXTEM. In patients with massive bleeding, several algorithms use the short-
ening of the CT value in APTEM in comparison to EXTEM, as a trigger for the
administration of an antifibrinolytic drug. Both TEG® and ROTEM® have been
shown to give reliable values for diagnosing and monitoring hyperfibrinolysis
and for guiding antifibrinolytic therapy in severely bleeding patients (Levrat et al.
2008; Hunt 1996). An assessment of fibrinolysis is based on the measurement of
the kinetics of clot destruction expressed as LY30/ML, measuring the decrease of
MA/MCF after its peak value. Additionally, ROTEM® provides a specific test, the
APTEM, which allows the comparison of clotting with (APTEM) and without
(EXTEM) the addition of an antifibrinolytic agent. In trauma patients, this test
has been shown to provide a specificity of 100 % and a high sensitivity of
75–100 % (Levrat et al. 2008).
38 C. Heim and P. Schoettker

c Fibrinogen deficiency:

EXTEM INTEM
CT: 109s CFT: 263s a: 48° CT: 236s CFT: 220s a: 55°
A10: 31mm MCF: 38mm ML: −% A10: 33mm MCF: 42mm ML: −%

FIBTEM APTEM
CT: 185s CFT: −s a: −° CT: 98s CFT: 276s a: 46°
A10: 3mm MCF: 3mm ML: −% A10: 31mm MCF: 40mm ML: −%

Fig. 3.5c (With permission from www.rotem.de)

3.7.5 Heparin Influence: Fig. 3.5e

Prolonged clotting time indicates that the activation of coagulation is perturbed.

Factor deficiency, or inactivation due to the presence of heparin, for example, needs
to be considered. Heparin reversal after cardiac surgery is traditionally guided by
measuring ACT, despite evidence that correlation to plasmatic heparin concentra-
tion is poor. TEG® and ROTEM® may provide useful information about residual
heparin effects after protamine reversal by comparing R or CT in whole blood with
and without the addition of heparinase (Ak et al. 2009) (Sect. 3.7.5).

3.7.6 Influence of Specific Coagulation Factors

R and CT are prolonged in cases of inherited or acquired coagulation factor defi-

ciencies. Normalization of these, after the administration of fresh frozen plasma,
fibrinogen concentrate or prothrombin complex concentrates, is an indicator of the
normalization of coagulation factor activity.
Correction of coagulation factor deficiencies will further increase clot strength
and can be seen in enhanced MA (TEG®) and MCF (ROTEM®). However, persis-
tent low MA or MCF, despite the substitution of coagulation factors, is mainly due
3 Viscoelastic Tests of Hemostasis 39

d Hyperfibrinolysis:

EXTEM INTEM
CT: 59s CFT: 130s a: 65° CT: 200s CFT: 88s a: 74°
A10: 44mm MCF: 48mm ML: 100% A10: 46mm MCF: 48mm ML: 100%

FIBTEM APTEM
CT: 51s CFT: −s a: −° CT: 62s CFT: 132s a: 64°
A10: 7mm MCF: 7mm ML: 94% A10: 44mm MCF: 55mm ML: 0%

Fig. 3.5d With permission from www.rotem.de

to a lack of either fibrinogen or platelets. Typically, R or CT will be normalized

whilst MA or MCF remains below reference values, producing a narrowed trace.
The distinction as to whether a lowered MA or MCF is due to fibrinogen or plate-
let deficiency can be made by adding platelet inhibitors, as in the functional fibrino-
gen test (TEG®) or the FIBTEM (ROTEM®), thus showing fibrinogen’s contribution
to clot firmness (Sect. 3.7.3).
ROTEM® and TEG® are both sensitive to the administration of rFVIIa, gener-
ally demonstrating a dose-dependent decrease of R or CT, with a concomitant
increase of MA or MCF. This response, however, is best seen in cases of inherited
coagulopathies and less in patients with acquired coagulation deficiencies
(Sorensen and Ingerslev 2005). According to the concept that an optimal response
to rFVIIa treatment necessitates the presence of sufficient clotting components, the
use of TEG® or ROTEM® may be helpful in optimizing coagulation profiles before
the administration of rFVIIa. The value of these devices for monitoring the efficacy
of this therapy is less clear.
FXIII contributes to the conversion of fibrin monomers into fibrin polymers and
therefore to clot firmness. Low levels of FXIII have been identified using ROTEM®
and expressed as a low MCF, increased clot formation time and fibrinolysis (Jambor
et al. 2009); substitution resulted in increased clot strength and reduced CFT
(Theusinger et al. 2010a). TEG® and ROTEM® may therefore be used to help guide
FXIII substitution therapy.
40 C. Heim and P. Schoettker

e Heparin influence:

EXTEM INTEM
CT: 67s CFT: 104s a: 68° CT: 852s CFT: 198s a: 51°
A10: 50mm MCF: 57mm ML: 0% A10: 41mm MCF: 48mm ML: 0%

FIBTEM HEPTEM
CT: 63s CFT: –s a: -° CT: 202s CFT: 75s a: 76°
A10: 6mm MCF: 8mm ML: 0% A10: 52mm MCF: 58mm ML: 0%

Fig. 3.5e With permission from www.rotem.de

3.8 Downsides and Caveats

Several issues are as yet unresolved with regard to the standardization of methodol-
ogy and the interpretation of currently available viscoelastic tests. To date, neither
TEG® nor ROTEM® has been validated for clinical use. Standardization of inter-
pretation and evidence-based treatment algorithms are lacking and subject to
intense research. Further, significant inter-laboratory variability has been revealed
(with coefficients of variation exceeding 10 %) and needs to be addressed (Kitchen
et al. 2010; Chitlur et al. 2011). Regular external quality controls and proficiency
testing should be mandatory. Personnel using these devices need to be adequately
trained to avoid manipulation errors (Ganter and Hofer 2008).
Due to the fact that it is a mechanical device, with its pin in free suspension,
TEG® is easily affected by external vibrations or shocks and thus needs to be per-
formed in a vibration-proof environment. This may indeed be a difficult require-
ment for a point-of-care device in an emergency setting. The automated pipette,
touch screen and intuitive software of ROTEM®, on the other hand, are seen by
many as particularly user friendly.
TEG® and ROTEM® analyses are commonly used as point-of-care coagulation
tests in emergency and operation rooms as well as in intensive care settings.
3 Viscoelastic Tests of Hemostasis 41

However, in some centres, these tests are performed in specialized, centralized

laboratories, thus allowing dedicated, qualified personnel to perform these moder-
ately complex coagulation assays under the appropriate quality control guidelines.
A rapid transport system to the laboratory, combined with a dedicated computer
network to provide an online display of the results at the point-of-care, makes
laboratory-conducted thromboelastography and thromboelastometry comparable
with bedside testing regarding turnaround times and results (Wallin et al. 2008).

Conclusion
TEG® and ROTEM® technology allows a real-time assessment of the viscoelas-
tic properties of clot formation and lysis in whole blood. Running several sam-
ples in parallel, using a variety of activators and inhibitors, allows detailed
separate analysis of clot initiation, propagation, stabilization and dissolution.
The influence of various components can be distinguished. Many newer diagno-
sis and treatment algorithms for bleeding patients include the use of TEG® or
ROTEM®. However, despite evidence that such algorithms reduce blood product
use and improve clinical outcomes, further studies are warranted in order to
determine a clinical correlation with their results and to allow for the develop-
ment of evidence-based treatment guidelines.

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Point-of-Care Platelet Function Tests
4
Gabriele Casso, Fabio Lanzi, and Carlo E. Marcucci

4.1 Introduction

Platelets are small, discoid, anucleate blood cells produced by cytoplasmic frag-
mentation of megakaryocytes (George 2000). In the adult, 1 × 1012 inactive blood
platelets are continuously flowing over 1,000 m2 of vascular surface with minimal
adhesion or aggregation (Versteeg et al. 2013). Platelets play a key role in primary
hemostasis. Their main function, when activated, is to stop hemorrhage after tissue
trauma and vascular injury. However, platelets are also important contributors to
pathological thrombotic disorders (e.g., acute coronary syndromes, ischemic stroke,
peripheral occlusive arterial disease) (Davi and Patrono 2007; Jennings 2009) and
an increasing number of patients require long-term antiplatelet therapy.
Platelet activation by the principal agonists during primary hemostasis and the
site of action of antiplatelet drugs are described in Fig. 4.1.
Even though inherited or acquired platelet dysfunction can influence bleeding
during surgery, evidence for the usefulness of perioperative platelet function analy-
sis is still controversial (Kehrel and Brodde 2013).
The European Society of Anaesthesiology (ESA) recently published guidelines
on the management of severe perioperative bleeding (Kozek-Langenecker et al.
2013). Recommendations about perioperative platelet function analysis are weak.
Preoperative platelet function testing is only suggested in relation to a positive
bleeding anamnesis. In cases with a suspicion of decreased platelet function caused
by medical conditions or by antiplatelet therapy, platelet function assessment can be
used preoperatively.

G. Casso (*) • F. Lanzi

Department of Cardiothoracic Anesthesia and Intensive Care, Cardiocentro Ticino,
Lugano, Switzerland
e-mail: [email protected]
C.E. Marcucci
Service of Anesthesiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 45

DOI 10.1007/978-3-642-55004-1_4, © Springer-Verlag Berlin Heidelberg 2015
46 G. Casso et al.

Inhibitor drugs
Platelet agonists

Thrombin Vorapaxar
Aggregation Thromboxane A2 COX-1 inhibitor
NSAID
Platelet PAR1/4 receptor
Fibrinogen
Thromboxane receptor

Ticlopidine
ADP Clopidogrel
Abcximab GPIIb/IIIa Prasugrel
Activation P2Y12 Ticagrelor
Eptifibatide
receptor Cangrelor
Tirofiban

GP Ib/IX/V Adhesion
GP VI von Willebrand factor
Collagen
Endothelial cell

Collagen fibers

Fig. 4.1 Platelet agonists involved in platelet activation and site of action of antiplatelet drugs

In 2012, the Society of Thoracic Surgeons (STS) published updated guidelines

on the use of antiplatelet drugs in patients having cardiac and noncardiac surgery
(Ferraris et al. 2012). Its experts recommended that for patients on dual antiplatelet
therapy it is reasonable to use objective tests, rather than arbitrarily defined delays,
to decide on the timing of surgery (Class IIa, level of evidence B). Preoperative
platelet function assessment may be useful to identify patients—those with high
residual platelet reactivity despite antiplatelet drugs—who can undergo surgery
without an increased risk of bleeding (Class IIb, level of evidence B). Finally, point-
of-care testing of perioperative platelet function may be useful in limiting blood
transfusions (Class IIb, level of evidence B).

4.2 Point-of-Care Platelet Devices

Various methods for platelet function analysis exist today (Harrison 2005; Michelson
2009; Pakala and Waksman 2011; Kehrel and Brodde 2013). Most of them must be
performed in a laboratory setting on centrifuged platelet-rich plasma: light transmis-
sion aggregometry, for example, originally described by Born in 1962 (Born 1962),
is still considered the “gold standard.” These laboratory tests are time-consuming
and require training and laboratory skills.
Recently, several whole blood point-of-care tests have been developed which
can be performed in a near-patient setting, for example, in operating theaters or
intensive care units (Enriquez and Shore-Lesserson 2009). The potential advan-
tages of these tests are simplified workflows (no transport of samples to labora-
tory), rapid turnaround times, and targeted management of coagulation disorders.
4 Point-of-Care Platelet Function Tests 47

As yet, a “perfect,” standardized, and widely accepted point-of-care platelet func-

tion assay that can be used in acute perioperative settings does not exist (Sambu
and Curzen 2011). All the techniques available have their strengths and weak-
nesses; therefore, it is important to understand the potential indications and limita-
tions of these different devices.
In this chapter, we will present the working mechanisms, normal values, inter-
pretation, clinical use, limitations, and pitfalls of the five point-of-care platelet func-
tion analyzers most widely used in perioperative care today. Unless stated otherwise,
the normal ranges described are those provided by the manufacturers. It is notewor-
thy that some manufacturers advise the establishment of local normal ranges.
The principle behind all of these devices is the same: platelets are activated
using selective receptor agonists—epinephrine, adenosine diphosphate (ADP),
collagen, arachidonic acid (AA), prostaglandin E1 (PGE1), thrombin, or thrombin
receptor-activating peptide (TRAP). After activation, maximum platelet function is
measured using different methods: one is based on shear stress (Platelet Function
Analyzer (PFA)-100/200®), three on platelet aggregation (Plateletworks®,
VerifyNow®, Multiplate®), and one on platelet contribution to clot strength (TEG
Platelet Mapping®). The presence of an antiplatelet drug will reduce platelet acti-
vation by the specific agonist; however, activation by the other agonists remains
possible (e.g., clopidogrel will only suppress activation by ADP). The failure of
antiplatelet therapy, whether labeled as low treatment response, drug resistance, or
high on-treatment platelet reactivity, can easily be determined using these tests
when a specific agonist can still activate platelets despite treatment using the cor-
responding receptor blocker. This finding is associated with an increased risk of
thromboembolic complications, such as thrombosis of a coronary stent. Low on-
treatment platelet reactivity, on the other hand, is diagnosed when a very high
degree of inhibition is found and is associated with an increased risk of bleeding
complications.
GP IIb/IIIa inhibitors do not interfere with platelet activation but interfere with
aggregation by inhibiting the platelet-fibrinogen interaction. The presence of these
drugs will thus reduce aggregometry measurements regardless of the activator
used.
Finally, in global platelet dysfunction, not related to antiplatelet drugs, all of the
agonists fail to sufficiently activate patients’ platelets.

4.2.1 Platelet Function Analyzer (PFA)-100/200®

4.2.1.1 Working Mechanism (Fig. 4.2)

The PFA-100/200® system (Siemens Healthcare Diagnostics, Deerfield, IL, USA)
simulates platelet adhesion, activation, and aggregation (primary hemostasis) under
high shear flow conditions in disposable cartridges. This can be defined as a kind of
in vitro bleeding time. Small amounts (0.8 ml) of citrated whole blood are aspirated
at high shear rates (5,000–6,000/s) through a small capillary toward a platelet-
activating membrane with a microscopic aperture (147 μm). The cartridge
48 G. Casso et al.

Small opening: 147 µm Membrane coated with platelet activators:

High shear rates (5,000–6,000/s) - Collagen/epinephrine
- Collagen/ADP
- ADP/Prostaglandin E1/Ca++

Platelet plug

Citrated whole blood

No blood flow
Blood flow

Closure time

Capillary tubes

Fig. 4.2 Working mechanism of the PFA 100/200® system

membranes are coated with collagen and either epinephrine (COL/EPI) or adenos-
ine diphosphate (COL/ADP). A new cartridge (Innovance® PFA P2Y) using a mem-
brane coated with ADP, prostaglandin E1, and calcium has recently become
available; it is supposed to be more sensitive to P2Y12 inhibitors. The activators, in
association with the high shear rates, induce platelet activation and aggregation
leading to a gradual occlusion of the small aperture by a growing platelet plug. Time
to complete occlusion of the membrane orifice, inducing cessation of blood flow, is
termed closure time (CT) and expressed in seconds (s). Platelet function is inversely
correlated to CT. The test is completed in 5–8 min (maximum CT 300 s) and must
be performed within 4 h of blood sample collection.

4.2.1.2 Normal Values and Interpretation

The normal values for PFA-100/200® are presented in Table 4.1.
A prolonged CT for both the COL/EPI and COL/ADP tests is indicative for anemia
(hematocrit >0.28), thrombocytopenia (platelet count <100 × 109/l), von Willebrand
disease (vWD), or an inherited/acquired platelet dysfunction (e.g., GP IIb/IIIa
inhibitors) (Madan et al. 2001, 2002)).
In the case of a prolonged CT for COL/EPI, but a normal COL/ADP test, platelet
dysfunction has most likely been induced by acetylsalicylic acid (ASA). An
Innovance® PFA P2Y CT of more than 106 s implies drug-induced inhibition of the
P2Y12 receptor (e.g., clopidogrel).
If the Innovance® PFA P2Y CT is less than 106 s in a patient treated with a
P2Y12 receptor-blocking agent, low treatment response is likely.
4 Point-of-Care Platelet Function Tests 49

Table 4.1 Normal values for the PFA- Assay CT

100/200® assays
COL/EPI ≤180 s
COL/ADP ≤110 s
INNOVANCE®PFA P2Y ≤106 s
CT closure time, s seconds

4.2.1.3 Clinical Use in Perioperative Care

PFA® is a simple and rapid global platelet function screening assay. In a recent
meta-analysis, the pooled, weighted sensitivity and specificity for the tests used to
detect a primary hemostasis disorder were 82.5 and 66.9 % for the COL/EPI and
88.7 and 85.5 % for the COL/ADP (Karger et al. 2007). The PFA® system has been
used to identify platelet function disorders before surgery (Cammerer et al. 2003;
Koscielny et al. 2004). In patients with a positive bleeding history, it demonstrates a
high sensitivity and specificity for preoperative platelet dysfunction (Koscielny
et al. 2004). In cardiac surgery, there are conflicting results about its capacity to
predict postoperative bleeding. Some studies seem positive (Cammerer et al. 2003;
Sucker et al. 2011), others negative (Wahba et al. 1998; Forestier et al. 2002;
Fattorutto et al. 2003). In orthopedic surgery, preoperative prolongation of the PFA-
100® test was correlated with increased postoperative drain output (Ng et al. 2009).
In neurosurgery, preoperative screening with the PFA® system increased the admin-
istration of desmopressin, without reducing perioperative bleeding or transfusions
(Karger et al. 2012).

4.2.1.4 Limitations and Pitfalls

CT increases progressively with decreases in hematocrit (<0.28 %) and if the plate-
let count falls below 100 × 109/l. CT is highly dependent on von Willebrand factor
(vWF) levels (inverse correlation). This test is not sensitive for all platelet function
disorders (e.g., gives a false negative in patients with storage pool disease or mild
type I vWD) (Favaloro 2001). There is little data on the validity of the new
Innovance® P2Y assay (Linnemann et al. 2010; Edwards et al. 2012; Tsantes et al.
2012; Scavone et al. 2014).
Advantages and disadvantages of the (PFA)-100/200® are presented in Table 4.2.

4.2.2 Plateletworks®

4.2.2.1 Working Mechanism

Plateletworks® (Helena Laboratories, Beaumont, TX, USA) is based on platelet
aggregation in a fresh whole blood sample. When activated by agonists, platelets
form aggregates resulting in a reduction in the number of plasmatic free platelets.
The Plateletworks® methodology is simple, and the test is quick to perform (less
than 5 min). The two-step method first involves using an impedance cell counter
(e.g., ICHOR® or IICHOR II® from Helena Laboratories, Beaumont, TX, USA) to
measure the baseline platelet count (BPC) in an EDTA anticoagulated whole blood
50 G. Casso et al.

Table 4.2 Drug sensitivity, advantages, and disadvantages of the (PFA)-100/200® system

Assessment of drug
effect
+ −
Aspirin Rapid, automated, and easy Requires pipetting
P2Y12 inhibitors test
Dependent on hematocrit
Can be used by non-skilled and platelet count
personnel

Whole blood, no requirements Depends on vWF levels

for sample preparation

Low sample volume (pediatric

use)

High shear condition rates

(physiological condition)

sample (1 ml). The second step is to repeat the platelet count on another citrated
sample that has been exposed to a known platelet agonist (collagen, ADP, or AA).
The agonist will stimulate functional platelets to aggregate into clumps. These
aggregates exceed the threshold limitations for platelet size and the cell counter no
longer counts them as platelets. The difference in the platelet count between the
baseline and agonist platelet count (APC) in the stimulated samples provides a
direct measurement of platelet aggregation.

4.2.2.2 Normal Values and Result Interpretation

The percentage of platelet aggregation is defined as [(BPC−APC)/BPC] × 100. The
percentage of platelet inhibition can be defined as (APC/BPC) × 100.
Thrombocytopenic samples (until platelet count >27 × 109/l) may be tested using
the Plateletworks® assay. Finally, the cell counting system provides a complete
blood count (CBC).
Normal ranges for the various activators are presented in Table 4.3.
Combining the results of the different tests allows for the detection of and dif-
ferentiation between various causes of platelet dysfunction (Table 4.4).

4.2.2.3 Clinical Use in Perioperative Care

The Plateletworks® assay has been used to monitor reversal of preoperative clopido-
grel and nonsteroidal anti-inflammatory drug (NSAID) inhibition in elective sur-
gery patients (Craft et al. 2005). In cardiac surgery, preoperative platelet inhibition
measured using the Plateletworks® collagen test was associated with increased post-
operative blood loss (Ostrowsky et al. 2004). A recent study also found a significant
correlation between reduced Plateletworks® ADP-induced platelet aggregation and
postoperative blood loss in patients treated with clopidogrel undergoing coronary
artery bypass grafting (CABG) (Dalen et al. 2012).
4 Point-of-Care Platelet Function Tests 51

Table 4.3 Reference ranges for the Assay Reference range

Plateletworks® assays
AA 60–100 % aggregation
ADP 86–100 % aggregation
Collagen 70–100 % aggregation
AA arachidonic acid, ADP adenosine diphosphate

Table 4.4 Interpretation of test results for the Plateletworks® assays

AA ADP Collagen
(aggregation) (aggregation) (aggregation) Interpretation

Normal Normal Normal Normal platelet function, no

60–100% 86–100% 70–100% significant effects of antiplatelet
drugs

Abnormal Normal Abnormal Aspirin (COX-1 inhibition)

<60% 86–100% <70 %

Normal Abnormal Abnormal P2Y12 inhibitor or GP IIb/IIIa

60–100% <86% <70% inhibitor

Abnormal Abnormal Abnormal P2Y12 inhibitor or GP IIb/IIIa

<60% <86% <70% inhibitor with aspirin

Normal Normal Abnormal Fibrinolysis or adhesion defect

60–100% 86–100% <70%

AA arachidonic acid, ADP adenosine diphosphate, COX-1 cyclooxygenase-1

4.2.2.4 Limitations and Pitfalls

The agonist tube should be tested within 10 min of the collection of the blood sam-
ple in order to avoid overestimation of platelet inhibition as a result of spontaneous
platelet disaggregation (van Werkum et al. 2010). Advantages and disadvantages of
the Plateletworks® assay are presented in Table 4.5.

4.2.3 VerifyNow®

4.2.3.1 Working Mechanism (Fig. 4.3)

VerifyNow® (Accumetrics, San Diego, CA, USA) is based on the former Ultegra
Rapid Platelet Function Assay (RPFA). The RPFA was introduced in 1998, primarily
for monitoring GP IIb/IIIa antagonist activity (Smith et al. 1999). The device is easy
to use and provides a result rapidly, using about 2 ml of citrated whole blood. It is a
fully automated point-of-care test that requires no pipetting. The tube containing the
52 G. Casso et al.

Table 4.5 Drug sensitivity, advantages, and disadvantages of the Plateletworks® system

Assessment of drug
effect
+ −
Aspirin Rapid and easy test Analysis time dependent
P2Y12 inhibitors (sample must be examined
GP IIb/IIIa inhibitors Whole blood, no requirements within 10 min of
for sample preparation collection)
Provides CBC and platelet
count Few clinical studies

Low sample volume (1ml)

Can be used in
thrombocytopenic patients

Mixing cartridges Light detectors

Citrated whole blood

Light source

Disposable cartridge

Mixing chambers
contain fibrinogen-coated
Agglutinated bead-platelet beads and platelet activators
complexes precipitate

GP IIb/IIIa Fibrinogen

Activated platelet Fibrinogen-coated beads Agglutinated complexes

Fig. 4.3 Working mechanism of the VerifyNow® system

blood sample is directly inserted onto a special disposable cartridge. The cartridges’
mixing chambers contain fibrinogen-coated polystyrene beads and platelet activa-
tors: 4 μM of TRAP in the VerifyNow IIb/IIIa test®, 1 mM of AA in the VerifyNow
Aspirin test®, and 20 μM ADP + 22 nM PGE1 in the VerifyNow PRU test®.
4 Point-of-Care Platelet Function Tests 53

Table 4.6 Baseline values and expected ranges after abciximab and eptifibatide treatment for the
VerifyNow IIb/IIIa ® assay
Drug Baseline prior to drug administration ≥80 % inhibition ≥95 % inhibition
abciximab 125–330 PAU 0–44 PAU 0–13 PAU
eptifibatide 136–288 PAU 0–31 PAU 0–10 PAU
PAU platelet aggregation units

Stimulated platelets will activate GP IIb/IIIa receptors on their surface, which

will bind to the fibrinogen, agglutinating the beads. Agglutinated bead-platelet com-
plexes will precipitate and the solution will become more transparent. The device
continuously measures light transmittance through the mixing chamber and directly
correlates this to the proportion of platelet activation. Direct pharmacological block-
ade of the GP IIb/IIIa receptors or indirect suppression of their expression by AA or
ADP inhibitor drugs diminishes platelet aggregation and therefore light transmit-
tance. The VerifyNow IIb/IIIa test® must be run within 15 min of drawing the blood
sample. The VerifyNow PRU test® and the VerifyNow Aspirin test® require sample
incubation times of 10 and 30 min, respectively.

4.2.3.2 Normal Values and Result Interpretation

4.2.3.2.1 VerifyNow IIb/IIIa Test®
This test measures GP IIb/IIIa receptor blockade in patients treated with abciximab
or eptifibatide. The GP IIb/IIIa test also detects platelet inhibition by tirofiban, but
no normal range or cutoff values are available for this drug; results for these patients
should therefore be interpreted with care.
In patients treated with abciximab, blood samples are collected in citrated tubes.
Heparinized tubes must be used in patients treated with eptifibatide.
TRAP-mediated expression of GP IIb/IIIa receptors involved in platelet aggrega-
tion is expressed in platelet aggregation units (PAU). Expected values are in the
range of 0–330 PAU.
Baseline and expected values are represented in Table 4.6.

4.2.3.2.2 VerifyNow Aspirin Test®

This test uses AA as its activator, which the platelets’ cyclooxygenase-1 (COX-1)
enzyme metabolizes to thromboxane-A2. The test measures platelet response to
ASA, the COX-1 inhibitor. Thromboxane A2-mediated expression of GP IIb/IIIa
receptors involved in platelet aggregation is expressed in aspirin reactions units
(ARU). Expected values are in the range of 350–700 ARU. The cutoff for aspirin’s
therapeutic effect is 550 ARU. More than 550 ARU in patients treated with aspirin
is indicative for aspirin resistance.

4.2.3.2.3 VerifyNow PRU Test®

This test measures platelet response to P2Y12 inhibitors (e.g., clopidogrel, prasugrel,
ticlopidine, and ticagrelor).
54 G. Casso et al.

The amount of ADP-mediated aggregation specific to the platelet P2Y12 receptor

is expressed in P2Y12 reaction units (PRU). The reference range is 194–418.
Values below 194 PRU are evidence of a P2Y12 inhibitor effect. For patients treated
with P2Y12 inhibitors, values above 208 PRU are considered high on-treatment
platelet reactivity with an increased risk of thrombotic events (e.g., stent thrombosis).
Conversely, values below 82 PRU are considered low on-treatment platelet reactivity
(LPR) with an increased risk of bleeding events (Tantry et al. 2013).
A percentage inhibition index (%inh) can be derived by using a second channel
with TRAP as the agonist. TRAP activates platelets through the thrombin receptor,
independently of the presence of P2Y12 inhibitors. The channel will thus provide a
baseline value (BASE) for platelet function. The inhibition index can be calculated
as [(PRU/BASE) × 100] and seems to be less dependent on the hematocrit than PRU
measurements (Voisin et al. 2011).

4.2.3.3 Clinical Use in Perioperative Care

VerifyNow® has been extensively studied in invasive cardiologic procedures to
monitor P2Y12 drug-induced blockade. Recently, two large randomized controlled
trials in percutaneous coronary artery revascularization showed no benefit in using
VerifyNow® for the clinical management of antiplatelet drugs (Price et al. 2011;
Collet et al. 2012). Only a few studies have been conducted in the perioperative set-
ting. In a recent retrospective study of trauma patients chronically treated with clop-
idogrel, low PRU values predicted higher platelet transfusion needs (Short et al.
2013). In cardiac surgery, a significant correlation was found between preoperative
platelet inhibition measured by VerifyNow PRU® and blood loss or transfusion
requirements (Alstrom et al. 2009).

4.2.3.4 Limitations and Pitfalls

Patients who have been treated with GP IIb/IIIa inhibitor drugs should not be tested
using the VerifyNow Aspirin® or the VerifyNow PRU® tests until platelet function
has totally recovered. This occurs approximately 14 days after discontinuation of
abciximab and up to 48 h after eptifibatide and tirofiban.
Patients with thrombocytopenia (platelet counts <100 × 109/l) or with congenital
platelet disorders (e.g., vWD) have not been studied using the VerifyNow® system.
Advantages and disadvantages of the VerifyNow® assay are presented in Table 4.7.

4.2.4 Multiple Electrode Aggregometry Analyzer (Multiplate®)

4.2.4.1 Working Mechanism (Fig. 4.4)

The Multiplate® analyzer (Roche Diagnostics, Rotkreuz, Switzerland) is a whole
blood platelet function assay based on electrical impedance aggregometry (Toth
et al. 2006). The impedance aggregometry method was developed by Cardinal and
Flower and has been used since 1979 (Cardinal and Flower 1979a, b). Impedance
aggregometry is based on the principle that platelets are non-thrombogenic in their
resting state but change shape and expose receptors on their surface when activated,
4 Point-of-Care Platelet Function Tests 55

Table 4.7 Drug sensitivity, advantages, and disadvantages of the VerifyNow® system

Assessment of drug
effect
+ −
Aspirin Rapid and simple test (real Long incubation time for
P2Y12 inhibitors point-of-care) VerifyNow Aspirin test®
GP IIb/IIIa inhibitors
Can be used by non-skilled Cannot be used to detect
personnel
congenital platelet disorders
Does not require pipetting
Influence of thrombocytopenia
No sample preparation is unknown
required

2 sensor units

Hirudin blood
+ agonist

Disposable test cell

Platelets inhibited Platelets activated by agonist
No response to activation Aggregation onto electrodes
No aggregation Rise in electrical impedance
No change in electrical impedance between electrodes
between electrodes

200 AU 200 AU
Aggregation (AU)

Aggregation (AU)

0 AU 0 AU
Time Time

Fig. 4.4 Working mechanism of impedance aggregometry Multiplate®. AU aggregation units

thus allowing them to adhere to vascular injuries and artificial surfaces. The
Multiplate® analyzer provides a disposable test cell containing two independent
sensor units, each consisting of two, fine, highly conductive electrodes. A small
quantity (300 μl) of hirudin-anticoagulated whole blood is pipetted in the test cell,
mixed with 300 μl of saline using a stirring magnetic bar, and incubated at 37 °C for
3 min. A specific platelet activator is then added to the solution. Activated platelets
56 G. Casso et al.

Table 4.8 Reference ranges for the Assay AUC reference ranges
Multiplate® assay
ASPI test 71–115 U
ADP test 57–113 U
TRAP test 94–156 U
COL test 46–116 U
RISTO test 90–201 U
AUC area under the curve, U aggregation unit

adhere to and aggregate on the sensor electrodes; this leads to an increase in the
impedance measured between them. The impedance is recorded over a 6-min period
and displayed graphically. Both sensor units in each test cell measure the rise in
impedance independently. As an internal quality assessment, the two measurements
must coincide for the test to be valid.
The Multiplate® analyzer is equipped with five channels for the simultaneous
measurement of different samples and/or agonists. A wide array of different platelet
agonists is available to permit a differentiated diagnosis of acquired and inherited
platelet dysfunction:
ASPI test: cyclooxygenase-dependent aggregation (stimulation by 0.5 mM of AA)
sensitive to ASA, NSAIDs, and other inhibitors of platelet COX-1.
ADP test: ADP-induced platelet activation (stimulation by 6.5 μM ADP) sensitive
to clopidogrel, prasugrel, ticagrelor, and other P2Y12 receptor antagonists.
TRAP test: platelet stimulation via the thrombin receptor (using 32 μM of thrombin
receptor-activating peptide), sensitive to GP IIb/IIIa receptor antagonists (e.g.,
abciximab, eptifibatide, and tirofiban).
COL test: collagen-induced aggregation (using 3.2 μg of collagen).
RISTO test: vWF- and GP Ib-dependent aggregation (using 0.77 mg/ml ristocetin).

4.2.4.2 Normal Values and Result Interpretation

Three parameters that represent the increase in impedance are calculated: area under
the aggregation curve (AUC), aggregation, and velocity. AUC is the parameter most
used since it depends on both the curve’s height and slope. It is expressed in units
(U) or sometimes as AU*min (for conversion, 10 AU*min equals 1U). Aggregation
is the maximum height of the curve and is expressed in arbitrary aggregation units
(AU). Finally, velocity represents the slope of the curve and is expressed in AU/min.
Reference ranges for AUC are presented in Table 4.8.
Less than 40 U in the ASPI test indicates adequate inhibition of COX-1 by
aspirin (Al-Azzam et al. 2012); less than 30 U is considered strong inhibition (von
Pape et al. 2007).
For patients using P2Y12 receptor blockers, a recent expert consensus defined an
ADP test of more than 46 U as high on-treatment platelet reactivity, which is associ-
ated with increased ischemic risk. ADP test results of less than 19 U are defined as
low on-treatment platelet reactivity, which is associated with an increased bleeding
risk (Tantry et al. 2013).
4 Point-of-Care Platelet Function Tests 57

Table 4.9 Drug sensitivity, advantages, and disadvantages of the Multiplate® system

Assessment of drug
effect
+ −

Aspirin Rapid (< 10 min), easy test Requires pipetting

P2Y12 inhibitors
GP IIb/IIIa inhibitors Whole blood, no requirements Sensitive to thrombocytopenia
for sample preparation

Low sample volume (0.3

ml/test)

Multiple agonists available

allowing a wide range of
different acquired and
inherited platelet dysfunction
detection

4.2.4.3 Clinical Use in Perioperative Care

In a trauma setting, a recent study found a correlation between decreased ADP
and TRAP test values on admission to the emergency room and increased mortal-
ity (Solomon et al. 2011). In cardiac surgery, preoperative platelet dysfunction
measured using the Multiplate® was associated with increased platelet transfu-
sion requirements and/or increased postoperative bleeding (Rahe-Meyer et al.
2009; Solomon et al. 2010; Ranucci et al. 2011). For patients on P2Y12 inhibi-
tory drugs, a preoperative ADP test value of less than 31 U was correlated with
increased postoperative bleeding and platelet transfusion requirements (Ranucci
et al. 2011).
Multiplate® technology allowed assessment of cardiopulmonary bypass-induced
platelet dysfunction and of enhanced platelet function following desmopressin
administration (Velik-Salchner et al. 2009; Weber et al. 2010, 2012; Steinlechner
et al. 2011). It was also possible to assess platelet transfusion requirements after
cardiac surgery using the ADP test (Rahe-Meyer et al. 2009).

4.2.4.4 Limitations and Pitfalls

In the Multiplate®, signal reaction requires a tight attachment of the platelets to the
sensor’s surface. The system seems, therefore, more dependent on physiological
calcium levels than other tests (e.g., PFA100/200®, VerifyNow®). Citrated blood
sampling tubes affect the free calcium concentration in blood, so hirudin coated
tubes are preferred. Samples should be analyzed within the period of 3 h after blood
collection. The Multiplate® system is sensitive to thrombocytopenia and the blood
samples used must have platelet counts of at least 150 × 109/l for the ASPI test, at
least 100 × 109/l for the ADP and COL tests, and at least 50 × 109/l for the TRAP test
(Stissing et al. 2011). Advantages and disadvantages of the VerifyNow® assay are
presented in Table 4.9.
58 G. Casso et al.

4.2.5 Thromboelastography Platelet Mapping®

4.2.5.1 Working Mechanism

Thromboelastography (TEG) provides assessment of the viscoelastic properties of
a blood clot in vitro. This technique is extensively described in Chap. 3. The TEG
Platelet Mapping® system (Haemoscope Corporation, Niles, IL, USA) is a recent
modification of the standard TEG technique designed to specifically asses platelet
contribution to clot strength (Craft et al. 2004). Platelet Mapping® determines the
reduction in maximum amplitude (MA) of the TEG assay due to antiplatelet ther-
apy. Three different sample analyses must be performed. Baseline thrombin-
induced clot strength is measured by adding kaolin to whole blood. Kaolin initiates
the intrinsic pathway, which leads to thrombin generation. Thrombin is a highly
potent platelet activator that mediates maximal expression of GP IIb/IIIa receptors,
cleaves fibrinogen into fibrin, and activates factor XIII for fibrin cross-linking.
The MA of this clot is named MAthrombin and represents the maximum capacity of
the platelets. In a second assay, activator F (reptilase and factor XIIIa) is added to
heparinized blood. Reptilase is an enzyme that cleaves fibrinogen to fibrin mono-
mers without activating platelets or other coagulation factors. Factor XIIIa cova-
lently binds the monomers to produce a stable fibrin clot. Maximal tensile strength
of this fibrin clot is named MAfibrin and represents a zero platelet contribution.
In the third assay, heparinized blood is stimulated by activator F and either 1 mmol/l
of AA (Platelet Mapping AA assay) or 2 μmol of adenosine diphosphate (Platelet
Mapping ADP assay). The MA of these platelet-fibrin clots is named MAAA or
MAADP, respectively.

4.2.5.2 Normal Values and Result Interpretation

The results of Platelet Mapping® are reported as percent inhibition and percent
aggregation. The percentage of platelet aggregation is calculated as % platelet
aggregation = [(MAAA or ADP − MAfibrin)/(MAthrombin − MAfibrin)] × 100. The percentage
of inhibition induced by antiplatelet drugs is calculated as % platelet inhibi-
tion = 100 − [(MAAA or ADP − MAfibrin)/(MAthrombin − MAfibrin)] × 100 (Fig. 4.5). Getting
the MA value from the TEG assays may take 30–40 min after the onset of the tests.
In order to get platelet function results sooner, an additional parameter called
percent of clotting inhibition (%CIn) has recently been proposed (Hobson et al.
2007). It compares the areas under the curve of the ADP or AA assays and throm-
bin-stimulated assays at 15 min (AUC15).
There is little data available on the normal values for MA. In 43 healthy patients,
MA for thrombin, fibrin, AA and ADP assays were MAthrombin, 60.9 ± 4.5 mm;
MAfibrin, 7.5 ± 2.7 mm; MAAA, 64.6 ± 2.7 mm; and MAADP, 51.1 ± 8.1 mm (Table 4.10)
(Bochsen et al. 2007).
While on treatment, aspirin resistance is defined as more than 50 % aggregation
or less than 50 % inhibition in the Platelet Mapping® AA assay (Tantry et al. 2005).
P2Y12 inhibitory drug resistance is defined as more than 50 % aggregation or
less than 50 % inhibition in the Platelet Mapping® ADP assay.
4 Point-of-Care Platelet Function Tests 59

100 % inhibition by antiplatelet drug

mm MAThrombin (complete activation) mm
MAThrombin
MAADP or AA (activation of non-inhibited platelets)

MAFibrin (no platelet activation)

MAThrombin = MAADP or AA

Time (min) Time (min)

0 % inhibition by antiplatelet drug

MAADP or AA – MAFibrin mm MAThrombin = MAADP or AA

% Aggregation = × 100
MAThrombin – MAFibrin

MAFibrin
MAADP or AA – MAFibrin
% Inhibition = 100 – × 100
MAThrombin – MAFibrin

Time (min)

Fig. 4.5 Calculation of TEG Platelet Mapping® results. MA maximum amplitude of the TEG
assay expressed in millimeter (mm)

Table 4.10 Normal values for Assay Normal values (mm)

healthy subjects not on antiplatelet MAthrombin 60.9 (±4.5)
therapy for the Platelet Mapping®
MAfibrin 7.5 (±2.7)
assay (Bochsen et al. 2007)
MAAA 64.6 (±2.7)
MAADP 51.1 (±8.1)

In literature on interventional cardiology, several definitions for high on-

treatment platelet reactivity while on P2Y12 inhibitory therapy are proposed:
≥70 % platelet aggregation (Bliden et al. 2007), MAADP >47 mm (Gurbel et al.
2010), or MAADP >50 mm for high reactivity, MAADP 35–50 mm for intermediate
reactivity, and MAADP <35 mm for low reactivity (Mahla et al. 2012).
A more recent expert consensus on the definition of on-treatment platelet reactiv-
ity to ADP associated with ischemia and bleeding determined the following cutoffs:
high on-treatment platelet reactivity, MAADP >47 mm, associated with increased
ischemic risk; and low on-treatment platelet reactivity, MAADP <31 mm, associated
with increased bleeding risk (Tantry et al. 2013).

4.2.5.3 Clinical Use in Perioperative Care

In trauma or urgent general surgery, Platelet Mapping® can be used preoperatively
to detect residual platelet inhibition by ASA or clopidogrel (Collyer et al. 2009).
Clopidogrel-induced platelet dysfunction, measured by Platelet Mapping®, was
associated with increased postoperative bleeding in cardiac surgery in patients on
dual antiplatelet therapy (Preisman et al. 2010). In off-pump CABG, a high percent-
age of inhibition by clopidogrel (% inhibition ≥70 %) predicts increased blood loss
and transfusion requirements (Kwak et al. 2010). Timing surgery after clopidogrel
cessation by using platelet function monitoring shortens the preoperative waiting
60 G. Casso et al.

Table 4.11 Drug sensitivity, advantages, and disadvantages of the TEG Platelet Mapping® system

Assessment of drug
effect
+ −
Aspirin Whole blood Use of 3 different channels for
P2Y12 inhibitors measurements (2 TEG
GP IIb/IIIa inhibitors Low sample volume devices)

Additional information about Requires pipetting

clot’s viscoelastic properties,
and coagulation pathway

period in comparison to applying arbitrary delays and results in blood loss compa-
rable to clopidogrel-naive patients undergoing the same type of surgery (Mahla
et al. 2012).

4.2.5.4 Limitations and Pitfalls

TEG Platelet Mapping® is technically more demanding than other point-of-care
platelet function tests. It requires repeated pipetting for sample preparation. The
Platelet Mapping® assay requires three measurement channels, employing two TEG
machines for one patient. Advantages and disadvantages of the TEG Platelet
Mapping® assay are presented in Table 4.11.

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cartridge in detection of clopidogrel resistance. Platelets 23(6):481–489
van Werkum JW, Kleibeuker M et al (2010) A comparison between the Plateletworks-assay and
light transmittance aggregometry for monitoring the inhibitory effects of clopidogrel. Int J
Cardiol 140(1):123–126
Velik-Salchner C, Maier S et al (2009) An assessment of cardiopulmonary bypass-induced changes
in platelet function using whole blood and classical light transmission aggregometry: the
results of a pilot study. Anesth Analg 108(6):1747–1754
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327–358
Voisin S, Bongard V et al (2011) Are P2Y12 reaction unit (PRU) and % inhibition index equivalent
for the expression of P2Y12 inhibition by the VerifyNow assay? Role of haematocrit and hae-
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Hemostasis Assessment
and Evaluation 5
Christoph Sucker and Rainer B. Zotz

5.1 Assessment of Plasmatic Hemostasis

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are the
most frequently used assays for the routine assessment of plasmatic hemostasis.
These widely available assays are employed to detect coagulation factor deficien-
cies, particularly those predisposing to perioperative bleeding. With regard to the
classic cascade or waterfall model of plasmatic hemostasis, PT detects factor defi-
ciencies localized in the extrinsic coagulation pathway and the final common path-
way, whereas aPTT is sensitive to defects in the intrinsic coagulation pathway and
the common pathway. Another assay, thrombin time (TT), detects an insufficient
conversion of fibrinogen to fibrin upon stimulation by thrombin. This assay is used
to diagnose an absence, deficiency, or dysfunction of fibrinogen but also factors
inhibiting or disturbing the action of thrombin on fibrinogen, such as heparin or
thrombin inhibitors. The effect of different coagulation defects on these screening
assays is reflected by the cascade or waterfall model of hemostasis (see Sect. 1.3).
The causes of prolonged PT and aPTT, whether or not they predispose to bleed-
ing, are summarized in Table 5.1. Notably, combinations of different defects of
plasmatic hemostasis may not only yield abnormal results in one test but may influ-
ence all screening assays. Since all the assays mentioned above are based on the
measurement of plasma turbidity for the detection of fibrin production, turbid
patient plasma, such as in severe hyperlipidemia, may interfere with them
significantly.

C. Sucker
LaboMed Gerinnungszentrum Berlin, Tauentzienstrasse 7 b/c, Berlin 10789, Germany
e-mail: [email protected]
R.B. Zotz (*)
Centrum für Blutgerinnungsstörungen und Transfusionsmedizin (CBT),
Immermannstrasse 65 a, Düsseldorf 40210, Germany
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 65

DOI 10.1007/978-3-642-55004-1_5, © Springer-Verlag Berlin Heidelberg 2015
66 C. Sucker and R.B. Zotz

Table 5.1 Routine coagulation assays distinguishing defects related or not related to bleeding
Defect related Defect not related
PT aPTT TT to bleeding to bleeding
Normal Normal Normal Factor XIII –
deficiency
Von Willebrand
disease (mild)
Prolonged Normal Normal Factor VII –
deficiency
Vitamin K
antagonist/
deficiency
Liver disease
Normal Prolonged Normal Factor VIII Lupus
deficiency anticoagulant
(hemophilia A) Factor XII
deficiency
Factor IX deficiency HMWK deficiency
(hemophilia B)
Factor XI deficiency (Pre)kallikrein
Von Willebrand deficiency
disease
Acquired
hemophilia
Prolonged Prolonged Normal Factor II deficiency ?
Factor V deficiency
Factor X deficiency
Combined
deficiencies
Normal/ Prolonged Prolonged Treatment with –
prolonged heparin, hirudin,
argatroban
Normal/ Normal Prolonged Afibrinogenemia Thrombotic
prolonged prolonged Hypofibrinogenemia dysfibrinogenemia
Hemorrhagic
dysfibrinogenemia
Heparin-like defects
Inhibitors of fibrin
polymerization
Treatment with
heparin, hirudin,
argatroban
Bleeding with normal screening assay and platelet count results can be caused by mild von
Willebrand disease, factor XIII deficiency, platelet defects or medication, low molecular weight
heparin (LMWH), hypothermia, acidosis, and hypocalcemia. Low platelet counts with normal
screening assays are found in cases of pseudothrombocytopenia, idiopathic thrombocytopenic pur-
pura (ITP), and hereditary platelet disorders (e.g., Bernard–Soulier syndrome, gray platelet syn-
drome). Low platelet counts with prolonged aPTT/PT are found in cases of disseminated
intravascular coagulation (DIC), hemodilution, and liver disease
5 Hemostasis Assessment and Evaluation 67

The screening assays for plasmatic hemostasis exhibit considerable weaknesses:

depending on which assay is used, sensitivity may not be sufficient when trying to
diagnose mild defects of plasmatic hemostasis, even in cases where they are associ-
ated with bleeding. The assays detect fibrin formation but are not sensitive to the
subsequent process of fibrin cross-linking or stabilization, and therefore they cannot
find deficiencies of coagulation factor XIII (fibrin stabilizing factor). To detect fac-
tor XIII deficiency, its activity has to be determined separately. Furthermore, these
screening assays may be prolonged not only in cases of defects predisposing to
bleeding but also in cases with irrelevant defects. In particular, aPTT may be pro-
longed in case of factor XII deficiency, in high molecular weight kininogen defi-
ciency, in (pre)kallikrein deficiency, or in the presence of lupus anticoagulant; none
of these defects predisposes to bleeding and they may be regarded as irrelevant in a
surgical context.

5.2 Assessment of Primary Hemostasis

Defects of primary hemostasis include quantitative and functional platelet disorders

and von Willebrand disease (vWD).
Decreased platelet counts are easily detectable by means of the blood cell count,
routinely performed prior to surgery. Notably, pseudothrombocytopenia caused by
EDTA-induced agglutination of platelets is not a rare phenomenon, but it can wrongly
suggest an increased risk for bleeding. Since the platelet count in the patient is nor-
mal, pseudothrombocytopenia is actually a laboratory phenomenon without relation
to bleeding. It can easily be diagnosed by determining the platelet count in a medium
other than EDTA, such as citrated blood, or in commercially available collection
tubes specifically made for platelet counts. A normal platelet count in either of these
media, in combination with a low platelet count in EDTA blood, rules out relevant
thrombocytopenia and proves irrelevant pseudothrombocytopenia.
In contrast to thrombocytopenia, platelet dysfunction is more difficult to detect
because the required assays are neither generally available nor routinely per-
formed. Congenital abnormalities of platelet function disorder are associated with
a heightened risk of bleeding. Typically, patients with a platelet function disorder
suffer from mucocutaneous bleeding of varying severity and bleed excessively
after surgery or trauma. The laboratory assessment appropriate for the evaluation
of a suspected inherited platelet function disorder should be based on a two-step
diagnostic strategy: the first step, based on screening tests, helps to build a diagnostic
hypothesis, which should then be tested by a second step, based on the use of
more specific tests (Podda et al. 2012).
Light transmission aggregometry is the classic assay for the detection of platelet
dysfunction. Platelets are stimulated with various agonists (collagen, epinephrine,
adenosine diphosphate (ADP), ristocetin, arachidonic acid) that induce platelet
aggregation in normal platelets. Upon platelet stimulation by the agonist, this
method determines their physiological aggregation response as light transmission
increases through platelet-rich plasma. By contrast, platelet-rich plasma will remain
68 C. Sucker and R.B. Zotz

turbid when platelets do not aggregate normally upon stimulation. Aggregometry

requires specialized skills and considerable time for sample preparation prior to
examination (Shah and Ma 2007). A variant of this method – impedance aggregometry –
does not depend on turbidity but measures changes in electrical resistance over
time. Impedance aggregometry is easier to perform and uses whole blood rather
than platelet-rich plasma.
In recent years, another device, namely, the platelet function analyzer (PFA-
100), has gained an important role in the diagnosis of defects in primary hemostasis.
The PFA-100 measures the time taken to close an aperture in a collagen-coated net
membrane containing a platelet agonist (epinephrine or ADP) when blood passes
through it under high-shear stress conditions. Defects of primary hemostasis (par-
ticularly thrombocytopenia, platelet function disorders, and vWD) will reduce clot
formation on the artificial collagen matrix, prolonging the closure time. This method
is highly sensitive for the detection of severe platelet-related defects, as well as
vWD. Congenital platelet disorders prolong PFA-100 closure times in a manner
proportional to their severity. However, PFA-100 is less sensitive to milder disorders
such as storage pool disease, primary secretion defects, and Hermansky–Pudlak
syndrome; false-negative results are also possible (Hayward et al. 2006).
Further classification of detected platelet defects is challenging and requires
specialized methods, such as flow cytometry for quantification of platelet receptors
and activation and electron microscopy. These methods are only available in a few
specialized laboratories that focus on the diagnostic assessment of rare platelet dis-
orders and do not play an important role in a surgical context.
Apart from platelet pathologies, vWD is another disorder affecting primary
hemostasis. The underlying absence, reduction, or dysfunction of the plasmatic pro-
tein, von Willebrand factor (vWF), may not be detected by the classic screening
assays of plasmatic hemostasis, PT, and aPTT. aPTT is only prolonged in approxi-
mately one third of vWD patients. Relevant vWD may be detected by a prolonga-
tion of the closure times in the platelet function analyzer, which has a high diagnostic
sensitivity for it. However, when the PFA-100 records prolonged closure times
(CT), it is necessary to distinguish a platelet disorder from vWD. Specific assays for
the diagnosis of this hemostatic defect include the determination of vWF antigen
levels (vWF:Ag) and vWF activity, mostly performed by determining the so-called
ristocetin cofactor (vWF:RCo) or collagen binding activity (vWF:CB). Further dif-
ferentiation of subtypes of vWD requires specialized assays such as multimeric
analysis, factor VIII binding assay, and ristocetin-induced platelet aggregation (RIPA).
These assays are only performed in specialized laboratories and in most cases are
not immediately available.
Bleeding time is no longer thought to be a valid screening test, preoperatively or
otherwise, and has been largely replaced by PFA-100. Bleeding time results are
poorly reproducible and exhibit low sensitivity and specificity. In the absence of a
clinical history of bleeding disorder, bleeding time is not a useful predictor of the
risk of hemorrhage associated with surgical procedures. Furthermore, a normal
bleeding time does not exclude the possibility of excessive hemorrhage associated
with invasive procedures (Shah and Ma 2007; Peterson et al. 1998).
5 Hemostasis Assessment and Evaluation 69

5.3 Preoperative Detection of Hemostatic Defects

In a normal setting, preoperative diagnostic assessment includes a platelet count and

measurement of PT and aPTT for the detection of potential defects associated with
bleeding. Using these assays, thrombocytopenia and most coagulation factor defi-
ciencies associated with bleeding will be identified. However, platelet function
defects, most cases of vWD and factor XIII deficiency, will remain undetected.
Since platelet dysfunction – mainly secondary to underlying disease or intake of
drugs – and vWD are by far the most common disorders associated with bleeding,
the usual preoperative diagnostic assessment does not at all exclude the presence of
clinically relevant hemostatic defects. However, there is increasing evidence that a
defect can be ruled out with greater accuracy if standard coagulation assays are
combined with a standardized questionnaire addressing the presence of potential
hemostatic defects (Table 5.2).

Table 5.2 Patient history for the preoperative exclusion of hemostatic defects associated with
bleeding
Patient history Important aspects
Bleeding symptoms Provoked bleeding: previous bleeding related to
surgery, dentistry, or trauma
Spontaneous bleeding: epistaxis, hematoma,
gingival bleeding, heavy menstrual bleeding, joint
and muscle bleeding
Diseases/conditions potentially Hepatic disease
associated with bleeding disorders Renal disease
Hematological disorders
Myelodysplastic disorder
Myeloproliferative disorder
Paraproteinemia
Cardiopulmonary bypass
Extracorporeal membrane oxygenation
Medication associated with Platelet inhibitors
bleeding disorders Aspirin, clopidogrel, prasugrel, ticagrelor,
dipyridamole
GpIIb/IIIa receptor inhibitors
Analgesics/antiphlogistics (ibuprofen,
diclofenac, etc.)
Cilostazol
Selective serotonin reuptake inhibitors (SSRI)
Beta-lactam antibiotics
Herbal medicine (e.g., ginkgo, garlic, ginger,
ginseng)
Oral anticoagulants
Cumarines, dabigatran, rivaroxaban, apixaban
Parenteral anticoagulants
Heparins, fondaparinux, hirudin, argatroban
Family history Increased bleeding tendency or defined
hemostatic defects in relatives
70 C. Sucker and R.B. Zotz

Patients, history

Suspicious Normal

Suspicious Routine coagulation

analysis

Normal

Further hemostasis Surgery

examinations
Optimization of hemostasis

Fig. 5.1 Proposed approach to preoperative assessment of hemostatic defects

An adequate standardized questionnaire of a patient’s history and the usual

screening assays can be used to rule out a relevant hemostatic defect. In particular,
the combined analysis of a patient’s history and the laboratory assays has a high
negative predictive value for the exclusion of defects associated with bleeding. By
contrast, a positive patient history is associated with the presence of a relevant
hemostatic defect in approximately 40 % of patients (Koscielny et al. 2004). Any
hint of a hemostatic defect should lead to postponement of elective surgery to allow
for further examination and preoperative optimization of hemostasis prior to sur-
gery. A feasible and practical approach is shown in Fig. 5.1. Further analyses in case
of normal screening results (PT, aPTT, TT, platelet count) may include platelet
functions assays, vWF activity, and factor XIII activity.

References
Hayward CP, Harrison P, Cattaneo M et al (2006) Platelet function analyzer (PFA)-100 closure
time in the evaluation of platelet disorders and platelet function. J Thromb Haemost
4:312–319
Koscielny J, Ziemer S, Radtke H et al (2004) A practical concept for preoperative identification of
patients with impaired primary hemostasis. Clin Appl Thromb Hemost 10:195–204
Peterson P, Hayes TE, Arkin CF et al (1998) The preoperative bleeding time test lacks clinical
benefit: College of American Pathologists’ and American Society of Clinical Pathologists’
position article. Arch Surg 133:134–139
Podda G, Femia EA, Pugliano M et al (2012) Congenital defects of platelet function. Platelets
23:552–563
Shah U, Ma AD (2007) Tests of platelet function. Curr Opin Hematol 14:432–437
Congenital Bleeding Disorders
6
Maria Martinez, Lukas Graf, and Dimitrios A. Tsakiris

6.1 Introduction

Congenital bleeding disorders are found in all the world’s racial groups. They can
affect the plasmatic coagulation cascade, as well as platelet function, with different
patterns of inheritance (sex-linked recessive, autosomal recessive, and autosomal
dominant). Taken all together, they affect roughly 1 in 200 people. Hemophilia
A and B are inherited in a sex-linked recessive way, and together with the more
frequent von Willebrand disease, they constitute the largest group of inherited plas-
matic bleeding disorders (Table 6.1).
In order to avoid catastrophic outcomes, the identification of a congenital bleeding
disorder is crucial for the optimization of hemostasis in a perioperative setting.
Useful diagnostic tools include the global tests of coagulation – as first-choice labo-
ratory tests – prothrombin time (PT/INR) and activated partial thromboplastin time
(aPTT). There are also platelet function screening tests, such as the thrombocyte
global test PFA-100 for initial hemostasis or whole blood impedance aggregometry.
Figure 6.1 gives an overview of the diagnostic efficacy of these tests.
In general, treatment of hereditary deficiencies of coagulation proteins consists
of an appropriate replacement therapy under the supervision of an experienced
hemostaseologist. Dosing and frequency of substitution are dependent on the clini-
cal problem, risk of bleeding, and pharmacokinetics of the factor concentrates used.
Elimination half-lives and target levels required for an adequate hemostatic effect
under physiological conditions are shown in Table 6.2.

M. Martinez, MD • L. Graf, MD • D.A. Tsakiris, MD (*)

Hemophilia Comprehensive Care Center, University Hospital Basel,
Basel, Switzerland
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 71

DOI 10.1007/978-3-642-55004-1_6, © Springer-Verlag Berlin Heidelberg 2015
72 M. Martinez et al.

Table 6.1 Prevalence of Factor deficiency Frequency

various bleeding disorders in
Fibrinogen 1:1 m
the general population
Factor II 1:2 m
Factor V 1:1 m
Factor V and factor VIII 1:1 m
Factor VII 1:0.5 m
Factor VIII 1:10,000
Factor IX 1:50,000
Factor X 1:1 m
Factor XI 1:1 m
Factor XIII 1:2 m
Von Willebrand type 3 1:250,000–1 m
Von Willebrand type 1 or 2 1:200
m million

Fig. 6.1 Classic overview of XII Platelets

the coagulation cascade with XI
positioning and diagnostic IX BT
efficacy of the global VIIa/TF
coagulation tests, distinguish- VIIIa
ing the extrinsic system (blue
arrow), the intrinsic system APTT Va PT
(red arrow), and the common
pathway (PT prothrombin ACT
time, APTT activated partial
Xa, Va , Ca++
thromboplastin time, ACT
activated clotting time, BT Fibrinogen
bleeding time) Fibrinolysis
Prothrombin Thrombin

D-Dimers
FIBRIN

Table 6.2 Elimination half-life (t ½) of various coagulation factors and their minimum concentra-
tions required in plasma for an adequate hemostatic effect under physiological conditions
Factor Name t ½ (h) Hemostatic level Preoperative target level
I Fibrinogen 90 0.5–1 g/l >1 g/l
II Prothrombin 70 20–40 % >50 %
V 24 15–20 % >20 %
VII 6 15 % >50 %
VIII 12 5–10 % >50–100 %
IX 24 5–10 % >50–100 %
X 40 15–20 % >50 %
XI 60 15–20 % >20 %
XII 52 <1 %
XIII 72 2–5 % >50–100 %
vWF 12 40 % >50–100
6 Congenital Bleeding Disorders 73

6.2 Autosomal Dominant Disorders

6.2.1 Von Willebrand Disease

Von Willebrand disease (vWD) is a hemorrhagic disorder caused by a deficiency of

von Willebrand factor (vWF) measured either as an activity or a protein. VWF
consists of multimeric protein units that are heterogeneous in size. As a rule, larger
vWF multimers show a higher hemostatic efficacy than smaller ones. Von
Willebrand multimers are produced in endothelial cells and megakaryocytes; they
are stored in the Weibel-Palade bodies of endothelial cells, in the alpha granules of
platelets, and in subendothelial connective tissue. VWF has two key functions: on
one hand, by binding to the GP Ib/V/IX complex on the platelet surface VWF
mediates platelet adhesion to subendothelial collagen at sites with high shear stress,
and on the other hand, VWF is the carrier protein for circulating factor VIII pre-
venting its rapid proteolysis. VWD is the most frequent congenital bleeding disor-
der, with an estimated prevalence of 1:200–300 in the general population. There are
three types of vWD, with several subtypes showing different clinical presentations
(Table 6.3).
The clinical presentation of vWD is mostly mucocutaneous bleeding, such as
easy bruising, epistaxis, bleeding after tooth extraction or other surgical interven-
tions, and menorrhagia.
Laboratory assays for the diagnosis of vWD are either quantitative or qualitative.
Quantitative immunoassays measure the amount of vWF present in plasma
expressed as von Willebrand antigen (vWF:Ag). The qualitative or functional assays
measure the activity of vWF. Qualitative assays can measure the vWF collagen-
binding activity (vWF:CB) or the vWF ristocetin cofactor activity (vWF:RCo).
Ristocetin is an antibiotic that causes platelet agglutination, but only in the presence
of large vWF multimers.
The diagnosis of vWD can be made easily in patients with vWF activity below
35 %. However, many patients with a bleeding history present borderline vWF
activity between 35 and 60 %. Patients belonging to this group may be difficult to
diagnose, since they can overlap with a low variant of normal persons with blood
group O, who physiologically have vWF activity at the lower limit of the normal

Table 6.3 Classification of von Willebrand disease (vWD)

Type vWD Description
1 Partial quantitative deficiency of vWF
2 Qualitative deficiency of vWF
2A Decreased platelet-dependent vWF function with lack of large multimers
2B Increased affinity of vWF to GPIb and loss of large and medium multimers
2M Decreased platelet-dependent vWF function with normal multimeric analysis
2N Decreased vWF affinity for FVIII
3 Complete deficiency of vWF
vWF von Willebrand factor, GPIb glycoprotein Ib, FVIII factor VIII
74 M. Martinez et al.

Table 6.4 Comparative laboratory findings in types of von Willebrand disease

Type vWD vWF:Ag vWF:RCo vWF:RCo/vWF:Ag Large vWF multimers
1 ↓ ↓ >0.6 Normal
2
2A ↓ ↓↓ <0.7 ↓
2B ↓ ↓↓ <0.7 ↓↓
2M ↓ ↓↓ <0.7 Normal
2N → or ↓ → or ↓ >0.6 Normal
3 ↓↓↓ ↓↓↓ – ↓↓↓

range, without clinical bleeding. Therefore, an adequate personal and family bleed-
ing history and an adequate laboratory workup, including platelet function testing,
are required in such cases.

6.2.1.1 Von Willebrand Disease Type 1

VWD type 1 presents a partial quantitative deficiency of vWF with both reduced
vWF antigen and vWF activity. It includes about 75 % of all patients with vWD.
The symptoms are easy bruising, epistaxis, gum bleeding, menorrhagia, bleeding
after dental procedures, postsurgical bleeding, or postpartum hemorrhage.

Laboratory Findings
Whereas PT/INR is normal, aPTT can be slightly increased in more severe forms of
vWD type 1, with low FVIII levels. VWF antigen and vWF activity are decreased
in parallel (Table 6.4).

6.2.1.2 Von Willebrand Disease Type 2

VWD type 2 presents with qualitative defects of the vWF multimers. According to
their specific defects, they are subdivided into type 2A, 2B, 2M, and 2N.

6.2.1.2.1 Von Willebrand Disease Type 2A

Type 2A is the most common of type 2 VWD. It presents a lack of large vWF mul-
timers, which leads to impaired platelet adhesion.

Laboratory Findings
PT, aPTT, and FVIII levels show the same patterns as in vWD type 1. VWF:Ag is
typically normal or slightly low, while vWF activity is clearly lower, which leads to
a ratio vWF:RCo/vWF:Ag below 0.7. Analysis of multimers reveals a lack of large
vWF multimers (Table 6.4).

6.2.1.2.2 Von Willebrand Disease Type 2B

In contrast to type 2A, type 2B shows an increased affinity and binding of vWF to
the von Willebrand receptor (GPIb/V/IX) on platelets as a result of a “gain-of-
function” mutation. This leads to a faster clearance of both von Willebrand multim-
ers (especially large- and medium-sized molecules) as well as platelets. Hence,
patients with this subtype often present with mild thrombocytopenia, which can be
6 Congenital Bleeding Disorders 75

aggravated under surgery, during pregnancy, or during substitution with vWF

concentrates.

Laboratory Findings
Laboratory assessment of PT/INR, aPTT, FVIII, vWF activity, and antigen is simi-
lar to vWD type 2A. Additionally, there is a typical multimeric pattern with a lack
of large- and middle-sized multimers. Typically, using ristocetin in lower than nor-
mal concentrations causes these patients’ platelets to aggregate. This finding distin-
guishes type 2B from 2A (Table 6.4).

6.2.1.2.3 Von Willebrand Disease Type 2M

In type 2M, vWF shows a reduced capacity to bind to the von Willebrand receptor
(GPIb/V/IX) on platelets, but in contrast to type 2A and 2B, normal (ultra) large
vWF multimers are present.

Laboratory Findings
VWF:Ag is normal, FVIII is normal or only slightly low, vWF activity is low, and
large vWF multimers are normal (Table 6.4).

6.2.1.2.4 Von Willebrand Disease Type 2N (vWF Normandy)

In this subtype, von Willebrand multimer interaction with platelets is maintained,
but the capacity to bind FVIII is decreased or even absent. This results in a faster
elimination of FVIII since its normal elimination half-life is only 2 h, instead of
12 h for vWF. Clinically, this entity cannot be distinguished from mild
hemophilia A.

Laboratory Findings
Findings are normal or prolonged aPTT, reduced FVIII activity, and normal or only
slightly decreased vWF antigen and activity (Table 6.4). Differentiating type 2N
from hemophilia A is only possible by measuring the FVIII binding capacity of
vWF (low in vWD 2N, normal in hemophilia A).

6.2.1.3 Von Willebrand Disease Type 3

Type 3 vWD is a rare defect presenting with undetectable or very low (<5 %) levels
of both vWF antigen and activity. The prevalence in the general population is esti-
mated to be one to three per million people.
The clinical phenotype of type 3 is a pronounced predisposition for mucocutane-
ous bleeding, such as easy bruising, epistaxis, menorrhagia in women, and bleeding
after tooth extraction or other surgical interventions. Muscle and joint bleeding
similar to severe hemophilia A or B can also occur, since very low levels of vWF
lead to artificially low levels of FVIII.

Laboratory Findings
Findings are normal PT/INR, prolonged aPTT due to the low FVIII levels, very low
or undetectable levels of vWF antigen and activity, and absence of the whole spec-
trum of vWF multimers in the multimeric analysis (Table 6.4).
76 M. Martinez et al.

Treatment of vWD
The mainstay for the treatment of vWD in situations of acute bleeding is substitu-
tion with a concentrate containing vWF (Haemate®, Wilate®, Wilfact®). Dosing is
usually weight adjusted. Elimination half-life of substituted vWF is 14–17 h; thus,
in most cases once or twice daily substitution is appropriate. Fresh frozen plasma
(FFP) is an insufficient source of vWF and should not be used for this purpose.
Cryoprecipitate preparations contain high concentrations of vWF, but are no longer
used because they are not pathogen inactivated.
Depending on the severity of the deficiency and the extent of the trauma, desmo-
pressin (DDAVP) (Octostim®, Minirin®) can be used as an alternative means to
increase endogenous vWF and FVIII levels by stimulating the release of vWF from
the endothelium. Desmopressin is given intravenously as a short infusion over 30 min
(0.3 μcg/kg body weight). Alternatively, it can be given subcutaneously, repeating
once or twice every 24 h. If active mucocutaneous bleeding is present, treatment
should include an antifibrinolytic agent (e.g., tranexamic acid 10 mg/kg bw IV)
because desmopressin also stimulates endogenous fibrinolysis by release of tissue
plasminogen activator. Intranasal application of desmopressin might be an option for
self-treatment in case of bleeding, but due to its variable bioavailability, it is not pre-
ferred in the perioperative setting. Desmopressin should be used cautiously in vWD
type 2B because it shows low efficacy and might aggravate thrombocytopenia: infu-
sion time can be prolonged to 60 min. Desmopressin has no effect in type 3 patients.
VWD type 3 is treated by substitution with a vWF/FVIII concentrate. The FVIII
component is essential in achieving adequate hemostasis at the beginning of the
treatment. High purity vWF concentrates with very low levels of FVIII, such as
Wilfact®, must initially be given together with an FVIII concentrate because it takes
hours for the endogenous FVIII level to rise after substitution with pure vWF.
Secondary prophylaxis with a vWF concentrate (10–20 IU/kg bw, two to three
times a week) is standard care in type 3 patients with recurrent bleeding
complications.

6.2.2 Fibrinogen Deficiency

Congenital fibrinogen deficiency is a rare bleeding disorder with a prevalence of one

in one million people. Afibrinogenemia and hypofibrinogenemia are quantitative
disorders describing a lack of or reduced fibrinogen, respectively. Fibrinogen is a
soluble protein that is abundant in plasma. It is involved in the final step of the
coagulation cascade: it forms the fibrin clot after enzymatic proteolysis by throm-
bin. Fibrinogen’s mean half-life is about 90 h, and the hemostatic level needed
under physiological conditions is 1.0–1.5 g/l. There is suggestive evidence that
higher levels are needed for a hemostatic effect (1.5–2.0 g/l) in conditions such as
trauma coagulopathy or postpartum hemorrhage.
Complete absence of fibrinogen causes a clinical phenotype with pronounced
bleeding complications, and the majority of those affected show bleeding episodes
from birth, with umbilical bleeding, and later with gastrointestinal and urogenital
6 Congenital Bleeding Disorders 77

hemorrhages. Patients with hypofibrinogenemia on the other hand do not bleed

spontaneously, but often show postoperative bleeding complications.
In addition to the quantitative fibrinogen disorders, dysfibrinogenemia, a qualita-
tive fibrinogen defect, has also been described. About 50 % of these patients are
asymptomatic, a quarter shows bleeding tendency, and about 20 % interestingly
present with thrombophilia. The exact pathophysiological mechanism of this higher
risk for thrombosis is not clear. Several mechanisms are postulated. One possible
explanation is that an impaired binding of thrombin to fibrinogen causes higher
circulating levels of thrombin, which in turn activate platelets and lead to a proco-
agulant state. Another possible explanation is a disturbance in fibrinolysis due to
defects of the fibrinogen molecule.

Laboratory Findings
Afibrinogenemia is characterized by prolonged aPTT, PT, and thrombin clotting
times. No detectable fibrinogen can be found. Hypofibrinogenemia has mostly nor-
mal global tests and variably decreased levels of functional fibrinogen.
Dysfibrinogenemia has decreased functional fibrinogen, but normal protein values
in the immunological assays.

Treatment of Fibrinogen Deficiency

Normally, most patients with hypofibrinogenemia or dysfibrinogenemia do not need
prophylactic treatment, and substitution should be given only when necessary. In
case of invasive procedures or surgery, fibrinogen levels should be corrected to nor-
mal by substitution with a fibrinogen concentrate. Caution is needed in cases of
dysfibrinogenemia because overdosing can cause thrombotic complications.
Patients with afibrinogenemia should receive regular secondary prophylaxis of
substitution with a fibrinogen concentrate once every 1 or 2 weeks. Traditionally,
the minimal level of fibrinogen required to prevent spontaneous bleeding had been
placed at 1.0–1.5 g/l. There is increasing suggestive evidence from observations of
coagulopathy in trauma that this level should be corrected to 1.5–2.0 g/l, depending
on the situation.
In cases with menorrhagia, antifibrinolytic treatment and/or hormonal treatment
may prove useful.
FFP is not a good source for fibrinogen, but it could be used in cases of a lack of
concentrates or when additional natural coagulation proteins and enzymes are
needed.

6.3 Sex-Linked Recessive Disorders

6.3.1 Hemophilia A (Factor VIII Deficiency)

Hemophilia A is a deficiency in FVIII and is the most common type of hemophilia.

FVIII is a complex plasma protein that is mostly synthesized in the hepatocytes and
circulates in a non-covalent complex with vWF. The prevalence of hemophilia A
78 M. Martinez et al.

Table 6.5 Severity of hemophilia A or B

Percentage of factor VIII International units per
Level or IX activity in plasma (%) milliliter of whole blood (IU)
Normal 50–150 0.5–1.5
Mild hemophilia 6–40 0.06–0.4
Moderate hemophilia 1–5 0.01–0.05
Severe hemophilia <1 <0.01

varies in different countries: it ranges from 0.7 to 1.3 in 10,000 people. FIX defi-
ciencies, or hemophilia B, are rarer, with a prevalence of 1 in 50,000 people.
Factor VIII or IX levels in hemophilia are found to be below 50 % and are clas-
sified in three severity groups (severe, moderate, and mild). Classification is based
on the factor concentration, reflecting the clinical phenotype (Table 6.5). Mild
hemophilia often only first presents as a bleeding episode after trauma or surgery.
Severe hemophilia often presents as a bleeding tendency when a child starts to walk
or sometimes days after birth. The severity of bleeding correlates very well with the
factor level measured. Spontaneous muscle and joint bleeding (specially the ankles,
knees, and elbows) is typical for the severe form of hemophilia. A tentative explana-
tion for joint bleeding in hemophilia is the fact that soft tissues in the joints express
very low levels of tissue factor, a protein which is crucial in the initiation of the
coagulation cascade.

Laboratory Findings
Hemophilia A has normal PT/INR, prolonged aPTT, reduced FVIII activity in the
specific assay, and normal bleeding time.

Treatment of Hemophilia A
Substitution with the missing protein is the modern mainstay of hemophilia A treat-
ment. Primary or secondary prophylaxis with regular substitution, two to four times
a week, is a common mode of application. Prophylaxis begins in the first year of life
and continues throughout adulthood. Regular prophylaxis has been shown to protect
from chronic joint arthropathy and acute bleeding. In case of invasive procedures,
surgery, or trauma, a more intensive substitution scheme is chosen. Table 6.6 gives
dosing and target levels of FVIII. About 15–30 % of severe hemophiliacs develop
acquired alloantibodies against FVIII after repeated substitution with FVIII concen-
trates. Special treatment protocols based on immunotolerance induction or immu-
nosuppression are then needed for eradication of the inhibitor.

6.3.2 Hemophilia B (Factor IX Deficiency)

Hemophilia B, the hereditary FIX deficiency, is the second most common form of
hemophilia. FIX is a vitamin K-dependent serine protease synthesized in the liver.
It is activated by FVIIa or FXIa and in its activated form catalyzes the conversion of
factor X to Xa.
6 Congenital Bleeding Disorders 79

Table 6.6 Indicated dosing of factor VIII concentrates in case of bleeding

Type of hemorrhage Desired level (IU/dl) Duration (days)
Joint 40–60 1–2
Superficial muscle 40–60 2–3
Iliopsoas and deep muscle or substantial blood loss
Initial 80–100 1–2
Maintenance 30–60 3–5
Central nervous system
Initial 80–100 1–7
Maintenance 50 8–21
Throat and neck
Initial 80–100 1–7
Maintenance 50 8–14
Gastrointestinal
Initial 80–100 1–6
Maintenance 50 7–14
Renal 50 3–5
Deep laceration 50 5–7
Major surgery
Preop 80–100 1–3
Postop 60–80 1–3
40–60 4–6
30–50 7–14
Minor surgery
Preop 50–80
Postop 30–80 1–5
Adapted from the World Federation of Hemophilia guidelines

The prevalence of congenital FIX deficiency varies in different regions of the

world, with 1.2–2.7 per 100,000 people. The clinical phenotype of hemophilia B
does not differ from that of hemophilia A. Bleeding appears very early in life and
mostly affects joints or muscles. Classification according to severity is the same as
for hemophilia A.

Laboratory Findings
Hemophilia B has normal PT/INR, prolonged aPTT, reduced FIX activity in the
specific assay, and normal bleeding time.

Treatment of Hemophilia B
Substitution with FIX concentrates in episodes of bleeding or suspected bleeding is
the mainstay of treatment for hemophilia B (Table 6.7). In severe forms, primary or
secondary prophylaxis with substitution is recommended two to three times a week.
Because FIX has a longer half-life than FVIII, it can be given at longer intervals.
After repeated substitution with concentrates, about 3–5 % of severe hemophilia B
patients develop acquired alloantibodies against FIX. Special treatment protocols
based on immunotolerance induction or immunosuppression are then needed to
eradicate the inhibitor.
80 M. Martinez et al.

Table 6.7 Indicated dosing of factor IX concentrates in case of bleeding

Type of hemorrhage Desired level (IU/dl) Duration (days)
Joint 40–60 1–2
Superficial muscle 40–60 2–3
Iliopsoas and deep muscle or substantial blood loss
Initial 60–80 1–2
Maintenance 30–60 3–5
Central nervous system
Initial 60–80 1–7
Maintenance 30 8–21
Throat and neck
Initial 60–80 1–7
Maintenance 30 8–14
Gastrointestinal
Initial 60–80 1–6
Maintenance 50 7–14
Renal 40 3–5
Deep laceration 40 5–7
Major surgery
Preop 60–80 1–3
Postop 40–60 1–3
30–50 4–6
20–40 7–14
Minor surgery
Preop 50–80
Postop 30–80 1–5
Adapted from guidelines of the World Federation of Hemophilia

6.4 Autosomal Recessive Bleeding Disorders

6.4.1 Factor II (Prothrombin) Deficiency

Prothrombin is a vitamin K-dependent factor, synthesized in the liver and activated

through factor Xa. The active form of prothrombin is thrombin. Thrombin plays a
pivotal role, converting fibrinogen to fibrin, simultaneously activating platelets as
well as the natural coagulation inhibitor, protein C. It is therefore a crucial element
in the regulation of the coagulation system.
Hereditary prothrombin deficiency is a rare disorder with a prevalence of about
one in two million people, and it is inherited in an autosomal recessive manner. Two
different phenotypes can be distinguished: type 1 presenting as hypoprothrombin-
emia and type 2 as dysprothrombinemia. The former shows lower antigen and activ-
ity levels, whereas the latter may reach normal levels of prothrombin antigen, but is
dysfunctional. Depending on the severity of the deficiency, the affected patients
may show spontaneous bleeding or suffer provoked hemorrhages. In general, slight
bleeding episodes such as epistaxis, gum bleeding, or menorrhagia predominate.
About 40 % of the normal FII level is necessary for adequate hemostatic function,
although the factor level does not always correlate with the bleeding tendency.
6 Congenital Bleeding Disorders 81

Laboratory Findings
Factor II deficiency exhibits prolonged aPTT and PT/INR, normal bleeding time,
and reduced FII levels in the specific assay.

Treatment
Treatment consists of on demand substitution with FII concentrates. These are
available in the form of four-factor prothrombin complex concentrates (4fPCC,
Prothromplex®, Beriplex®, Octaplex®), containing FIX, FX, and FVII in addition to
FII. If these are not available, FFP can also be used as a source of FII, if appropri-
ately dosed (10 ml/kg BW).

6.4.2 Factor V Deficiency

The incidence of FV deficiency is estimated at one in one million people and is

phenotypically almost exclusively inherited as a type 1 deficiency (activity and anti-
gen are lower in parallel). FV is a protein synthesized in the liver and acts as a cofac-
tor in the prothrombinase complex. This complex activates prothrombin into
thrombin. About 80 % FV circulates in plasma, and 20 % is stored in the alpha
granules of platelets. The origin of the FV found in the platelets is not yet well
understood. It is known that megakaryocytes are able to acquire FV by endocytosis,
as well as synthesize FV. The required level of the protein in plasma for an adequate
hemostatic effect is about 40 %. Only some of the affected patients with a heterozy-
gous mutation show a clinically increased bleeding tendency with epistaxis, menor-
rhagia, or mucosal bleeding. Bleeding complications occur mostly as provoked
events after surgery or invasive diagnostic procedures. The homozygous form pres-
ents with spontaneous bleeding and an increased tendency of hematoma, as well as
joint and muscle bleeding.
The severity of the bleeding does not correlate well with the plasma protein level.

Laboratory Findings
Factor V deficiency exhibits prolonged PT/INR and aPTT, normal bleeding time,
and decreased FV activity in the specific assay.

Treatment
Treatment consists in substituting FV on demand. As there is no FV concentrate avail-
able, FFP is the only source. FV is an unstable protein even under proper storage condi-
tions. Retention values of FFP after thawing give no more than 60 % of FV activity
with respect to the original material before deep freezing. Alternatively, recombinant
activated factor VII (rFVIIa, NovoSeven®) could be used off-label for hemostasis.

6.4.3 Combined Deficiency of Factors V and VIII

The incidence of this defect is about one in two million people. The genetic defect
which causes this combined factor deficiency affects the transport system between
82 M. Martinez et al.

the endoplasmic reticulum and the Golgi apparatus of factor-producing cells.

Postsurgical and mucosal bleeding are the most common clinical presentations;
spontaneous muscle and joint bleeding is not usual.

Laboratory Findings
PT and aPTT are prolonged. Isolated reduction in factor V and VIII activities is
found in the specific assay.

Treatment
Depending on the severity of the deficit, FVIII concentrates and FFP can be used. In
mild bleeding, antifibrinolytics may also be an alternative.

6.4.4 Factor VII Deficiency

The congenital FVII deficiency is the most frequent of the rare bleeding disorders
(30 %). The prevalence of its severe form (FVII <2 %) is estimated to be about 1 in
500,000 people. The clinical phenotype presents a wide spectrum of bleeding from
mucosal to intracranial hemorrhages. The minimum FVII level required for an
adequate hemostatic effect is 10–15 %.

Laboratory Findings
Factor VII deficiency exhibits prolonged PT/INR, normal aPTT, and low FVII
activity levels in the specific assays.

Treatment
Factor VII concentrates can be used for substitution in cases of bleeding (high purity
FVII, recombinant FVIIa, or 4fPCC). Preferably nonactivated forms of concentrates
should be used. In heterozygous deficiencies, no substitution is normally required
even in case of surgery, since levels of FVII in these cases range from 20 to 50 %.
Caution is required in cases of potential vitamin K deficiency, where FVII can soon
reach inappropriately low levels. Although its elimination half-life of 5 h is short, a
less frequent substitution scheme turns out to be adequate even in case of surgery.
In severe cases, especially in children, prophylactic substitution can be given
three times a week.

6.4.5 Combined Deficiency of the Vitamin K-Dependent

Clotting Factors

In this combined deficiency, the defect is situated in the enzyme responsible for the
gamma-glutamyl carboxylation of the coagulation factors. Vitamin K acts as cofac-
tor for gamma-glutamyl carboxylase. Carboxylation takes place in the liver and
enables specific proteins to bind calcium. This step is essential for the coagulation
enzymes to anchor on the coagulation-active phospholipids of platelets and cell
membranes. Affected patients not only have low levels of procoagulant factors II,
6 Congenital Bleeding Disorders 83

VII, IX, and X but also of the natural coagulation inhibitors, proteins C and S.
Clinically, this bleeding disorder manifests itself early in life, with umbilical cord
bleeding and central nervous system hemorrhages.

Laboratory Findings
This combined deficiency exhibits prolonged PT/INR and aPTT and low levels of
FII, FVII, FIX, FX, and proteins C and S.

Treatment
Treatment consists in on demand substitution of the missing coagulation proteins
using a concentrate. Four-factor PCC products are used for this purpose
(Prothromplex®, Beriplex®, Octaplex®). High doses of vitamin K in adults (1 × 10–15
mg daily) orally or intravenously might also lead to a partial increase of the factor
levels and prevent major bleeding. If not otherwise possible, fresh frozen plasma
(FFP) can be used as a source of FII, FVII, FIX, and FX. Depending on the severity
of the clinical phenotype, a secondary chronic prophylaxis with high-dose vitamin
K or four-factor PCC might be considered.

6.4.6 Factor X Deficiency

Congenital FX deficiency affects one in one million people. FX is synthesized in the

liver and is physiologically activated by the complex tissue factor/FVIIa or FIXa/
FVIIIa, so that thrombin can subsequently be generated. FX deficiency is ranked
among the most severe of the rare coagulation defects. We can differentiate type 1
with low antigen and activity levels and type 2 with an almost normal antigen level,
but lower antigen activity.
Bleeding complications begin early in life, with umbilical cord and central ner-
vous system bleeding. Other common presentations are muscle and joint bleeding,
bleeding in the gastrointestinal tract, and menorrhagia.

Laboratory Findings
Prolonged PT/INR and aPTT and low factor X activity.

Treatment
Treatment consists in FX substitution using a concentrate. There are no high-purity
FX concentrates available. Four-factor PCC products are used for this purpose
(Prothromplex®, Beriplex®, Octaplex®). Alternatively, a combined FIX/FX product
can be used (Factor IX/X Behring®). If these are not available, FFP can be used as a
source of FX. Treatment can be combined with antifibrinolytics.

6.4.7 Factor XI Deficiency

Factor XI is a serine protease synthesized in the liver. In plasma, it forms a complex

with high molecular weight kininogen, which protects it from degradation while in
84 M. Martinez et al.

circulation. Thrombin activates FXI. The activated FXIa further catalyzes the acti-
vation of FIX.
The majority of people affected by FXI deficiency have a low but detectable FXI
level. The severity of bleeding, however, does not correlate with the factor levels
measured. Bleeding manifests itself as mucosal or surgical bleeding. Joint or mus-
cle bleeding is not common at all. FXI deficiency is the second most common bleed-
ing disorder in women after vWD.

Laboratory Findings
FXI deficiency exhibits prolonged aPTT, normal PT/INR, and low FXI levels in the
specific assays.

Treatment
Treatment consists of substitution with FXI concentrate (Hemoleven®). Dosing
should be calculated cautiously, because overdosing or even correction to high nor-
mal levels can cause thrombotic complications. FFP may be used as an alternative
source for FXI. Treatment may be combined with antifibrinolytics.

6.4.8 Factor XII Deficiency

Congenital deficiency of FXII is not associated with bleeding, so that it is not con-
sidered a hemorrhagic disorder. On the contrary, there is suggestive evidence that it
might cause a tendency to thrombosis, since FXII is involved in the activation of the
complement pathway and of fibrinolysis.

Laboratory Findings
Factor XII deficiency exhibits normal PT/INR, prolonged aPTT, and reduced levels
of FXII activity in the specific assays.

Treatment
There is currently no recognized indication for FXII substitution.

6.4.9 Factor XIII Deficiency

FXIII is an additional factor in the coagulation cascade; present as a proenzyme in

plasma, it is activated by calcium and thrombin. Activated FXIIIa, a transglutamin-
ase, catalyzes the cross-linking between the fibrin monomers and turns them into
fibrin; it also protects fibrin clots from fibrinolysis by incorporating antiplasmin and
other factors into the structure.
Congenital FXIII deficiency in its severe form (FXIII activity <5 %) is rare and
manifests as a severe bleeding disorder. Furthermore, it is the hereditary bleeding
disorder with the highest incidence of central nervous system hemorrhages (30 %):
affected patients show hematomas, muscle bleeding, and delayed postsurgical hem-
orrhages. The occurrence of umbilical cord bleeding is 80 %.
6 Congenital Bleeding Disorders 85

At FXIII activity levels below 60 %, there is suggestive evidence of correlation

with intra- and postoperative bleeding. Bleeding in these patients can be prevented
after correction of the deficiency with substitution of FXIII.

Laboratory Findings
FXIII deficiency exhibits normal PT/INR and activated aPTT and low levels of
FXIII activity and antigen in the specific assays.

Treatment
Treatment consists of FXIII substitution on demand using a FXIII concentrate
(Fibrogammin®). A single dose of 1,250 IE is usually sufficient for a long-lasting
effect since the protein’s elimination half-life is long (72 h). In severe cases, regular
secondary prophylaxis may be required every 4–6 weeks.

6.4.10 Glanzmann’s Thrombasthenia

Glanzmann’s thrombasthenia is an inherited platelet disorder caused by a congenital

deficiency of the fibrinogen receptor on the platelet surface (GP IIb/IIIa). It has a
prevalence of one in one million in the general population. Although each compo-
nent of this integrin is genetically coded by a different chromosomal locus, lack of
expression of one component, either IIb or IIIa, causes deficiency of the whole
receptor on the platelet surface. GP IIb/IIIa is essential for the last step of platelet
aggregation and formation of the platelet thrombus using fibrinogen as a ligand.
Lack of GP IIb/IIIa mostly causes mucocutaneous bleeding (usually provoked) and
less often muscle or joint bleeding. Three levels of severity have been described:
type 1 with <5 % of GP IIb/IIIa, type 2 with 10–20 % of GP IIb/IIIa, and type 3 with
normal but nonfunctional GP IIb/IIIa.

Laboratory Findings
Glanzmann’s thrombasthenia exhibits normal PT/INR and aPTT, but prolonged BT.
In platelet aggregation assays, it shows a specific pattern in the responsiveness of
platelets to various agonists. Using flow cytometry, it shows a loss or severe reduc-
tion of GP IIb/IIIa density on platelets.

Treatment
The most efficient treatment for this disorder is transfusion of normal platelets.
However, this may cause rare transfusion-associated adverse events, such as the gen-
eration of iso- or alloantibodies against GP IIb/IIIa. Although the risk of alloimmuniza-
tion has clearly been reduced since the introduction of leukocyte filtration and
single-donor thrombocytapheresis in transfusion medicine, platelet transfusions should
be avoided if possible. Very often, surgery cannot be performed on these patients with-
out platelet transfusion. In such cases, human leukocyte antigen-compatible products
should be chosen, and the number of transfusions should be kept to a minimum periop-
eratively. Antifibrinolytics combined with rFVIIa (NovoSeven®) are successfully used
in mild or moderate bleeding. Desmopressin might also help in case of mild bleeding.
86 M. Martinez et al.

6.4.11 Bernard-Soulier Disease

Bernard-Soulier disease (BSD) is an inherited platelet disorder caused by a con-

genital deficiency of the vWF receptor on the platelet surface (GP Ib/V/IX).
Prevalence in the general population is less than one in one million. Although each
component of this integrin is genetically coded by different chromosomal loci, lack
of expression of either component Ib or IX causes total deficiency of the receptor on
the platelet surface. GP Ib/V/IX is essential for the first steps of platelet adhesion
and aggregation using vWF as a ligand to bind to other platelets or to endothelial
cells. Additionally, lack of GP Ib/IX causes loss of symmetry of the platelet mem-
brane leading to large platelets and mild thrombocytopenia. The clinical picture
involves mucocutaneous bleeding (usually provoked), menorrhagia, and less often
muscle or joint bleeding.

Laboratory Findings
BSD exhibits normal PT/INR, normal aPTT, prolonged BT, and thrombocytopenia
with large platelet volume (MPV >10 fl). Platelet aggregation assays show a specific
pattern in the responsiveness of platelets to various agonists. Using flow cytometry,
it shows loss or severe reduction of GP Ib/IX density on platelets.

Treatment
The most efficient treatment of BSD is transfusion of normal platelets. However, this
might cause rare transfusion-associated adverse events, such as iso- or alloantibodies
against GPIb/IX. Although the risk of alloimmunization has clearly been reduced
since the introduction of leukocyte filtration and single-donor thrombocytapheresis
in transfusion medicine, platelet transfusions should be avoided if possible. Very
often surgery cannot be performed on these patients without platelet transfusion. In
such cases, human leukocyte antigen-compatible products should be chosen, and the
number of transfusions should be kept to a minimum perioperatively. Antifibrinolytics,
along with rFVIIa (NovoSeven®), are successfully used in mild or moderate bleed-
ing. Desmopressin might also help in case of mild bleeding.

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Acquired Hemostatic Disorders
7
Stefano Barelli, Sabine Blum, and Anne Angelillo-Scherrer

7.1 Introduction

Hemostatic disorders may be inherited or acquired. Acquired hemostatic disorders

comprise thrombocytopenia and platelet dysfunction, coagulation factor deficien-
cies, excessive anticoagulation, and hemorrhagic complications due antiplatelet
drugs, anticoagulation, and thrombolysis. Blood disorders associated with myelo-
proliferative neoplasms and disseminated intravascular coagulation (DIC) can cause
both bleeding and thrombosis. Heparin-induced thrombocytopenia (HIT), antiphos-
pholipid antibody syndrome, and thrombotic microangiopathies are conditions that
cause thrombocytopenia, but they are more frequently responsible for thrombosis
than for bleeding (Fig. 7.1). The present chapter focuses on acquired disorders
(congenital coagulopathies are presented in Chap. 6). Antiplatelet and anticoagulant
drug complications are presented in Chap. 8.

7.2 Thrombocytopenia

7.2.1 Acquired Thrombocytopenia

Acquired thrombocytopenia is the most common cause of thrombocytopenia. In the

absence of a platelet function disorder, spontaneous bleeding may occur when the
platelet count is <10–20 G/L of blood. Thrombocytopenia may result from decreased
platelet production in cases of bone marrow infiltration by neoplastic cells, acute
alcohol toxicity, infections, and vitamin B12 or folate deprivation. It may also be
drug induced. Thrombocytopenia can be isolated or part of a more general process
such as bone marrow failure, acute leukemia, DIC, chronic liver disease, or

S. Barelli • S. Blum • A. Angelillo-Scherrer (*)

Service of Hematology, Lausanne University Hospital (CHUV),
CH-1011 Lausanne, Switzerland
e-mail: [email protected]; [email protected]; [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 89

DOI 10.1007/978-3-642-55004-1_7, © Springer-Verlag Berlin Heidelberg 2015
90 S. Barelli et al.

Thrombotic microangiopathy
Early stage liver disease
Dilution Drugs
Antiphospholipid antibodies
DIC HIT
Vitamin K defect
Hemorrhage ITP
Anticoagulation
Cirrhosis Sepsis
Inflammation
Hypersplenism

Coagulopathy Thrombocytopenia

Fig. 7.1 The critically ill patient. DIC disseminated intravascular coagulation, HIT heparin-
induced thrombocytopenia, ITP immune thrombocytopenia

thrombotic microangiopathy. The causes of thrombocytopenia can be classified by

taking into account the clinical setting, such as outpatient versus inpatient
(Table 7.1).
HIV infection often results in thrombocytopenia, and immune thrombocytopenia
(ITP) occurs in about 40 % of HIV-infected patients and 2.6 % of hepatitis C
patients. Thrombocytopenia is a common feature of sepsis, where it probably results
from a combination of impaired platelet production and platelet consumption.
Primary ITP is an autoimmune disorder and the most common cause of isolated
thrombocytopenia. Thrombocytopenia is caused by autoantibodies, directed against
platelet antigens, which increase the clearance of circulating platelets and decrease
platelet production by bone marrow megakaryocytes. Bleeding symptoms such as
intracranial hemorrhage are uncommon except in severe ITP. First-line therapy is
usually given when platelet counts are <30–50 G/L; it consists of glucocorticoid
therapy at 1 mg/kg/day and/or intravenous immunoglobulins at 2 g/kg for 2–5 days
(Provan et al. 2010). Tranexamic acid – an antifibrinolytic drug – may be adminis-
tered together with a platelet transfusion, particularly when bleeding occurs at the
mucosal level. Splenectomy, rituximab, and thrombopoietin receptor agonists are
second-line therapies.
Drug-induced thrombocytopenia is common and may be caused by marrow sup-
pression as well as immune or nonimmune thrombocytopenia. A list of potentially
offending drugs can be found on http://www.ouhsc.edu/platelets/ditp.html. In
immune-mediated drug-induced thrombocytopenia, platelet counts recover
promptly after treatment interruption, usually 5–10 days after the withdrawal of the
drug (Stasi 2012). The correct diagnosis is a challenge when the substance causing
the thrombocytopenia is not a drug but is in a beverage, food, or herbal remedy
(Stasi 2012). Glucocorticoid therapy 1 mg/kg/day is administered when platelets
are <10 G/L and if bleeding is not severe. In case of severe bleeding, treatment
7 Acquired Hemostatic Disorders 91

Table 7.1 Causes of thrombocytopenia with regard to the clinical setting

Outpatients
ITP
Drug-induced thrombocytopenia
Infections (HIV, hepatitis C, CMV, other recent viral infections, Helicobacter pylori)
Hypersplenism
Autoimmune disorders
Hematological malignancies
Bone marrow failure
Chemotherapy-induced thrombocytopenia
Chronic DIC
Inherited thrombocytopenia
Common variable immunodeficiency
Inpatients
Inpatients in ICU or with multisystemic illness
Infections
Drug-induced thrombocytopenia
Acute or chronic DIC
Liver disease
HIT
Bone marrow disorders, including hematological malignancies
TTP/HUS
Macrophage activation syndrome
Chemotherapy-induced thrombocytopenia
Dilutional thrombocytopenia
Posttransfusion purpura
Inpatients with cardiac disease
HIT
Cardiopulmonary bypass
Intra-aortic balloon pump/ECMO
GPIIb/IIIa inhibitors
Other drug-induced thrombocytopenia
Dilutional thrombocytopenia
Patients in the emergency department
ITP
Drug-induced thrombocytopenia
Alcohol toxicity
Bone marrow disorders
DIC
Liver disease
Chemotherapy-induced thrombocytopenia
TTP/HUS
Pregnancy/postpartum patients
Gestational thrombocytopenia
ITP
HELLP syndrome
Preeclampsia
Abruptio placentae
TTP/HUS
Adapted from Aird and Mark (2002), Stasi (2012)
ITP immune thrombocytopenia, DIC disseminated intravascular coagulation, HIT heparin-induced
thrombocytopenia, TTP/HUS thrombotic thrombocytopenic purpura/hemolytic uremic syndrome,
ECMO extracorporeal membrane oxygenation, HELLP syndrome hemolysis, elevated liver
enzymes, and low platelets
92 S. Barelli et al.

combines platelet transfusion with intravenous immunoglobulins and high-dose

glucocorticoids. Patients often suffer from petechial hemorrhages and urinary or
gastrointestinal tract bleeding. Intracranial bleeding is rare.
GPIIb/IIIa inhibitors are antiplatelet agents that may also induce thrombocyto-
penia (see Chap. 8). HIT is detailed below (Sect. 7.2.2). Emergency surgery in the
context of thrombocytopenia can be performed if a platelet transfusion is provided
immediately before surgery. If necessary, additional platelet concentrates can be
administered during and after surgery. When appropriate, specifically if the surgi-
cal procedure involves mucosae, the treatment can be completed with tranexamic
acid.

7.2.2 Heparin-Induced Thrombocytopenia

HIT is a “clinical-pathological syndrome” occurring during heparin therapy. HIT is

caused by IgG antibodies that bind platelet receptors and recognize PF4-heparin
complexes. Because the IgG antibodies activate platelets and induce platelet clear-
ance, they are responsible for a decrease in platelets and a prothrombotic state dur-
ing heparin therapy. Previous exposure to unfractionated heparin (UFH) and, less
frequently, to low-molecular-weight heparin (LMWH) is necessary for the initiation
of the process.
Few patients with suspected HIT have true HIT. The diagnosis requires a clear
clinical picture and laboratory confirmation of platelet-activating antibodies. Even
if anti-PF4-heparin antibodies are easily detectable using enzyme immunoassays
(EIAs), only a minority of these antibodies are truly platelet activating, respecting
an “iceberg model”; these platelet-activating properties are best detected by activa-
tion or aggregation assays.
The following steps are recommended to avoid overdiagnosing HIT (Warkentin
2011):
• Assessment of pretest probability with the 4Ts scoring system: the score is a
simple clinical tool to help decide whether further investigation and a change of
anticoagulation is appropriate (Table 7.2).
• Laboratory testing: this should be ordered only if the 4Ts score is intermediate
or high. EIAs are widely available and highly sensitive, but not sufficiently spe-
cific for platelet-activating antibodies. All positive EIA results need to be con-
firmed by activating or aggregation assays (serotonin-release assay or
heparin-induced platelet activation test).
One mainstay of HIT treatment is the discontinuation of all forms of heparin
treatment and the administration of an alternative anticoagulant. Anti-vitamin K
anticoagulants (AVK) are contraindicated as an initial treatment due to their tran-
sient procoagulant properties (reduction of protein C level). Half of those individu-
als identified as having HIT concomitantly face the risk of a thrombosis; therefore,
an ultrasound screening of the lower limbs is recommended. The risk of thrombosis
remains elevated for at least 30 days after heparin therapy and as long as the platelet
count has not returned to the normal range.
7 Acquired Hemostatic Disorders 93

Table 7.2 4T pretest HIT scoring system

4Ts 2 points 1 point 0 points
Thrombocytopenia PC fall >50 % and PC fall 30–50 % or platelet PC fall
platelet nadir ≥20 × 109/l nadir 10–19 × 109/l <30 % and
platelet nadir
<10 × 109/l
Timing of platelet Clear onset between Consistent with 5–10 days fall PC fall
count fall days 5–10 or PC fall but not clear (e.g., missing PC); <4 days
≤1 day (prior heparin onset after day 10; or fall without
exposure within 30 ≤1 day (prior heparin exposure recent
days) 30 –100 days ago) exposure
Thrombosis or other New thrombosis Progressive or recurrent None
sequelae (confirmed); skin thrombosis: non-necrotizing
necrosis; acute ischemic (erythematous) skin lesions;
reaction post suspected thrombosis (not
intravenous UFH bolus proved)
Other causes for None apparent Possible Definite
thrombocytopenia
Adapted from Lo et al. (2006)
Pretest score 6–8 = high probability, 4–5 = intermediate probability, 0–3 = low probability
PC platelet count, UFH unfractionated heparin

• There are two alternative classes of anticoagulants for HIT treatment:

(1) Antithrombin-dependent activated factor X (Xa) inhibitors, such as sodium
danaparoid. Anticoagulant activity can be easily monitored by anti-Xa activ-
ity measurement. Their long half-life is a disadvantage in perioperative
contexts.
(2) Direct thrombin inhibitors, such as argatroban, have a short half-life.
Monitoring can be performed by measuring activated partial thromboplastin
time and specific antithrombin (IIa) activity.
Before hematological referral, the following aspects should be assessed
(Warkentin 2011):
1. The overall likelihood of HIT.
2. The indication for therapeutic anticoagulation.
3. The renal/hepatic function.
4. The type of surgical procedure planned.
Further reading on HIT management can be found in (Selleng et al. 2007) and in
the Clinical Practice Guideline on the management of HIT on www.hematology.
org/practice/guidelines.

7.3 Acquired Platelet Dysfunction

Whereas inherited platelet dysfunction is rare, acquired platelet dysfunction is com-

mon. Platelet function may be affected by drugs, such as antiplatelet drugs or anti-
depressants, or by systemic disorders like uremia, liver failure, and myelodysplastic
or myeloproliferative disorders.
94 S. Barelli et al.

In case of bleeding, platelet transfusion may be required. Desmopressin is a

vasopressin analog that favors release of von Willebrand factor (vWF) from tissue
stores (mainly endothelial cells) and may be used in acquired platelet disorders such
as uremia. Desmopressin is administered at the dose of 0.3 μg/kg, intravenously in
50 mL of saline over 30 min or subcutaneously (Mannucci and Tripodi 2012).
Recombinant activated factor VII (rFVIIa) may be used in the context of hemor-
rhagic complications (Franchini et al. 2008).

7.4 Acquired Multifactorial Deficiencies

Acquired multifactorial deficiencies are common and may result from vitamin K
deficiency, liver disease, or DIC.

7.4.1 Vitamin K Deficiency

A lack of vitamin K impairs posttranslation γ-carboxylation of vitamin K-dependent

proteins: factors II, VII, IX, and X, as well as proteins C, S, and Z. Vitamin K defi-
ciency is frequent in neonates, to whom it should be provided systematically to
prevent bleeding. In adults, vitamin K deficiency is mainly due to malabsorption as
well as vitamin K metabolism impairment by VKA, antibiotics, or rodenticides.

7.4.2 Chronic Liver Disease

The hemostatic process is a complex interplay between the endothelium, platelets,

coagulation factors, and the fibrinolytic system. It is balanced by prohemostatic and
antihemostatic drivers; however, in chronic liver disease (CLD), this balance is
altered (Fig. 7.2) (Lisman and Leebeek 2007). Most procoagulant factors decrease
in parallel to the anticoagulant factors (Tripodi and Mannucci 2011). Thrombin –
the pivotal factor of coagulation – is synthesized in amounts comparable to healthy
subjects, but its generation is reduced by thrombocytopenia. In CLD, prohemostatic
factors that are not exclusively synthesized by the liver have unusually high levels
(vWF, which restores platelet adhesion to endothelium, and factor VIII, which
drives thrombin generation). Tissue plasminogen activator levels are increased due
to enhanced release by activated endothelium and/or by decreased hepatic
clearance.
In CLD, simple defects are the result of complex pathological processes (Lisman
and Leebeek 2007; Roberts et al. 2010):
• Thrombocytopenia: reduced megakaryopoiesis (reduced thrombopoietin, coin-
fection, alcohol abuse, folate deficiency, and medication), splenic sequestration,
viral infections, primary biliary cirrhosis, or DIC
• Defective platelet function: acquired storage pool defect, defective transmem-
brane signal transduction, decreased levels of functional platelet receptors, or
reduced hematocrit, and dyslipidemia
7 Acquired Hemostatic Disorders 95

Qualitative
defects of
fibrinogen
and
platelets

Parallel decrease
Endothelium
of
Platelets Elevated vWF
procoagulant
Coagulation Elevated FVIII
and
Fibrinolysis
anticoagulant
factors

Classic
comorbidities
and
complications
of CLD

Fig. 7.2 Hemostasis in chronic liver disease (CLD). vWF von Willebrand factor, FVIII factor VIII

• Low or defective coagulation factors: reduced hepatic synthesis function, vita-

min K deficiency, DIC, dysfunctional circulating fibrinogen, and altered fibrin
polymerization due to excessive sialic acid content
In CLD, the laboratory pattern sometimes resembles the DIC pattern, but DIC
should always be suspected in the presence of a trigger (e.g., sepsis) with evolving
hemostatic abnormalities (consumption of factors and platelets).

7.4.2.1 Management
The correction of a coagulopathy in a non-bleeding patient is not required (Roberts
et al. 2010; Gines et al. 2012). Conservative measures such as vitamin K substitu-
tion are recommended for the optimization of hemostasis in CLD. Predicting bleed-
ing complications in CLD patients is challenging. The clinician should base her/his
evaluation on three indicators:
1. Patient
The majority of hemorrhages are due to the rupture of portosystemic varices
(Lisman and Leebeek 2007). Bacterial infections, vitamin K deficiency (low
dietary intake, loss of intestinal bacterial flora after antibiotherapy, intra-/extra-
hepatic cholestasis), and renal failure increase the tendency to bleed.
96 S. Barelli et al.

2. Laboratory values
Current routine coagulation tests offer only limited help in the proper evalua-
tion of the state of hemostatic balance in CLD (Tripodi and Mannucci 2011). For
example, a prolonged prothrombin time (PT) does not necessarily indicate that
the CLD patient is naturally anticoagulated, and a borderline PT could underes-
timate the risk of bleeding. Emerging global coagulation tests better reflect the
interplay of all the factors involved in hemostasis (thrombin generation tests,
thromboelastography) (Roberts et al. 2010).
3. Type of bleeding or surgery
Acute variceal bleeding is mainly the consequence of anatomical changes
and depends on the Child-Pugh score and endoscopic features. It is best treated
with fluid resuscitation, pharmacological treatment, and endoscopy. For elec-
tive surgical procedures (paracentesis, central venous catheter insertion, or
liver biopsy), the potential need for transfusion must anticipated. Transfusions
should target a hemoglobin level of >70–80 g/l and platelet counts >50 G/L.
Prophylactic transfusion of fresh frozen plasma (FFP) is associated with a risk
of volume overload, infection, and transfusion-related acute lung injury
(TRALI). This makes the use of prothrombin complex concentrates (PCC)
more appropriate. There is no advantage to using recombinant FVIIa (Bosch
et al. 2008).

7.4.3 Disseminated Intravascular Coagulation

DIC is a generalized coagulation process secondary to increased thrombin genera-

tion and fibrin deposition. Microvascular thrombi lead to organ dysfunction.
Consumption of platelets and coagulation factors lead to bleeding (Levi and Ten
Cate 1999; Levi et al. 2002). DIC is a systemic process without a specific anatomi-
cal localization. Due to its bad prognosis, DIC is also known as the acronym for
“Death Is Coming.” Interleukin-6 and tumor necrosis factor-α play pivotal roles in
thrombin generation.
DIC can develop acutely or remain chronic. Acute DIC occurs in patients with
sepsis, after surgery, trauma, or an incompatible blood transfusion, as an obstetrical
complication, or as a complication of acute promyelocytic leukemia. Chronic DIC
is more common in solid malignancies but can also be observed in large aortic
aneurysms.
The principal triggers of DIC are listed below and can be memorized with the
acronym “LAST HOME”:
• Liver failure
• Angiopathy (macro and micro)
• Sepsis/severe inflammation
• Trauma (head trauma, fat embolism, tissue destruction)
• HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets
syndrome)
• Obstetric events (amniotic fluid embolism, abruptio placentae)
7 Acquired Hemostatic Disorders 97

• Malignancies (myeloproliferative neoplasms, solid tumors)

• Exogenous materials (drugs, transfusion products, toxins, prosthetic materials)
DIC is probably the main mechanism underlying thrombocytopenia in intensive care
units. Independent of the severity and the cause of illness, DIC is a marker for severe
homeostatic disturbance and predicts a fatal outcome (Vanderschueren et al. 2000).

7.4.3.1 Diagnosis
DIC is not a disease in itself, but a syndrome (Levi et al. 2002). Several clinical
conditions mimic the hemostatic pattern of DIC. Overall, DIC should be suspected
when a patient presents with:
• An underlying medical or surgical condition compatible with DIC
• Multiple organ failure
• Bleeding and/or thrombotic diathesis
• Thrombocytopenia associated with multiple coagulation factor deficiencies and
hyperfibrinolysis (low fibrinogen, high D-Dimers, fibrin degradation products,
and fibrin monomer levels).
We recommend using the scoring system of the International Society on
Thrombosis and Haemostasis (ISTH) to easily identify overt DIC (Taylor et al.
2001) (Table 7.3).

7.4.3.2 Management
Treatment options should target the cause of DIC and aim to improve the patient’s
condition rather than the laboratory values (Levi et al. 2009; Thachil and Toh 2012;
Wada et al. 2013).
Transfusion of blood components is indicated ONLY during active bleeding or in
periprocedural situations. Target blood component levels are:
• Platelets >50 G/L in case of active bleeding and >20 G/L in patients with a high
risk of bleeding. Platelet concentrates can be administered.
• PT or aPTT <1.5 times the upper limit of the normal range. FFP should be privi-
leged. PCC may be considered in actively bleeding patients if FFP transfusion is
impossible.
• Fibrinogen >1.5 g/l. The administration of fibrinogen concentrate or cryoprecipi-
tate may be recommended in actively bleeding patients with fibrinogen levels
persistently <1.5 g/l despite FFP replacement.

Table 7.3 Diagnosis of disseminated intravascular coagulation (DIC)

0 1 2
PLT [G/L] >100 <100 <50
FBN [g/l] >1 <1
D-dimers [μg/l] <200 200–3,200 >3,200
PT [%] >55 55–40 <40
Adapted from Taylor et al. (2001)
A score >5 indicates overt DIC. An underlying disorder known to be associated with DIC is man-
datory for the use of this score
PLT platelet, FBN fibrinogen, PT prothrombin time
98 S. Barelli et al.

When using anticoagulant drugs, LMWH is preferable to UFH; however, it is worth

noting that there is no direct evidence of the effects of anticoagulants on DIC.
• Therapeutic doses of UFH or LMWH can be considered in cases of DIC with a
predominance of thrombosis.
• Prophylactic anticoagulation with UFH or LMWH is recommended in critically
ill, non-bleeding patients to prevent venous thromboembolism (VTE).
Antifibrinolytic agents (e.g., tranexamic acid) may be beneficial in several DIC pro-
cesses because DIC leads to hyperfibrinolysis. These processes include:
• Trauma if bleeding persists despite FFP transfusion
• Massive postpartum hemorrhage

7.4.3.3 Conclusion
Critically ill patients are at risk of developing DIC, and thus this diagnosis should
be assessed as early as possible.
Platelet count and simple coagulation tests (PT, fibrinogen level, or D-dimers)
are of great value in identifying overt DIC and following its process.

7.5 Acquired Coagulation Factor Deficiencies

Inhibitors are autologous antibodies to coagulation factors that can develop in dif-
ferent clinical circumstances, such as acquired hemophilia A in the peripartum or in
the context of lymphoproliferative neoplasms (alloantibodies only develop in the
context of factor substitution for hemophilia A or B). In theory, it is possible to
develop an inhibitor to any given coagulation factor; however, inhibitors to FVIII
and vWF (see Sect. 7.6) are the most frequent. Patients with acquired FVIII defi-
ciency (also called “acquired hemophilia A”) present a broad spectrum of clinical
signs ranging from superficial bruising to life-threatening bleeding. The incidence
of acquired FVIII deficiency is 1.4/million/year (Collins 2012). The main treatment
consists in treating the underlying clinical problem, if it can be clearly identified, for
example, as a lymphoproliferative syndrome. If this is not possible, in most of the
cases, the hematologist will initiate an immunosuppressive treatment with cortico-
steroids, monoclonal anti-CD20 antibodies (rituximab), or cyclophosphamide, or a
combination of those therapies. However, no treatment will correct the targeted
coagulation factor immediately. Should a surgical procedure be necessary, adequate
hemostasis must be reached using a treatment that bypasses the targeted coagulation
factor. Invasive procedures should thus be avoided when possible. One drug used to
overcome the inhibitors of coagulation factors is rFVIIa (NovoSeven®). It bypasses
factors VIII and IX and directly activates factor X, which then activates prothrom-
bin to thrombin. Another possible bypassing agent is factor VIII inhibitor bypassing
activity (FEIBA®). Both agents seem to have about the same effect on hemostasis
(Baudo et al. 2012). Standardized laboratory assays cannot monitor responses to
either of these agents. The performances of thrombelastography and thrombin gen-
eration, as well as the interpretation of aPTT graphs, are promising indicators, but
are not yet standardized (Pivalizza and Escobar 2008). If neither hemostatic agent
succeeds in stopping the hemorrhagic process, one option for rapid inhibitor
7 Acquired Hemostatic Disorders 99

eradication is immunoadsorption. This technique is neither a standard procedure

nor is it available in most hospitals. Most surgical experience has come from hemo-
philia patients with inhibitors, but bleeding patterns can differ significantly com-
pared to patients with acquired hemophilia and the same aPTT or antibody levels.
The recommended prophylaxis for surgery in patients with FVIII inhibitors is
90–150 μg/kg of rFVIIa every 2–6 h, with increasing time intervals after the first or
second postoperative day. Alternatively, a continuous infusion of 50 μg/kg/h can be
administered (Huth-Kuhne et al. 2009; Baudo et al. 2010), but it must be noted that
no trials have compared continuous and bolus treatment or different dosages.
Following major surgery, the alternative treatment is FEIBA® with a recommended
loading dose of 100 IU/kg followed by 200 IU/kg every 8 h for 3 days and then a
tapering of the daily dose to 150–100 IU/kg for 9–17 days (Tjonnfjord 2004).
Acquired FV inhibitors are rare, with fewer than 200 cases described in the lit-
erature. The resulting tendency to bleed can vary and is not necessarily associated
with residual plasma levels (Franchini and Lippi 2011). Both PT and aPTT are
prolonged. Most cases have been provoked by exposition to bovine thrombin prod-
ucts, which are used in surgery for localized hemostasis, but the condition can occur
in other circumstances (malignancies, autoimmune diseases, etc.). In case of clini-
cal bleeding, platelet transfusion and FFP are the treatments of choice – effective in
about 70–80 % of cases (Ang et al. 2009) – as platelets protect FV from circulating
inhibitors. Some published cases have described the successful use of rFVIIa (Jeimy
et al. 2008; Lebrun et al. 2008; William 2008); others describe plasmapheresis and
immunoadsorption as effective (Tribl et al. 1995; Fu et al. 1996). High-dose intra-
venous immunoglobulins also seem to rapidly increase FV levels (Buclin et al.
1992; de Raucourt et al. 2003).
Acquired FXIII inhibitors have been described. They can occur in patients using
large doses of antibiotics or other drugs, suffering from autoimmune diseases or
monoclonal gammopathies, or even spontaneously (Otis et al. 1974; Milner et al.
1977; Ahmad et al. 1996; Luo et al. 2010). As with all acquired factor deficiencies
due to inhibitors, eradication of the inhibitor would be the ideal treatment for FXIII
inhibitors. In case of bleeding or emergency surgery, treatment options are limited
as FXIII is the last factor in the coagulation cascade stabilizing the fibrin clot.
Replacement therapy with FFP has been tried, but has not been reliably successful.
FXIII concentrate (Fibrogammin®) can increase FXIII levels with doses between 50
and 150 IU/kg (Luo and Zhang 2011), but there have been reports of unsuccessful
results (Miesbach 2005). In one case with severe hemorrhages, rFVIIa and
tranexamic acid were provided in addition to FXIII concentrate (Boehlen et al.
2013). Immunoglobulin infusions take several days to become effective; the same is
true for rituximab treatment, which takes even longer.

7.6 Acquired von Willebrand Syndrome

Acquired von Willebrand syndrome (AvWS) is a rare disorder, but probably more
frequent than we might expect. It is normally associated to an underlying disorder,
such as lymphoproliferative or myeloproliferative neoplasms, other malignancies,
100 S. Barelli et al.

Table 7.4 Treatment of acquired von Willebrand syndrome

First choice in AvWS Second choice in AvWS
Intravenous immunoglobulins 2 g/kg on 2 days (not if monoclonal Desmopressin
IgM) with expected effect after 12–72 h
Haemate P® 30 IU/kg before and 20–30 IU/kg 2 h into surgery, Plasma exchange (3–4 l/
postoperative 20–30 IU/kg 3×/day for 5 days day)
Antifibrinolytic drugs if a site with high fibrinolytic activity rFVIIa 90 μg/kg
Refs. Federici et al. (2000), Maddox et al. (2005), Tiede et al. (2011)
AvWS acquired von Willebrand syndrome, rFVIIa recombinant activated factor VII

aortic stenosis (also when part of the Heyde syndrome), or, more rarely, autoim-
mune diseases. In these conditions vWF is eliminated more rapidly, either due to
autoantibodies or to absorption on the surface of platelets or malignant cells. Infused
vWF and FVIII concentrates will also rapidly be eliminated, if the underlying con-
dition has not been treated. The same holds true when desmopressin is administered
to increase endogenous vWF and FVIII. Table 7.4 summarizes treatment option for
AvWS. Anecdotal reports mention the efficacy of plasma exchanges with 3–4 l/day
of FFP for several days (Bovill et al. 1986; Silberstein et al. 1987; Federici et al.
2000; Maddox et al. 2005). This method can be useful, but it is not feasible for
emergency procedures. It is recommended that emergency patients receive immu-
noglobulins intravenously (2 g/kg, if possible divided into 2 doses, infused 24 h
apart). However, this treatment is ineffective in patients with AvWS in a monoclonal
IgM setting (Federici et al. 2000). Factor improvement occurs 12–72 h after treat-
ment and can last from days to weeks (Tiede et al. 2011). In cases showing no factor
correction or cases of emergency surgery, 30–100 IU/kg of Haemate P® can be
infused before surgery and 20–30 IU/kg two hours into surgery. In the postoperative
setting, 20–30 IU/kg of Haemate P® 3 times daily for 5 days seems to be an ade-
quate treatment (Maddox et al. 2005; Tiede et al. 2011). If the response to Haemate
P® is diminishing, a further dose of 1 g/kg of immunoglobulins can be given intra-
venously. rFVIIa is another possibility to control bleeding, administered at the usual
dosage of 90 μg/kg. However, there is currently only a limited experience of this
treatment. Antifibrinolytic drugs, such as tranexamic acid, can be used in surgery on
sites with a high fibrinolytic activity, such as the gastrointestinal tract or the oral
cavity, but they are contraindicated in patients with macrohematuria.
During surgery, normal factor levels should be aimed for; in the postoperative
setting, plasma levels of at least 50 % seem to be sufficient (Frank et al. 2002).

7.7 Coagulation Impairment Secondary to Drug Therapy

7.7.1 Opioid Abuse

In cases of chronic opioid abuse, morphological and rheological platelet changes

can occur. An accumulation of free fatty acids can induce these changes (Zvetkova
et al. 2010).
7 Acquired Hemostatic Disorders 101

7.7.2 Antiplatelet Drugs and Anticoagulants

See Chap. 8

7.7.3 Antidepressant Drugs

Selective serotonin reuptake inhibitors (SSRIs) are known to have an influence on

platelet function. In combination with oral anticoagulation therapy such as warfarin,
the bleeding risk is even higher (Cochran et al. 2011). This holds true only for SSRIs
and serotonin and norepinephrine reuptake inhibitors (SSNRIs). Other antidepres-
sants do not increase the risk of bleeding when given concomitantly with warfarin,
and the classic tricyclic antidepressants do not seem to alter platelet function.
SSRIs are known to alter platelet aggregation (Sarma and Horne 2006) and
increase the risk of gastrointestinal bleeding (Dalton et al. 2003). Platelet aggrega-
tion is altered by different mechanisms, such as the inhibition of the serotonin trans-
porters (Abdelmalik et al. 2008) and the depletion of serotonin inside the platelets
(Dalton et al. 2003), but also by decreasing platelet count (Ataoglu and Canan
2009). Before elective surgery, it would be suitable to discontinue the use of these
drugs to allow normal platelet function. In emergency surgery platelet concentrates
should be given only in case of bleeding, as not every patient under SSRIs will show
a tendency to bleed.

7.7.4 Thrombolytic Drugs

Thrombolysis is performed by intravenous or intra-arterial administration of plas-

minogen activators, such as recombinant tissue plasminogen activator (rTPA), in
order to induce blood vessel recanalization. Cerebral hemorrhage is the most severe
complication of thrombolysis.
Recommendations for the prevention of complications due to thrombolysis are
(Trouillas and von Kummer 2006):
• Respect the guidelines regarding the contraindications to thrombolysis.
• Do not prescribe LMWH during the 24 h following thrombolysis.
• Avoid UFH immediately after thrombolysis.
• Analysis of hemostasis should be performed before and 2 h after the start of
thrombolysis with a blood count and determination of the levels of fibrinogen
and fibrinogen degradation products or D-dimers.

7.8 Malignancies

A recent retrospective analysis has shown an “unacceptably” high risk of throm-

botic events in patients with malignancies (Moore et al. 2011). Venous events
include deep vein thrombosis (DVT), pulmonary embolism (PE), and visceral/
102 S. Barelli et al.

splanchnic and cerebral vein thrombosis. Some patients may also present superficial
vein thrombosis. Venous malignancy per se is a risk factor for DVT (Prandoni et al.
2005). About 10 % of patients with idiopathic DVT have an underlying malignancy.
Arterial events comprise stroke, myocardial infarction, and arterial embolism.
The activation of coagulation in patients with a malignancy is caused by the
acute-phase reaction, anticancer treatments, and prothrombotic properties of tumor
cells. The latter induce tissue factor, protease-activating factor X, plasminogen acti-
vator inhibitors which lead to impaired fibrinolysis and cytokines targeting the
endothelium, leukocytes, and platelets. The whole process is influenced by the stage
of the disease, invasive procedures (e.g., central venous catheter), and the patient’s
profile (inherent thrombophilia).

7.8.1 Diagnosis

Indicators of a possible undiscovered malignant process in a patient with DVT are:

• No apparent classic risk factors for DVT
• Recurrent DVT
• Bilateral involvement
• A high level of D-dimers (>4,000 mg/l) at presentation
• DVT in a patient younger than 60 years old
The stage of malignancy influences the thrombotic pattern: arterial embolism
can be seen in ongoing chemotherapy or in the presence of a nonbacterial endocar-
ditis; DIC can be found in metastatic disease.

7.8.2 Management

For patients with cancer, the initiation of antithrombotic prophylaxis is particularly

recommended in:
• Metastatic disease
• Surgical procedure
• Placement of a central venous catheter
• Inflammatory and/or infectious conditions
UFH and particularly LMWH are the cornerstones of DVT prophylaxis. Oral
anticoagulation by VKA is difficult to manage because of pharmacokinetic con-
cerns (poor nutrition, co-medication, or liver dysfunction), hemorrhagic concerns
(thrombocytopenia secondary to chemotherapy, to radiotherapy, or to medullar
spread of cancer), or surgical concerns (long half-life imposing reversal by factor
concentrates in case of emergency).

7.8.3 Conclusions for Clinical Practice

These conclusions are based on guidelines of the American College of Chest

Physicians http://www.chestnet.org/accp/guidelines.
7 Acquired Hemostatic Disorders 103

For patients with a high risk of VTE who are undergoing abdominal or pelvic
surgery for cancer, but who do not otherwise exhibit a high risk for major bleeding
complications, extended pharmacological prophylaxis with LMWH is recom-
mended (4 weeks).
In patients with DVT of the leg and/or a PE and active cancer, treatment with
LMWH is recommended over VKA therapy. In patients with DVT and cancer who
are not treated with LMWH, VKA is suggested over dabigatran or rivaroxaban as a
long-term therapy.
In patients with acute DVT and/or PE and a contraindication to anticoagulation
(hemorrhage, surgery, or thrombocytopenia), the use of an inferior vena cava filter
is recommended (see also Chap. 8). A conventional course of anticoagulant therapy
should be considered as soon as the risk of bleeding resolves.
In cancer patients who have upper extremity DVT that is associated with a cen-
tral venous catheter, 3 months of anticoagulation treatment is recommended if the
catheter is removed. If the catheter is not removed, anticoagulation treatment should
be continued as long as the central venous catheter remains.

7.9 Monoclonal Gammopathies

7.9.1 Mechanism

Monoclonal gammopathies interfere with coagulation through several mechanisms:

• Shear wall stress due to increased blood viscosity.
• Fibrin polymerization with the loss of a harmonious clot structure.
• Autoantibody-like behavior of monoclonal proteins on coagulation factors
(thrombin, FVIII, and vWF) with enhanced clearance (e.g., acquired von
Willebrand syndrome).
• Absorption of coagulation factors (mostly FX) by subendothelial paraprotein
deposits in AL amyloidosis. It is usually associated with a prolonged aPTT (this
condition requires a hematologist’s expertise).
• Heparin-like activity of certain monoclonal proteins.

7.9.2 Diagnosis

Paraprotein interference with hemostasis can be suspected in the following

situations:
• History of lymphoproliferative disorders or plasma cell dyscrasia (chronic lym-
phocytic leukemia, Waldenström disease, MGUS, multiple myeloma)
• Bleeding complications with normal classic coagulation tests
• New onset mildly prolonged aPTT
• Abnormal primary hemostasis tests such as PFA-100.
• Poor response to Desmopressin
• Etiologic diagnosis of AvWS
• Monoclonal gammopathy
104 S. Barelli et al.

• Essential thrombocytosis
• Severe aortic stenosis (Heyde syndrome triad)

7.10 BCR/ABL-Negative Myeloproliferative Neoplasms

BCR/ABL-negative myeloproliferative syndromes (MPS) can be associated with

either hemorrhagic complications or, more often, thrombotic complications, or
worse, both.

7.10.1 Thrombotic Complications

Polycythemia vera (PV) and essential thrombocythemia (ET) are two types of MPS
that are associated with up to 50 % of thrombotic events (Elliott and Tefferi 2005),
with arterial thrombotic events being more common than venous events (Fenaux et al.
1990; De Stefano et al. 2008). The most common events among patients with PV and
ET are ischemic strokes (De Stefano et al. 2008). The prevalence of splanchnic and
cerebral vein thrombosis is unusually high in patients with MPS, and such events
might be the presenting feature of the disease, even before diagnosis (Reikvam and
Tiu 2012). Thrombotic risk is higher due to elevated hematocrit with hyperviscosity,
thrombocytosis, and leukocytosis (Wolanskyj et al. 2006). Janus kinase 2 (JAK2)
mutations can also add to the thrombotic risk through increased red cell adhesiveness
(Buss et al. 1985) and altered platelet signaling (Falanga et al. 2007). Patients with
MPS are treated with aspirin and/or cytoreduction, according to their risk level.

7.10.2 Hemorrhagic Complications

Most patients with hemorrhagic complications suffer from ET associated with a

high platelet count or are patients with secondary bleeding due to anticoagulation
for thrombotic risk (De Stefano et al. 2008; Tartaglia et al. 1986). Bleeding in
patients with thrombocytosis is normally due to AvWS and occurs when platelets
rise over 1000 G/L, in association with the loss of large multimers due to the bind-
ing of vWF to platelets (Michiels et al. 2001). Dysfunctional platelets can be a fur-
ther problem (Elliott and Tefferi 2005; Landolfi et al. 1995).

7.10.3 Treatment

Both thrombotic and hemorrhagic complications can be treated by cytoreduction,

such as hydroxyurea treatment, with effect on all blood lineages. A high hematocrit
alone can be treated with phlebotomy; a high platelet count alone can be lowered
with anagrelide. Another option for lowering peripheral blood cell counts is inter-
feron. Normally, patients with MPS take aspirin on a regular basis. If possible,
peripheral blood cell counts should be within normal ranges before surgical
7 Acquired Hemostatic Disorders 105

procedures. In emergency, surgery platelet count should be at least <100 × 109/l to

reduce the risk of bleeding. With regard to thrombotic complications, patients at high
risk should receive an appropriate antithrombotic prophylaxis with, for example,
LMWH.

7.11 Antiphospholipid Antibody Syndrome

The antiphospholipid antibody syndrome is an acquired autoimmune tendency to

thrombosis that is diagnosed when antiphospholipid antibodies are present, together
with a history of thrombosis and/or complications during pregnancy. Treatment
comprises antithrombotic drugs. In the perioperative setting, the management of
antiphospholipid antibody syndrome requires input from a hematologist.
One category of antiphospholipid antibodies, called “lupus anticoagulant,” can
interfere with in vitro coagulation tests such as PT, aPTT, and ACT. It is important
to be aware of the impact of this interference on patient monitoring in the periopera-
tive setting, particularly if a cardiopulmonary bypass must be performed. Interference
can be circumvented by using a Hepcon® test or by measuring the heparin concen-
tration by anti-Xa activity tests (Jervis et al. 2009).

7.12 Thrombotic Microangiopathies

Thrombotic microangiopathies are characterized by direct antiglobulin test-negative

hemolytic anemia, thrombocytopenia, petechial hemorrhages, fever, and/or renal
and neurological complications. Diagnosis of thrombotic microangiopathies may
prove difficult, and the input of a hematologist is required to best define periopera-
tive management.

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Antiplatelet Therapy
and Anticoagulation 8
Pierre-Guy Chassot, Stefano Barelli, Sabine Blum,
Anne Angelillo-Scherrer, and Carlo E. Marcucci

8.1 Antiplatelet agents

8.1.1 Introduction

Perioperative management of antiplatelet (AP) drugs is a major challenge. Dual AP

therapy (aspirin plus clopidogrel, prasugrel, or ticagrelor) is the key to preventing
myocardial infarction (MI) after acute coronary syndrome (ACS) or stent thrombo-
sis (ST) following the implant of bare-metal (BMS) or drug-eluting stents (DES). In
this population, platelet inhibition in the perioperative period is particularly impor-
tant because of the increased platelet activity associated with the postoperative
acute inflammatory response. Unfortunately, AP drugs also increase the risk of sur-
gical bleeding. The key question is whether the risk of thrombosis when AP agents
are withdrawn is higher than the risk of hemorrhage when they are maintained.
Current recommendations are based on the results of highly reliable cardiologic tri-
als (level of evidence A) and on large observational or prospective studies collected
in surgery and anesthesiology (level of evidence B). Taken together, these data can
be considered as adequate for defining the safest possible strategy.

P.-G. Chassot (*) • C.E. Marcucci

Service of Anesthesiology, Lausanne University Hospital (CHUV),
Lausanne CH-1011, Switzerland
e-mail: [email protected]; [email protected]
S. Barelli • S. Blum • A. Angelillo-Scherrer
Service of Hematology, Lausanne University Hospital (CHUV),
Lausanne CH-1011, Switzerland
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 109

DOI 10.1007/978-3-642-55004-1_8, © Springer-Verlag Berlin Heidelberg 2015
110 P.-G. Chassot et al.

Irreversible COX-1 inhib.:

aspirin
Irreversible ADP inhibitor:
Reversible COX-1 inhib.:
clopidogrel
NSAID
Thrombin prasugrel

TXA2 ADP

Reversible
ADP inhib.:
ticagrelor
cangrelor
α-granule elinogrel
GP IIb/IIIa

GP Ib/V/IX

TXA2
ADP
Reversible
GP IIb/IIIa inhib.:
vWF Fib abciximab
eptifibatide
tirofiban

Fig. 8.1 Classification of the different AP agents. Blockers of von Willebrand factor/adhesion
molecules and thrombin receptor blockers are under investigation (Adapted with permission from
www.pac4.ch). ADP adenosine diphosphate, cAMP cyclic adenosine monophosphate, COX-1
cyclooxygenase-1, Fib fibrinogen, inhib inhibitor, NSAID nonsteroidal anti-inflammatory drug,
TXA2 thromboxane A2, vWF von Willebrand factor

8.1.2 Antiplatelet Therapy

The different AP agents are classified according to the type of receptor they inhibit
on the platelet (Fig. 8.1). Their pharmacology is described in Tables 8.1 and 8.2. At
doses of 50–160 mg/day, aspirin completely inhibits the cyclooxygenase-1 (COX-1)
enzyme which converts arachidonic acid to thromboxane A2 (TXA2), the ligand for
the homonymous platelet receptor. However, 6–10 % of the population shows a low
response to aspirin treatment, resulting in insufficient platelet inhibition. In some
patients, this is due to insufficient inhibition of the COX-1 enzyme by aspirin. Yet
in others, due to a predominance of alternative activation pathways (e.g., ADP,
thrombin), the platelet function remains normal in spite of sufficient COX-1 inhibi-
tion. Competitive interaction with nonsteroidal anti-inflammatory drugs (NSAIDs)
may also reduce aspirin efficiency (Patrono and Rocca 2010).
Clopidogrel (Plavix™, Iscover™) is a prodrug which is oxidized into an active
metabolite in a two-step process by hepatic cytochromes. This metabolite irrevers-
ibly blocks the adenosine diphosphate (ADP) receptor (P2Y12) and reduces platelet
activity by 50–60 % (Hall and Mazer 2011). Clopidogrel’s efficiency may be
8 Antiplatelet Therapy and Anticoagulation 111

Table 8.1 Activity and route of administration of antiplatelet drugs

Link with
Receptor receptor Biotransformation Route
Aspirin COX-1 (TXA2) Irreversible None Oral
Clopidogrel ADP P2Y12 Irreversible P450 (liver, 2-steps) Oral
Prasugrel ADP P2Y12 Irreversible P450 (liver) Oral
Ticagrelor ADP P2Y12 Reversible None Oral
Abciximab GP IIb/IIIa Irreversible None Intravenous
Tirofiban GP IIb/IIIa Reversible None Intravenous
Eptifibatide GP IIb/IIIa Reversible None Intravenous
Adapted with permission from www.pac4.ch

Table 8.2 Pharmacokinetics of antiplatelet drugs

Time-to-peak
Loading dose Maintenance dose effect Half-life
Aspirin 160–325 mg 50–160 mg/day <1 h <1 ha
Clopidogrel 300–600 mg 75 mg/day (150 mg/day) 3 (600)–6 h 7.5 h (metab <1 h)a
(300 mg)
Prasugrel 60 mg 10 mg/day 1h 3.7 h (metabolite)a
Ticagrelor 180 mg 2 × 90 mg/day 2h 7–10 h
Abciximab 0.25 mg/kg 0.125 mcg/kg/min 2h 23 h
Tirofiban 0.4 mcg/kg/min 0.1 mcg/kg/min 15 min 2.0 h
Eptifibatide 180 mcg/kg 2.0 mcg/kg/min 10 min 2.5 h
Adapted with permission from www.pac4.ch
Perf continuous perfusion, Iv intravenous, Metab metabolite
a
The pharmacological half-life does not correspond to the clinical effect for irreversibly blocking
agents because termination of clinical activity relies on platelet renewal (10 %/day)

lowered because of competition for the same cytochromes by midazolam, fluox-

etine, some lipophilic statins (particularly atorvastatin), and some proton pump
inhibitors (particularly omeprazole). Although the evidence for an increase in car-
diovascular complications is modest, it is safer to avoid the administration of atorv-
astatin, omeprazole, and clopidogrel simultaneously (Bates et al. 2011). There are
no major differences in terms of bleeding between aspirin and clopidogrel mono-
therapy. After cessation of aspirin or clopidogrel, bleeding time and global platelet
activity return to baseline levels in 5 days (Bhatt et al. 2006).
Up to 30 % of patients respond poorly to clopidogrel. One reason is polymor-
phism in the genes that code the hepatic enzymes involved in the synthesis of the
active metabolite. Patients with abnormal alleles are 1.6–3.5 times more likely to
experience cardiovascular complications and stent thrombosis when treated with
clopidogrel (Mega et al. 2010). Patients who maintain a residual platelet activity
after a loading dose of clopidogrel are four to six times more likely to suffer infarc-
tion and stent thrombosis than normal responders (Aradi et al. 2010) (Fig. 8.2).
Compared to clopidogrel, prasugrel (Effient™) is faster acting, is more potent,
and has a much lower rate of low responders. It is more efficient in diabetics and
patients with ST-elevation MI and is twice as efficient in preventing stent
112 P.-G. Chassot et al.

Rate of MACE (%)

20
Haemorrhagic Optimal
risk window
15 Thrombotic
risk

10

Q1 Q2 Q3 Q4
Residual platelet activity (quartiles)

Fig. 8.2 Rate of major adverse cardiac events (MACE, in blue) after percutaneous coronary inter-
vention and stenting according to the residual platelet activity after a loading dose of aspirin and
clopidogrel. Since adverse events cluster in the highest quartile (Q4), there is a larger benefit to
decrease platelet activity from Q4 to 50 % than from 50 % to Q1. The curve for hemorrhagic risk
(in red) is mirrorlike and varies in the opposite direction. These two curves determine an optimal
window with the best combination of minimal risk of bleeding and maximal platelet inhibition
(Adapted with permission from Price (2009))

thrombosis. However, it does increase the risk of spontaneous hemorrhage 1.5 times
and of surgical bleeding up to four times (Wiviott et al. 2007). Considering its
potency, prasugrel cessation 7 days before surgery is recommended.
Ticagrelor (Brilinta™, Brilique™, Possia™) is a powerful and reversible ADP
receptor blocker. One hour after a loading dose, 80 % of platelet activity is inhibited
and after cessation, it takes 3 days for platelet function to recover (Gurbel et al.
2009). Ticagrelor is more efficient than clopidogrel in preventing stent thrombosis,
yet does not increase the hemorrhagic risk (Wallentin et al. 2009). Because some
patients produce a long-acting metabolite, it is recommended to stop ticagrelor 5
days before an operation.
Cangrelor is an intravenous fast onset and offset drug, which will be useful for
preoperative substitution of long-acting agents. It abolishes platelet aggregation but
allows a complete recovery of platelet activity within 1–3 h of stopping the perfu-
sion (Angiolillo et al. 2012).
Dual AP therapy is essential after ACS or stent implantation because vascular
lesions and stents behave like unstable plaques if they are not fully covered by a
cellular layer. It takes 6 weeks for the frame of a BMS to become covered by smooth
muscle cells and 3 months to be protected by a normal endothelium. DES have a
slower endothelialization rate: 20 % at 3 months and 60 % at 1 year (Joner et al.
2006). Thus, the minimal duration of dual AP therapy following implantation is 6
8 Antiplatelet Therapy and Anticoagulation 113

Table 8.3 Recommended duration of antiplatelet therapy

Aspirin (75–325 mg/day): lifelong therapy, without interruption
Dual therapy: aspirin plus clopidogrel (75–150 mg/day) or prasugrel (10 mg/day) or ticagrelor
(90 mg 2×/day)
Simple angioplasty without stenting 4–6 weeks
PCI and bare-metal stents Min 6 weeks, optimally 6–12 months
Myocardial infarction Minimum 6 months
Acute coronary syndrome (unstable) 12 months
PCI and drug-eluting stents (first generation) Minimum 12 months
PCI and drug-eluting stents (second to third 6–12 months
generation):
High-risk situations >12 months, occasionally lifelong
Adapted with permission from www.pac4.ch
PCI percutaneous coronary intervention

weeks for BMS and 12 months for DES (Table 8.3) (Task Force on Myocardial
Revascularization of the European Society of, the European Association for Cardio-
Thoracic et al. 2010). These periods can be prolonged beyond 1 year for high-risk
stents (DES implanted in dominant, ostial, or bifurcated positions) and high-risk
patients (previous ST, diabetes, cardiac or renal failure). Late DES thrombosis is a
rare (0.6 %/year) but catastrophic event with a mortality of 9–45 % since it leads to
the acute interruption of flow in a previously normal vessel (Dangas et al. 2011).
New-generation DES have a faster rate of endothelialization and a lower incidence
of ST; depending on the type of stent, the duration of dual AP therapy is 6–12
months.

8.1.3 Withdrawal of AP Agents

Cessation of AP therapy is associated with an increased mortality and ischemic risk:

the shorter the duration, the higher the complication rate. Aspirin withdrawal is
associated with an increased risk of cardio- and cerebrovascular complications
(Biondi-Zoccai et al. 2006). Cases of acute DES thrombosis following aspirin with-
drawal have been reported more than 3 years after stent implantation (Artang and
Dieter 2007; Fujimoto et al. 2009). Thrombotic events peak 7 days after interrup-
tion, whatever the duration of treatment (Eisenberg et al. 2009). Therefore, aspirin
should be a lifelong therapy, never interrupted (Task Force on Myocardial
Revascularization of the European Society of, the European Association for Cardio-
Thoracic et al. 2010). Stopping clopidogrel is the most significant independent pre-
dictor for ST (Gaglia and Waksman 2011). During the first 6 months of therapy, the
average delay between clopidogrel cessation and ST is 9 days (Schulz et al. 2009).
Although the usefulness of prolonging dual therapy beyond 1 year remains unset-
tled, there is clear clinical evidence that its cessation during that first year is exceed-
ingly dangerous (Valgimigli et al. 2012).
114 P.-G. Chassot et al.

Mortality (%)

50
BMS, CABG
40 DES

30

20

10

1 3 6 12
Delay (months)

Fig. 8.3 Schematic illustration of the relationship between mortality for noncardiac surgery and
time since revascularization in case of perioperative interruption of dual antiplatelet therapy.
During the first 6 weeks after coronary artery bypass graft surgery (CABG), bare-metal stents
(BMS), or drug-eluting stents (DES), mortality is around 30 %. After BMS and CABG, it takes
3 months for postoperative mortality to reach the level of patients with no active coronary artery
disease, whereas after DES the plateau of the curve is reached only after 12 months

The interruption of AP drugs is more hazardous in the perioperative period

because of the ensuing increased platelet stimulation and the acute systemic inflam-
matory reaction. Interruption is the major independent factor predicting cardiac
complications after noncardiac surgery (Barash and Akhtar 2010). Stopping dual
AP therapy to allow major surgery during the first 3 months after angioplasty and
stenting (BMS or DES) leads to an average cardiac mortality of 30–50 %, whereas
it is ≤5 % when the treatment is maintained perioperatively (Sharma et al. 2004;
Schouten et al. 2007; Nuttall et al. 2008; Rabbitts et al. 2008). Mortality is inversely
related to the delay between revascularization and surgery (Fig. 8.3).
The recommended delays between revascularization and noncardiac surgery are
as follows:
• Angioplasty without stenting: 2–4 weeks (vital surgery only).
• BMS and coronary artery bypass graft (CABG): 6 weeks for vital surgery and
3 months for elective surgery.
• DES: >12 months for elective surgery; vital surgery could be performed within
2–12 months under full AP therapy.

8.1.4 Hemorrhagic Risk Linked to AP Agents

The body of evidence shows that aspirin or clopidogrel taken alone increase average
blood loss by 20 % during noncardiac surgery (Chassot et al. 2007). Some opera-
tions can show a significant increase in postoperative hemorrhage, such as
8 Antiplatelet Therapy and Anticoagulation 115

tonsillectomy or transurethral prostatectomy. Life-threatening hemorrhage has only

been reported in intracranial neurosurgery. A meta-analysis including 474 studies
comparing surgical bleeding across all kinds of surgery reports no difference in
mortality and complication rates between patients who took aspirin and those who
did not (Burger et al. 2005).
With aspirin and clopidogrel dual therapy, the relative risk of bleeding increases
by up to 50 %, as observed in orthopedic, vascular, abdominal, thoracic, urologi-
cal, and endoscopic surgery (Moore and Power 2004; Albaladejo et al. 2011;
Chernoguz et al. 2011; Taylor et al. 2011). Although hemostasis is difficult and
tedious, particularly because of the increased oozing from bones and raw tissues,
surgical mortality and long-term morbidity are not increased. In series comparing
general surgery with and without dual AP therapy, the transfusion rate is inconsis-
tently affected (relative increase: 4, 12, 16, and 17 %) (Wilson et al. 2003;
Schouten et al. 2007; Rabbitts et al. 2008; Chernoguz et al. 2011). Aspirin and
clopidogrel do not appear to cause an increase in surgical complications, except
for surgery in a closed space (intracranial neurosurgery, surgery of the spinal
canal or the posterior ocular chamber) or surgery associated with massive hemor-
rhage and difficult hemostasis. In these cases, clopidogrel, prasugrel, and ticagre-
lor should be interrupted or substituted by a short-acting agent (Chassot et al.
2007; Eberli et al. 2010). In cardiac surgery, the situation is more critical due to
the full heparinization during heart-lung bypass: blood loss and reoperation for
bleeding control are more than doubled; the transfusion rate is increased up to
four times; however, mortality remains unchanged (Task Force on Myocardial
Revascularization of the European Society of, the European Association for
Cardio-Thoracic et al. 2010).

8.1.5 Recommendations and Guidelines

Current recommendations are based on the safest possible management of the dan-
gers of discontinuing AP agents prematurely (Douketis et al. 2008; American
Society of Anesthesiologists Task Force on Neuraxial et al. 2009; Task Force on
Myocardial Revascularization of the European Society of, the European Association
for Cardio-Thoracic et al. 2010; Korte et al. 2011). They are illustrated as an algo-
rithm in Fig. 8.4 and are summarized in Table 8.4.
• Aspirin for primary prevention can be interrupted 5 days before surgery, except
in high-risk cases, such as diabetics.
• Aspirin or clopidogrel monotherapy for secondary prevention after a stroke,
ACS, MI, or coronary revascularization should be maintained throughout the
perioperative period, whatever the duration of treatment.
• Aspirin plus dipyridamole dual therapy after stroke should be maintained
throughout the perioperative period.
• Aspirin plus clopidogrel/prasugrel/ticagrelor dual therapy in patients with a low
cardiovascular risk: maintain continuous treatment with aspirin; stop clopidogrel
5 days, prasugrel 7 days, and ticagrelor 5 days before surgery; restart
116 P.-G. Chassot et al.

Patients on aspirin (75-325 mg/day) Patients on aspirin and

or clopidogrel alone (75 mg/day) clopidogrel, prasugrel or ticagrelor

High-risk cardiac situations:

<6 weeks after PCI, BMS, stroke Low-risk
Primary Secondary prevention
<3 months after MI, ACS cardiac
prevention and primary prevention
<12 months after DES situations
in high-risk patients
>12 months in high-risk stents1

High-risk
surgery
Elective Vital/urgent
High-risk All surgery surgery
intracranial surgery
Stop clopidogrel3
neurosurgery
Maintain aspirin
Delay Excessive
surgery bleeding risk2

Stop 5 days Operation under Stop clopidogrel3 + substitution

before operation continuous Maintain aspirin
as needed treatment Restart clopidogrel <24h postop

Fig. 8.4 Algorithm for the preoperative management of patients under antiplatelet therapy. Low-
risk conditions are depicted in yellow, high-risk conditions in red, and decisions in magenta. 1
High-risk stents: multiple stents, long stent, proximal location (left main), and bifurcation lesions;
patients with previous stent thrombosis; stent in unique patent vessel. 2 Excessive risk of bleeding:
invasive surgery associated with severe bleeding and difficult hemostasis, or bleeding in closed
spaces (intracranial neurosurgery, intramedullary canal surgery, posterior eye chamber ophthalmic
surgery). 3 The same recommendations apply to prasugrel and ticagrelor. In all cases, restart AP
within 24 h postoperative. BMS bare-metal stent, DES drug-eluting stent, ACS acute coronary syn-
drome, MI myocardial infarction, PCI percutaneous coronary intervention, CABG coronary artery
bypass graft surgery (Adapted with permission from www.pac4.ch and form Eberli et al. (2010))

clopidogrel/prasugrel/ticagrelor within 24 h after surgery, preferably with a load-

ing dose (if hemorrhagic risk is low).
• Aspirin plus clopidogrel/prasugrel/ticagrelor dual therapy in patients with high
cardiovascular risk: delay elective surgery for 3 months after a stroke, BMS, or
CABG, 6 months after acute coronary syndrome or infarction, and 12 months
after DES. Beyond these delays: maintain aspirin; if clopidogrel/prasugrel/
ticagrelor is still prescribed, discuss with the cardiologist and the surgeon
whether to stop or maintain. Delay vital or semi-urgent surgery for at least 6
weeks if possible; maintain both aspirin and dual therapy.
During the first 6 weeks after ACS or revascularization, the operative risk is
exceedingly high – even higher than without coronary revascularization. The full
benefit of revascularization only manifests itself 3 months after BMS or CABG and
12 months after DES, when mortality returns to the level of noncoronary patients.
All elective operations should therefore be postponed beyond these delays. Only
vital surgery should be performed on patients still on dual AP therapy; unless the
8 Antiplatelet Therapy and Anticoagulation 117

Table 8.4 Recommended preoperative management of patients under antiplatelet therapy accord-
ing to the hemorrhagic risk of surgery
Low-risk patient Intermediate risk High-risk patient
>3 months after 6–12 weeks after PCI, <6 weeks after PCI,
PCI, BMS, BMS, CABG, or CVA BMS, CABG, ACS, CVA
CABG or CVA 3–6 months after MI or <3 months MI or ACS
>6 months after ACS <6 months after MI or
ACS or MI >12 months after ACS with complications
>12 months high-risk DES <12 months after DES
after regular
DES
Low hemorrhagic risk Maintain aspirin Proceed with elective Postpone elective surgery
Transfusion not or clopidogrel surgery: maintain Proceed with vital/urgent
required aspirin surgery: maintain aspirin
Peripheral and wall Maintain clopidogrel, and clopidogrel,
surgery, minor ENT and prasugrel, or ticagrelor prasugrel, or ticagrelor
orthopedics, endoscopy if prescribed without interruption
without biopsy/
resection, eye anterior
chamber, dentistry
Intermediate risk Maintain aspirin Postpone elective Postpone elective surgery
Transfusion may be or clopidogrel surgery according to Proceed with vital
required risk balance surgery: maintain aspirin
Visceral and vascular Proceed with vital and clopidogrel,
surgery, major ENT and surgery: maintain prasugrel, or ticagrelor
orthopedics, urology, aspirin, maintain without interruption
endoscopy with biopsy/ clopidogrel, prasugrel,
resection or ticagrelor if
prescribed
High hemorrhagic risk Stop aspirin or Postpone elective Postpone elective surgery
Transfusion required clopidogrel if surgery Proceed with vital/urgent
Cardiac surgery, surgery necessary Proceed with vital/ surgery: maintain aspirin
with massive bleeding (5 days urgent surgery: Stop clopidogrel (5 days),
Surgery in closed space preoperatively) maintain aspirin prasugrel (7 days),
(intracranial, Restart <24 h Stop clopidogrel ticagrelor (3–5 days).
intramedullary canal, postoperatively (5 days), prasugrel Substitution with
posterior eye chamber) (7 days), or ticagrelor tirofiban or eptifibatide
(3–5 days) if (3–4 days perfusion)
prescribed, restart
<24 h postoperatively
Adapted with permission from Chassot et al. (2010) and from www.pac4.ch
ACS acute coronary syndrome, BMS bare-metal stents, CABG coronary artery bypass graft, CVA
cerebrovascular accident, DES drug-eluting stent, ENT ear, nose and throat surgery, MI myocardial
infarction, PCI percutaneous coronary intervention

hemorrhagic risk is excessive, dual AP therapy should not be interrupted before

surgery. Heparin and LMWHs have no AP activity and are not adequate substitutes
for long-acting AP drugs since stent thrombosis is a platelet-mediated phenomenon.
A bridge using a 3-day continuous perfusion of a short-acting anti-GP IIb/IIIa agent,
such as eptifibatide or tirofiban, is the only effective substitute for clopidogrel or
118 P.-G. Chassot et al.

prasugrel, when aspirin is maintained (Savonitto et al. 2010). The perfusion can be
stopped 6–8 h before surgery. After the operation, AP therapy should be resumed
within the first 24 h.

8.1.6 Intraoperative Management

Intrathecal and epidural anesthesia are strictly contraindicated in case of dual AP

therapy, although they are allowed in patients taking aspirin only, up to 325 mg/day
(Gogarten et al. 2010). Although they undoubtedly improve patient comfort, their
impact on cardiovascular outcomes is negligible. With a five- to tenfold increase in
MI, the risk linked to AP withdrawal is obviously much higher than the benefit
expected from neuraxial blockade. Stopping AP drugs in order to perform an intra-
thecal or epidural anesthesia is therefore clearly unjustified.
Aspirin, clopidogrel, and prasugrel are irreversible blockers. Since they have no
antidotes, platelet renewal (10 %/day) is the only way for platelet aggregation to
return to normal. As soon as 50 % of platelets have been renewed, blood hemostasis
functions normally. Therefore, 5–7 days without AP therapy are required to prevent
excessive surgical bleeding. It is commonly accepted that a substance’s plasma level
is negligible after 3 half-lives. Therefore, 24 h after the last intake of clopidogrel
(half-life: 7.5 h) and 12 h after the last dose of prasugrel (half-life: 3.7 h), there is no
residual AP activity in the plasma. Although the patient’s native platelets are still
inhibited, the platelets transfused after these delays will function adequately.
After cessation of the reversible AP drug ticagrelor, platelet function recovers
more rapidly compared to clopidogrel, since it is not dependent on platelet renewal.
Yet, 48 h after interruption of either drug, platelets still show the same degree in
inhibition. Only 3 days after cessation, ticagrelor shows a lower degree of inhibition
than clopidogrel (Gurbel et al. 2009).
As a reversible drug, ticagrelor will be redistributed from circulating platelet
receptors to the receptors of transfused platelets. Platelet transfusion my therefore
not be efficient to reverse the AP effect in emergency situations.
Postoperative stent thrombosis – usually manifested as an acute ST-elevation MI
leading to cardiogenic shock – is an extreme emergency. It must be treated within
3 h by PCI and angioplasty and has a survival rate of only 65 % (Berger et al. 2001).

8.2 Anticoagulants

8.2.1 Introduction

Anticoagulant therapy is an integral part of perioperative management. The mecha-

nisms of action of currently used anticoagulant drugs are described in Fig. 8.5, and
their effects on coagulation are listed in Table 8.5.
Patients can be prescribed prophylactic doses of anticoagulants to prevent venous
thromboembolism. They can receive therapeutic doses of anticoagulants to treat or
8 Antiplatelet Therapy and Anticoagulation 119

prevent recurrence of a venous thromboembolism or to prevent stroke or systemic

arterial embolism in a context of atrial fibrillation, heart failure, or after the place-
ment of prosthetic heart valves.
During the preoperative phase, the indications for anticoagulation therapy have
to be confirmed in order to determine, on one hand, the thrombotic risk in case of
interruption and, on the other hand, the risk of bleeding when continuing anticoagu-
lation (Kearon et al. 2012).
Following this investigation, a detailed protocol comprising the pre-, peri-, and
postoperative phases can be established. The urgency of the surgical procedure must
also be taken into account when setting up of the protocol.
In this section, we will review existing anticoagulants and propose strategies for
their use in a perioperative context.

8.2.2 Heparins and Fondaparinux

8.2.2.1 Introduction
Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH) are
polysaccharides that bind to antithrombin (AT) and potentiate its inhibitory effect
on thrombin (FIIa) and activated factor X (FXa) (Fig. 8.5). This effect varies accord-
ing to the type of heparin molecule used:
• UFH predominantly potentiates anti-IIa activity.
• LMWHs predominantly potentiate anti-Xa activity.
Fondaparinux is a synthetic pentasaccharide that selectively binds and activates
AT. It is too short a molecule to enable bridging between AT and thrombin; thus, it
selectively potentiates the anti-Xa activation of AT without effecting thrombin; see
Fig. 8.5 (Garcia et al. 2012).

8.2.2.2 Monitoring
The anticoagulant response to UFH varies between patients; it is therefore standard
practice to monitor UFH and adjust the dose based on the results of coagulation
tests. When administered at therapeutic doses, the anticoagulant effect of UFH is
usually monitored using the activated partial thromboplastin time (aPTT). Activated
clotting time (ACT) allows monitoring of the higher UFH doses given in the context
of PCI or cardiac surgery. A therapeutic aPTT range of 1.5–2.5 times the control
time is widely accepted (Basu et al. 1972; Garcia et al. 2012). UFH levels can also
be monitored using anti-Xa assays. “Heparin resistance” is a term used when
patients require unusually high doses of heparin to achieve a therapeutic aPTT
(Green et al. 1994; Levine et al. 1994; Anand et al. 1997; Garcia et al. 2012). Several
mechanisms explain heparin resistance: AT deficiency (Olson et al. 1998), increased
UFH clearance (Hirsh et al. 1976; Green et al. 1994), high levels of heparin-binding
proteins (Whitfield et al. 1983; Brey 1992), and elevated levels of FVIII (Edson
et al. 1967; Levine et al. 1994) and/or fibrinogen (Edson et al. 1967).
Monitoring LMWH and fondaparinux is unnecessary, except in the contexts
of obesity, renal failure, or pregnancy (Garcia et al. 2012). LMWH and
120 P.-G. Chassot et al.

Intrinsic pathway Common pathway Extrinsic pathway

aPTT
PT/INR

Rivaroxaban
LMWH Apixaban
UFH

Dabigatran
TT

AT
Xa Xa Rivaroxaban
Apixaban

AT AT

AT
IIa IIa Dabigatran

Coagulation factor LMWH Low molecular weight heparin

Vitamin K dependant Coagulation factor UFH Unfractionnated heparin

Pentasaccharide LMWH UFH

8 Antiplatelet Therapy and Anticoagulation 121

Fig. 8.5 Anticoagulants and their targets (anticoagulation in the context of heparin-induced
thrombocytopenia is presented in Chap. 7). Vitamin K antagonists produce their anticoagulant
effect by interfering with the γ-carboxylation of the vitamin K-dependent factors II, VII, IX, and
X (in black). Unfractionated heparin (UFH) is an indirect anticoagulant that binds to antithrombin
(AT), enhancing its ability to inhibit activated factor X (FXa), thrombin (FIIa), and other coagula-
tion factors. Low-molecular-weight heparins (LMWH) derived from UFH by chemical or enzy-
matic depolymerization and fondaparinux is a synthetic analog of the AT-binding pentasaccharide
found in UFH and LMWH. Fondaparinux, too short to enable bridging between AT and thrombin,
selectively potentiates the anti-FXa activity of AT. Similarly LMWHs only have a marginal impact
on thrombin. Dabigatran is a direct, selective inhibitor of thrombin, hence independent of AT activ-
ity. Rivaroxaban and apixaban are direct, highly selective, factor Xa inhibitors. Clot-based assays
comprise the prothrombin time (PT), the activated partial thromboplastin time (aPTT), and the
thrombin time (TT). PT is used to assess the extrinsic and common pathways of coagulation.
Clotting is initiated by recalcifying citrated plasma in the presence of thromboplastin (a mixture of
tissue factor and phospholipids). In order to promote standardization of the PT, the World Health
Organization (WHO) developed an international reference thromboplastin and recommends that
the PT ratio be expressed as the International Normalized Ratio or INR to evaluate the effect of
anti-vitamin K anticoagulants. aPTT is used to assess the integrity of the intrinsic coagulation
pathway (prekallikrein, high-molecular-weight kininogen, factors XII, XI, IX, VIII) and final com-
mon pathway (factors II, V, X, and fibrinogen). It is performed by recalcifying citrated plasma in
the presence of a thromboplastic material that does not have tissue factor activity (hence the term
partial thromboplastin) and a negatively charged substance (i.e., celite, kaolin, or silica). TT mea-
sures the final step of the clotting pathway, the conversion of fibrinogen to fibrin. The test is per-
formed by recalcifying citrated plasma in the presence of dilute bovine or human thrombin
(Adapted with permission from EHM Swiss Medical Publishers Ltd. Gavillet and Angelillo-
Scherrer (2012))

Table 8.5 Effects of anticoagulants on coagulation tests

Anti-
Anticoagulant Target aPTT PT INR TT Fibrinogen d-dimers Anti-Xa IIa
Vitamin K II, VII, IX, X, ↑ ↑ ↑ ↑ ↔ ↔ ↔ ↔
antagonists protein C and S
Unfractionated IIa and Xa ↑ ↔ ↔ ↑ ↔ ↔ ↑ ↑
heparin (AT-dependent)
Low- Mainly Xa ↔ ↔ ↔ ↑ ↔ ↔ ↑ ↔
molecular- (AT-dependent)
weight heparin
Dabigatran IIaa ↑ ↑ ↑ ↑ ↔ ↔ ↔ ↑
Rivaroxaban Xaa ↑ ↑ ↑ ↔ ↔ ↔ ↑ ↔
Apixaban Xaa ↑ ↑ ↑ ↔ ↔ ↔ ↑ ↔
Refs. Barrett et al. (2010), Pengo et al. (2011), Ageno et al. (2012), Asmis et al. (2012), Garcia
et al. (2012), Samama et al. (2012)
AT antithrombin, coagulation factors are indicated by roman numbers, the “a” suffix stands for
“activated”
a
Free and bound form
122 P.-G. Chassot et al.

fondaparinux monitoring is done by measuring the peak anti-Xa level reached

3–5 h after the subcutaneous injection of the anticoagulant. The anticoagulation
is considered to be well adapted if the peak anti-Xa level is within the target
range. In the context of renal failure, it is useful to measure the trough level in
order to verify that the LMWH level is low enough to perform surgery without
an augmented risk of bleeding. To lower the risk of prosthetic valve thrombosis
in pregnant women receiving LMWH, the trough and peak anti-Xa levels can be
measured to guide dose adjustments. In this context, the trough can be more use-
ful than the peak anti-Xa level for determining an adequate baseline anticoagu-
lant effect.

8.2.2.3 Reversal
Protamine sulfate is a basic protein that was originally extracted from salmon testi-
cles. It displaces AT and neutralizes heparin by forming a complex with it, and it has
a partial antagonist effect on LMWH. In the absence of heparin, protamine sulfate
shows an anticoagulant effect. It is routinely used after cardiopulmonary bypass,
but rarely for bleeding resulting from heparin administration. The administration of
protamine sulfate can be associated with hemodynamic changes ranging from mild
systemic hypotension to severe pulmonary hypertension with hemodynamic col-
lapse. Several mechanisms can contribute to these effects: direct protamine-induced
histamine release, anaphylactic reactions (IgE mediated), and anaphylactoid reac-
tions (IgG mediated). The immune-mediated reactions can be based on anti-prot-
amine antibodies or on anti-heparin-protamine complex antibodies. It is generally
recommended to slowly administer protamine through a peripheral venous line,
since central venous administration could exacerbate the adverse reactions. Three
elements need to be specified in order to calculate a correct dosage:
1. Route of heparin administration (subcutaneous half-life > intravenous half-life)
2. Type of heparin (half-life of LMWH > half-life of UFH)
3. Delay between heparin administration and protamine sulfate administration
Dosage is also based on the fact that 1 mg of protamine sulfate inactivates 100 IU
of heparin or 100 IU anti-Xa of LMWH.
When the clinical setting requires the neutralization of LMWH’s anticoagulant
effect, the following approach is proposed (Garcia et al. 2012):
• If LMWH was administered within 8 h, protamine sulfate must be given at a dose
of 1 mg per 100 IU of anti-Xa activity up to a maximum single dose of 50 mg
(1 mg enoxaparin equals approximately 100 IU anti-Xa).
• A second dose of 0.5 mg protamine sulfate per 100 IU anti-Xa should be pro-
vided if bleeding persists.
• Smaller doses of protamine sulfate can be administered if the time since LMWH
administration is longer than 8 h.
It is important to accurately calculate the necessary protamine dose since it has
an intrinsic anticoagulant effect, which may lead to increased bleeding in case of an
overdose. Fondaparinux does not bind to protamine sulfate. If uncontrollable bleed-
ing occurs with fondaparinux, recombinant activated FVII may be effective
(Bijsterveld et al. 2002).
8 Antiplatelet Therapy and Anticoagulation 123

8.2.3 Vitamin K Antagonists

Vitamin K antagonists (VKA) are classic oral anticoagulation drugs that generate the
same effect as a vitamin K deficiency. They include phenprocoumon, warfarin, and
acenocoumarol. In elective perioperative settings, these drugs are replaced by UFH,
LMWH, or fondaparinux, as these periods are associated with a thromboembolic risk
of 0–2 % if VKA are interrupted (Mourelo et al. 2008) and a bleeding risk of 2–25 %
if VKA are continued during surgery (Jaffer et al. 2010). There are several ways to
reverse the anti-vitamin K effect. For elective surgery, the patient can simply stop
taking VKA with overlapping treatment of LMWH. If surgery is more urgent, but not
immediate, the patient can receive a vitamin K supplement, for example, 10 mg/day
of intravenous vitamin K1. Finally, for same-day urgent surgery, prothrombin com-
plex concentrates (PCC) can be administered. For a 70 kg patient with an estimated
plasma volume of 2,500 ml, the substitution dose is calculated as follows:

éë( PT aimed% - PT measured% ) / 100 ùû ´ 2, 500

If the patient’s weight is significantly different, the plasma volume can be esti-
mated according to the following formula:

Weight ( kg ) ´ 40 = plasma volume ( ml )

For a durable reversible effect, vitamin K1 is associated with PCC. The duration
of vitamin K1 administration depends on the VKA half-life.

8.2.4 Novel Oral Anticoagulants

8.2.4.1 Introduction
Novel oral anticoagulants (NOACs) specifically target either thrombin or FXa
(Fig. 8.5). They have a rapid onset of action, few drug interactions, and predictable
pharmacokinetics and pharmacodynamics, making routine coagulation monitoring
unnecessary. However, there are situations in which assessment of the anticoagulant
effect of OACs is important: these include hemorrhage or thrombosis occurring
under anticoagulation, emergency surgery, polypharmacy, overdose, renal or liver
failure, compliance monitoring, and extreme bodyweights. Moreover, NOACs
affect routine coagulation tests (Table 8.5).
Management protocols of NOACs prior to elective surgery exist, but clinical
experience is currently insufficient to provide solid guidelines on the management
of emergencies including major bleeding in patients receiving NOACs. No specific
antidotes are available at present.

8.2.4.2 Pharmacology Review

Dabigatran is a selective, competitive, reversible, direct thrombin inhibitor. It is not
absorbed by the intestine and therefore given as an absorbable prodrug, dabigatran
etexilate (Pradaxa™) (Ageno et al. 2012). Its oral bioavailability is low
124 P.-G. Chassot et al.

(approximately 6 %) (Stangier et al. 2007). Absorption of dabigatran etexilate is

influenced by gastric pH; to optimize intestinal absorption, capsules contain tartaric
acid (Connolly et al. 2009). The prodrug is converted into the active compound by
plasma esterases. Peak plasma concentration is reached 1–2 h after intake. In healthy
volunteers, the terminal half-life is ~9 h following a single dose and 12–17 h after
repeated dosing (Stangier et al. 2007; Ageno et al. 2012). A steady-state level is
reached in 2–3 days (Ageno et al. 2012). One-third of the circulating drug is bound
to plasma proteins, and the drug is mainly cleared by the kidneys. Consequently, it
is not recommended to administer the drug to patients with a creatinine clearance
<30 ml/min. Similarly, the drug should not be prescribed to patients with severe
liver failure and should be avoided in pregnant or lactating women.
Rivaroxaban (Xarelto™) specifically and competitively binds to the active site of
FXa and prevents its interaction with prothrombin. Its bioavailability is high (80–
100 %). Peak plasma concentrations are reached after 2–4 h after intake, and the
terminal half-life is between 5 and 13 h (Kubitza et al. 2005; Weitz 2010; Ageno
et al. 2012). Plasma protein binding is high (92–95 %). One-third of the drug is
secreted unchanged by the kidneys, and two-thirds undergo hepatic metabolization
into inactive metabolites by cytochrome P450 CYP3A4. Rivaroxaban is also a sub-
strate of the transporter protein P-glycoprotein. Therefore, competition with other
drugs for either CYP3A4 or P-glycoprotein could lead to clinically significant drug
interactions. The drug should not be prescribed to patients with creatinine clearance
<30 ml/min (Patel et al. 2011), to patients with severe liver dysfunction, or to preg-
nant or lactating women.
Apixaban (Eliquis™) is a selective, reversible, direct FXa inhibitor. This active
drug has a mean bioavailability of 52 %. Plasma concentration peaks 3–4 h after
intake and elimination half-life is 9–14 h (Kubitza et al. 2005; Weitz 2010; Ageno
et al. 2012). Plasma protein binding is high (about 87 %). Apixaban is eliminated by
oxidative metabolism and renal (27 %) and intestinal routes (Zhang et al. 2009).
Similarly to rivaroxaban, any drug interfering with either CYP3A4 or P-glycoprotein
could lead to a clinically significant drug interaction. Apixaban should not be pre-
scribed to patients with severe renal (creatinine clearance <15 ml/min) or hepatic
failure. It should be avoided in pregnant or lactating women.

8.2.4.3 Reversal Prior to Elective Surgery

The reversal strategy for dabigatran should take into account renal function.
Creatinine needs to be checked – and the creatinine clearance calculated – several
days before elective surgery. The interruption protocol for dabigatran further takes
into account bleeding risk and type of surgery (Table 8.6). Thrombin time should be
measured 6–12 h before surgery in patients at high risk of bleeding or if major sur-
gery is planned (van Ryn et al. 2010). A normal result would exclude any residual
anticoagulant effect of dabigatran. If the thrombin time is prolonged, specific tests
should be performed to assess dabigatran concentration (Stangier et al. 2007).
Hemodialysis might be considered in patients with severe renal impairment and
persistently elevated dabigatran plasma concentrations (van Ryn et al. 2010).
For the direct FXa inhibitors, considering their short half-life, cessation of medi-
cation may be sufficient to reverse the anticoagulant effect. However, we suggest
8 Antiplatelet Therapy and Anticoagulation 125

Table 8.6 Reversal of novel anticoagulants prior to elective surgery

Rivaroxaban/apixaban Dabigatran
Invasive High thromboembolic risk High thromboembolic risk
procedures Consider bridging with UFH/ Consider bridging with UFH/LMWH
LMWH
Start with parenteral Start with parenteral anticoagulation
anticoagulation
12–24 h after the last dose of 12–24 h after the last dose of dabigatran
rivaroxaban/apixaban
Low thromboembolic risk or Standard bleeding riskb
high bleeding riska
CrCl ≥50 ml/min: last dose of CrCL ≥80 ml/min: stop dabigatran 24 h before
rivaroxaban ≥24 h before the the procedure
procedure
CrCl <50 ml/min: stop CrCL 50–79 ml/min: stop dabigatran 1–2 days
rivaroxaban at least 24–48 h before the procedure
before the procedure CrCL 30–49 ml/min: stop dabigatran 2–3 days
before the procedure
High bleeding risk/major surgeryb
CrCL ≥80 ml/min: stop dabigatran 2 days
before the procedure
CrCL 50–79 ml/min: stop dabigatran 2–3 days
before the procedure
CrCL 30–49 ml/min: stop dabigatran 4 days
before the procedure
Dental Most dental procedures can be performed without interrupting anticoagulation.
procedures However, the decision needs to be personalized for each patient
Be aware of drug-drug interactions that could influence the elimination of anticoagulants
UFH unfractionated heparin, LMWH low-molecular-weight heparin, CrCl creatinine clearance
a
From Ref. Pengo et al. (2011), Ageno et al. (2012)
b
From Ref. Stangier et al. (2007), Gavillet and Angelillo-Scherrer (2012)

checking renal function and slightly modify the reversal protocol in case of renal
failure (Table 8.6). Reversal can be monitored by measuring anti-FXa activity (spe-
cific assays) (Barrett et al. 2010; Samama et al. 2012).

8.2.4.4 Reversal in an Emergency

There is no evidence-based strategy for emergency reversal of NOACs (Pengo et al.
2011; Ageno et al. 2012). In case of major bleeding, general measures comprise the
following: the discontinuation of the NOAC; the initiation of appropriate clinical
support, including mechanical compression and local as well as surgical hemosta-
sis; blood product transfusion; volume substitution; inotropic drugs; and mainte-
nance of adequate diuresis (Table 8.7). Transfusion of platelet concentrates might
be proposed if thrombocytopenia is present or in case antiplatelet drugs have been
administered. If the initial support described above is insufficient, PCCs, recombi-
nant FVIIa, or FEIBA™ (factor eight inhibitor bypass activity) might be infused
empirically in cases of life-threatening bleeding or emergency surgery (Table 8.7).
The decision to administrate these products should be based upon the clinical
126 P.-G. Chassot et al.

Table 8.7 Reversal of novel anticoagulants in emergency

Bleeding severity Recommendations
Low Delay the next dose of NOAC or stop the treatment
Moderate Appropriate treatment of symptoms
Mechanical compression
Surgical hemostasis
Volume substitution, inotropic drugs, maintenance of an
adequate diuresis
Blood product transfusion
Severe or failure of 1. Prothrombin complex concentrates (PCCs) 25–50 IU/kg IV
symptomatic treatments 2. Factor Eight Inhibitor Bypassing Activity (FEIBA™) 30–50 IU/
kg IV
3. Recombinant activated factor VII (NovoSeven™)
4. Overdose: activated charcoal to reduce absorption (ingestion
<8 h before)
5. Consider hemodialysis for dabigatran
6. Consider plasmapheresis for rivaroxaban or apixaban
Refs. Pharma (2009), Eerenberg et al. (2011), Pengo et al. (2011), Ageno et al. (2012), Warkentin
et al. (2012)
Nota bene: The efficacy of the abovementioned treatments is not evidence based

situation and not on laboratory tests. It is important to realize that these products
are highly prothrombotic and that their administration might be complicated by
thrombotic events. Their use should therefore be limited to life-threatening situa-
tions. For dabigatran, reversal can be monitored by measuring the thrombin time
(see Sect. 8.2.4.3). However, because this test is highly sensitive to dabigatran, an
assessment of its concentration by specific tests would be more accurate (Stangier
et al. 2007). For anti-Xa drugs, reversal can be monitored by measuring anti-Xa
activity (Barrett et al. 2010; Samama et al. 2012). Hemodialysis could complete the
reversal strategy for dabigatran (Warkentin et al. 2012).

8.2.5 Vena Cava Filters

The use of inferior vena cava filter is recommended in patients with acute proximal
deep vein thrombosis and/or pulmonary embolism who have a contraindication to
anticoagulants, i.e., an unacceptable risk of bleeding (Garcia et al. 2012). If the
contraindication to anticoagulation is temporary (e.g., during active bleeding), it is
possible to insert a temporary retrievable filter and remove it when anticoagulation
treatment can be safely restarted. However, it is worth noting that most retrievable
filters are not removed (Mismetti et al. 2007; Dabbagh et al. 2010; Jaff et al. 2011;
Garcia et al. 2012). Furthermore, retrievable filters that do not get removed might
display a higher complication rate than permanent filters (Mismetti et al. 2007,
p 223; Dabbagh et al. 2010, p 493; Nicholson et al. 2010, p 1827).
8 Antiplatelet Therapy and Anticoagulation 127

Insertion of an inferior vena cava filter does not eliminate the risk of pulmonary
embolism and does increase the risk of deep vein thrombosis. Consequently, it is
suggested that patients who have an inferior vena cava filter inserted should receive
a conventional course of anticoagulants when the contraindication to anticoagula-
tion is withdrawn (Garcia et al. 2012). Venous thrombosis at the site of filter inser-
tion occurs in about 10 % of patients (Streiff 2000).

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Intravenous Fluids and Coagulation
9
Herbert Schöchl, Christoph Schlimp,
and Wolfgang Voelckel

9.1 Introduction

In hemorrhagic shock, intravascular hypovolemia is one of the key factors contrib-

uting to insufficient oxygen delivery and subsequent tissue hypoxemia. Thus, in
order to restore tissue perfusion, restoration of intravascular volume is one of the
main aims of shock therapy. Both crystalloid and colloid solutions are frequently
used. Compared to colloids, higher volumes of crystalloids are required to exert an
equal intravascular volume effect (Jacob et al. 2012). It is noteworthy that large
quantities of crystalloids have significant side effects, such as tissue edema, dimin-
ished blood viscosity, and hemostatic alterations. Colloids provide larger increases
in intravascular volume, resulting in faster hemodynamic stabilization. However,
artificial colloids can also cause adverse effects such as anaphylactic reactions,
impairment of renal function, and alteration of hemostasis, which is potentially
associated with an increased tendency to bleed (Choi et al. 1999).
Controversy regarding the optimal choice and composition of resuscitation flu-
ids is ongoing. Randomized controlled trials (RCTs) have failed to prove that
resuscitation with colloid solutions provides survival benefits compared to fluid
therapy with crystalloids (Perel and Roberts 2012). The use of colloids is associ-
ated with an increased mortality compared to crystalloids in patients with severe
sepsis and in trauma patients (Perner et al. 2012). This finding could be related to
the negative effects of colloids on blood coagulation and platelet function

H. Schöchl (*)
AUVA Trauma Center, Salzburg, Austria
Ludwig Boltzmann Institute for experimental and clinical Traumatology, Viennna, Austria
e-mail: [email protected]
C. Schlimp
Ludwig Boltzmann Institute for experimental and clinical Traumatology, Viennna, Austria
W. Voelckel
AUVA Trauma Center, Salzburg, Austria

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 131

DOI 10.1007/978-3-642-55004-1_9, © Springer-Verlag Berlin Heidelberg 2015
132 H. Schöchl et al.

Table 9.1 Mechanisms Direct effects of hemodilution on

potentially related to the (a) Coagulation factor activity
effects of fluid therapy on (b) Inhibitors of the coagulation system
hemostasis
(c) Platelet count
Reduction of coagulation factors
(a) Factor VIII
(b) von Willebrand factor
Diminished fibrin polymerization
(a) Reduction in clot strength
(b) Increased fibrinolysis
Direct effects on platelet function
(a) Coating
(b) Intracellular signal transduction
Changes in blood viscosity

Fig. 9.1 ROTEM® results from an in vitro model of 33 % hemodilution. Two ROTEM® tests were
performed: an extrinsically activated test using tissue factor (EXTEM) and an extrinsically acti-
vated test without platelet component (FIBTEM). The most pronounced reduction in maximum
clot firmness (MCF) was observed with 6 % HES 130/0.4. Dilution of whole blood with 5 %
human albumin and 4 % gelatin produced similar reductions in MCF. Normal saline induced only
moderate changes in MCF

(Schierhout and Roberts 1998). There is a paucity of evidence that one colloid is
superior to another with regard to survival (Bunn and Trivedi 2012).
Infusion of large amounts of fluid results in nonspecific dilution of coagulation
factors, coagulation inhibitors, and platelets (Table 9.1). In addition, the administra-
tion of artificial colloids leads to specific alterations of coagulation factors. Acquired
von Willebrand syndrome and low FVIII activity can be observed, impairing both
9 Intravenous Fluids and Coagulation 133

primary and secondary hemostasis (Kozek-Langenecker 2009). Viscoelastic tests

such as thromboelastometry (ROTEM®) or thrombelastography (TEG®) have shown
that clot strength (i.e., clot quality) is reduced following dilution with artificial col-
loids both in vitro and in vivo (Fig. 9.1) (Jones et al. 2003; Mittermayr et al. 2007;
Fenger-Eriksen et al. 2009). This effect is due to the inhibition of fibrin polymeriza-
tion (Fries et al. 2002; Fenger-Eriksen et al. 2009). Scanning electron microscopy
revealed impairment of the reticular network of fibrin strands following dilution of
blood samples with artificial colloids (Fig. 9.2) (Mardel et al. 1998; Fries et al.
2005; Sorensen and Fries 2012). Platelet dysfunction has also been reported after
infusion of artificial colloids (Gamsjager et al. 2002; Deusch et al. 2004).

9.2 Crystalloid Solutions

Crystalloid fluids are widely used for volume resuscitation. These solutions are safe
and well tolerated at low volumes, but their intravascular volume expansion effect
is low. Within minutes, 80 % or more of the infused volume can cross the capillary

a b

Control Ringer’s lactate

c d

Voluven® Gelofusion®

Fig. 9.2 In vitro effects on clotting of 50 % dilution of whole blood with different fluids: (a) no
dilution (whole blood), (b) Ringer’s lactate, (c) 6 % HES 130/0.4, and (d) 4 % gelatin. 6 % HES
130/0.4 disturbed the fibrin meshwork more than Ringer’s lactate or gelatin (With permission from
Sorensen and Fries (2012))
134 H. Schöchl et al.

membrane from the intravascular compartment into the interstitial space (McIlroy
and Kharasch 2003). Therefore, large amounts of crystalloids are often necessary to
provide a sufficient increase in intravascular volume, introducing a significant risk
of soft tissue edema.
Normal saline (NS) is a solution with 0.9 % of sodium chloride, with an osmo-
lality of 308 mOsm/l. It contains 154 mmol/l of sodium and 154 mmol/l of chlo-
ride. It can therefore be considered neither physiological nor balanced, yet NS is
frequently used as a plasma substitute. In contrast, balanced electrolyte solutions
are isotonic and have electrolyte compositions close to that of plasma (Guidet et al.
2010).

9.2.1 Effect on Coagulation Factors and Thrombin Generation

In vivo and in vitro studies have suggested a hypercoagulable state following mod-
erate hemodilution with crystalloids (Ruttmann 2002; Ruttmann et al. 1996, 2001,
2006; Petroianu et al. 2000; Ng et al. 2002). Other investigators refute such a pro-
hemostatic effect and suggest that these findings are an in vitro phenomenon only
(Innerhofer et al. 2002).
High-volume crystalloid replacement therapy results in dilution not only of pro-
hemostatic coagulation factors but also of coagulation system inhibitors, such as
antithrombin III (AT III) and proteins S and C (Ruttmann et al. 1996). A variety of
positive feedback loops in the clotting mechanism are regulated by AT III; there-
fore, a small change in its concentration may have a profound effect on the initiation
and amplification of the clotting process – potentially much greater than that sug-
gested by the change in absolute concentration (Jesty 1986). Indeed, Dunbar and
Chandler measured thrombin generation in plasma diluted to 40 % of normal,
which resulted in an increase in thrombin generation. Dilution in excess of 40 %,
however, caused a decline in thrombin generation. Thus, when all plasma proteins
decrease at the same time, including inhibitory factors such as AT III, thrombin
generation initially increases (Dunbar and Chandler 2009).

9.2.2 Viscoelastic Findings

Ng et al. studied the effect of hemodilution with NS in patients undergoing major

hepatobiliary surgery. Seven milliliter per kilogram of blood were withdrawn and
simultaneously replaced with 14 ml/kg of NS. They observed decreases in r-time
and in k-time indicating hypercoagulability (Ng et al. 2002). Ruttmann et al.
reported comparable results in patients scheduled for vascular surgery. Randomly
allocated patients received either 1,000 ml Ringer’s lactate (RL) or 500 ml 6 %
hydroxyethyl starch (HES) 200/0.5. In the crystalloid group, TEG measurements
revealed a faster onset of coagulation, an increased rate of clot formation, and an
increase in clot strength. The observed shortening of r- and k-times suggests an
9 Intravenous Fluids and Coagulation 135

imbalance between activated procoagulants and a reduction in anticoagulants, par-

ticularly AT III (Ruttmann et al. 2006).

9.3 Balanced Fluids

When using large quantities of crystalloid solutions, such as NS, development of

dilutional hyperchloremic acidosis has been described (Rehm and Finsterer 2003).
It is well known that acidosis impairs coagulation, particularly platelet function and
thrombin generation (Kermode et al. 1999; Meng et al. 2003). Therefore, it has been
speculated that balanced solutions may potentially avoid or minimize these effects.
However, there is poor evidence that high volumes of NS have a clinically relevant,
negative impact on coagulation, bleeding tendency, or the need for allogeneic blood
transfusion (Gamsjager et al. 2002).

9.3.1 Effects on Coagulation Factors and Thrombin Generation

Brummel-Ziedins et al. measured thrombin production in a dilution model using

different fluids. Fifty percent dilution with NS rapidly decreased thrombin genera-
tion, whereas RL dilution was associated with a constant thrombin generation level.
The authors suggested that this might be explained by RL’s higher Ca++ content
(Brummel-Ziedins et al. 2006).

9.3.2 Clinical Studies

In vivo studies comparing both fluids reported only minor differences between bal-
anced and non-balanced solutions. Waters et al. compared RL with NS in major
aortic surgery. Only minor, nonsignificant differences in blood loss, in favor of RL,
were observed. There were no differences in transfusion of red blood cells (RBCs)
or fresh frozen plasma (FFP) (Waters et al. 2001).
Studies comparing colloids in NS with balanced electrolyte solutions have not
reported relevant differences in blood loss. For example, Casutt et al. revealed that
HES 130/0.4 in a balanced solvent had similar effects on hemostasis (Casutt et al.
2010). Kulla et al. investigated patients undergoing abdominal surgery. No significant
differences in coagulation parameters and blood loss were observed between bal-
anced and unbalanced HES solutions (Kulla et al. 2008). Schaden et al. recently com-
pared two different HES preparations containing tetrastarch in balanced solution, or
NS, in healthy volunteers. Blood was subjected to a blood gas analysis, an assessment
of platelet function by multiple electrode aggregometry, and thromboelastometry.
After infusion of either 20 ml/kg HES in balanced solution or in NS, there was no
significant change in calcium concentration, and only a minor impact on platelet
aggregation and clot formation as assessed by ROTEM® (Schaden et al. 2012).
136 H. Schöchl et al.

9.4 Colloid Solutions

9.4.1 Albumin

Albumin is the major serum protein synthesized in the liver. It contributes to 80 %

of plasma colloid oncotic pressure. The molecular weight (MW) is approximately
66–69 kDa. Intravenous human albumin (HA) is derived from pooled human
plasma, which introduces a theoretical risk of pathogen transmission.
HA is available for intravenous infusion either as an iso-oncotic 4–5 % solution
or as a hyperoncotic 20–25 % solution. It is dissolved in isotonic saline. The volume
efficacy of 4–5 % HA is low. In contrast, the high oncotic load of 25 % HA increases
intravascular volume by approximately five times the volume administered (Hauser
et al. 1980). The serum half-life is about 16–18 h (Scatchard et al. 1944).
The cost of HA is higher than that of colloids or crystalloids, which may limit its
use for routine volume replacement. For patients with hypovolemic shock, there is
no evidence that HA reduces mortality when compared with less expensive alterna-
tives such as crystalloids (Roberts et al. 2011). A large double-blind RCT failed to
demonstrate that 4 % HA confers a clear benefit over NS in critically ill patients
(Finfer et al. 2004). In a subgroup of patients with severe brain trauma, higher mor-
tality was observed among patients receiving 4 % HA, compared with those receiv-
ing NS (Myburgh et al. 2007).

9.4.1.1 Effects on Coagulation Factors and Thrombin Generation

Compared to artificial colloids, the effect of HA on coagulation factor and fibrino-
gen concentration is minor (Lucas et al. 1982; Denis et al. 1987; Myburgh et al.
2007). However, similarly to synthetic colloids, the oncotic pressure of HA can
cause an efflux of plasma proteins to the interstitial fluid space which might affect
coagulation (Lucas et al. 1982; Denis et al. 1987). An animal study revealed that,
compared with crystalloid resuscitation, HA-supplemented fluid therapy signifi-
cantly reduced fibrinogen and factor VIII concentration and increased prothrombin
time (PT) (Johnson et al. 1979).
Kheirabadi et al. compared 5 % HA with 6 % HES 670/0.7 (Hextend™) and 6 %
dextran 70 in a 40 % hemodilution model in rabbits. Thrombin generation assays
revealed a shortened lag time in the HA group. Total thrombin generation and maxi-
mum thrombin concentration were unchanged in HA-diluted samples but decreased
significantly following dilution with synthetic colloids. Total blood loss was lowest
in the HA group (Kheirabadi et al. 2008).

9.4.1.2 Viscoelastic Findings

TEG analyses from the Kheirabadi study revealed a shortened r-time in the albumin
group. Maximum clot strength was significantly reduced in all three groups but
again decreased less in the HA group (Kheirabadi et al. 2008). Coats et al. studied
in vitro dilution of whole blood to 40 % using different resuscitation fluids. A
Sonoclot™ device was used to measure the clots’ viscoelastic properties. Of all the
investigated colloids, 3.5 % urea cross-linked gelatin (Haemaccel®) had the fewest
9 Intravenous Fluids and Coagulation 137

effects on dynamic clot formation, followed by HA. The latter reduced activated
clotting time by 2 % and exhibited a 47 % reduction in clot rate (rate of fibrin forma-
tion) (Coats et al. 2006).
Our own group recently compared NS with 5 % HA, 4 % gelatin, and 6 % HES
130/0.4 in an in vitro dilution model investigating ROTEM® variables. Compared to
undiluted whole blood, 33 % in vitro hemodilution with 5 % HA reduced maximum
clot firmness in the extrinsically activated EXTEM test, and a more pronounced
reduction was observed in the fibrin polymerization test (FIBTEM). Our in vitro
study confirmed the observation that 5 % HA has less effect on ROTEM® test results
than other colloids (Schlimp et al. 2013).

9.4.1.3 Effects on Platelets

Evans et al. investigated the effects of different fluids on platelet aggregation and
agglutination in orthopedic patients. HA significantly reduced aggregation in
response to collagen. In contrast, a small but significant increase in agglutination
was also observed in the albumin group (Evans et al. 2003).

9.4.1.4 Clinical Studies

Niemi et al. studied the effect of 4 % HA and 6 % HES 120/0.7 in patients undergo-
ing total hip arthroplasty. Postoperatively, Von Willebrand factor (vWF) was higher
in the HA group, but no differences were observed in blood loss (Niemi et al. 2005).
The same group investigated the effect of postoperative administration of different
colloids on hemostasis in 45 patients following cardiac surgery. The most pro-
nounced impairment of coagulation was found after administration of 6 % HES
200/0.5. HA appeared to have the least effect on hemostatic variables, including
ROTEM® parameters (Niemi et al. 2006) (Table 9.2).
One study has reported hemostatic alterations following HA administration.
Johnson et al. found impaired coagulation in trauma patients after administering HA
as a supplement to massive transfusion. During the first 5 postoperative days, patients
receiving HA required more RBC units (7.1 vs. 3.8) and more FFP (455 ml vs. 317 ml).
The authors suggested that HA may exert antihemostatic and platelet-lowering effects,
with a risk of increased blood loss after surgery or trauma (Johnson and Criddle 2004).

9.4.2 Dextran

Dextrans are mixtures of polydisperse polysaccharides of various sizes and MWs.

They are produced by the dextransucrase enzyme during growth of Leuconostoc
bacteria in media containing sucrose. Between 50 and 70 % of dextran molecules
are excreted unchanged via urine. Dextranase completely metabolizes the remain-
ing dextran molecules to CO2 and H2O. Dextrans have MWs ranging from 40 to
70 kDa and are dissolved in NS. Dextran 70 is usually available as a 6 % solution,
while dextran 40 is usually a 10 % solution. Due to its higher concentration, dextran
40 is a more potent volume expander than dextran 70, exerting higher colloid
oncotic pressure. However, the volume expansion effect of dextran 40 is short lived
138 H. Schöchl et al.

Table 9.2 Effects of different fluids on hemostatic variables

Heta/penta HS/
Crystalloids Albumin Dextrane Gelatin starch Tetrastarch HHS
Levels of ↔ ↔ ↓↓↓ ↓ ↓↓ ↓ ↔
vWF and F
VIII
Thrombin ↑ ↔ ↓ ↓ ↔
generation
Viscoelastic
coagulation
tests
r + k-time ↑ ↓ ↓↓↓ ↓ ↓ ↓↓
CT, CFT
Maximum ↓ ↓ ↓↓↓ ↓↓ ↓↓↓ ↓↓↓ ↓
clot firmness
Platelet ↔ ↔ ↓↓↓ ↓ ↓↓ ↓ ↓↓
function
CT coagulation time, CFT clot formation time, k-time clotting time, r-time reaction time, vWF von
Willebrand factor, HS/HSS hypertonic saline/hyperoncotic-hypertonic solutions

due to the fact that it is eliminated by the kidneys more quickly than other colloids
(de Jonge and Levi 2001).
In most European countries, dextrans have disappeared from the market due to
potentially life-threatening side effects such as severe anaphylactic reactions, acute
renal failure, and bleeding diatheses.

9.4.2.1 Effects on Coagulation Factors and Thrombin Generation

Both dextran 40 and dextran 70 produce dose-related hemostatic defects additional to
the effects of hemodilution. Dextran 70 appears to cause a significantly greater impair-
ment of coagulation than dextran 40 (Batlle et al. 1985; de Jonge and Levi 2001).
Dextran’s inhibitory effects on coagulation have been attributed to reductions in the
activity or plasma levels of factors V, VII and VIII, and vWF (Batlle et al. 1985).
Furthermore, increased fibrinolysis has been reported following dextran infusion. It
has been suggested that increased plasma concentrations of tissue plasminogen activa-
tor (t-PA) and decreased levels of its most important antagonist, plasminogen activator
inhibitor 1 (PAI-1), are responsible for these findings (Eriksson and Saldeen 1995).

9.4.2.2 Viscoelastic Findings

TEG measurements indicate that dextrans bind to fibrinogen and interfere with
fibrin cross-linking, reducing clot elasticity or clot strength. Fifty percent dilution of
blood with 10 % dextran 40 completely inhibited clot formation in TEG analysis
(Mortier et al. 1997).

9.4.2.3 Effects on Platelets

Dextran’s effect on platelet function is multifactorial; they relate to reductions in
platelet adhesion and aggregation and vWF inhibition (Batlle et al. 1985). Dextran
molecules are understood to exert a coating effect on cellular elements of the blood,
9 Intravenous Fluids and Coagulation 139

including platelets. Prolonged bleeding times, observed after dextran infusion, are
in part related to diminished platelet function (Alexander et al. 1975).

9.4.2.4 Clinical Studies

Dextrans have been used for the prevention of postoperative venous thrombosis and
pulmonary embolism (Clagett et al. 1995; de Jonge and Levi 2001). In order to
minimize the risk of bleeding, dextran infusion should be restricted to patients with
normal hemostasis. An upper limit of 20 ml/kg/day should not be exceeded. Patients
with renal insufficiency face an increased risk of bleeding because of dextran’s pro-
longed intravascular half-life and the likelihood of uremic platelet dysfunction (de
Jonge and Levi 2001).

9.4.3 Gelatin

Gelatins are polydisperse polypeptides with an MW of approximately 35 kDa, man-

ufactured by degradation of bovine collagen (de Jonge et al. 1998). Two different
formulations of gelatin are available: 4 % succinylated gelatin (Gelofusine®) and
3.5 % polygeline (Haemaccel®; degraded gelatin polypeptides cross-linked by
urea). Due to their small MW, up to 50 % of gelatins are cleared within 4–6 h after
administration, and complete plasma clearance is achieved within 3 days. Gelatins
have the advantage of an unlimited daily dose. However, of all the artificial colloids,
gelatins carry the highest risk of anaphylactic reaction (Laxenaire and Mertes 2001),
and like other artificial colloids, they affect the coagulation system and platelet
function (Van der Linden and Schmartz 1992).

9.4.3.1 Effect on Coagulation Factors and Thrombin Generation

Infusion of 1 l of gelatin-based solution in healthy volunteers decreases thrombin
generation, as assessed by the measurement of thrombin–antithrombin complexes and
prothrombin fragment F1 + 2. Compared with NS, a 1.7-fold increase in bleeding time
has been observed at 60 min and a 1.4-fold increase at 120 min (de Jonge et al. 1998).

9.4.3.2 Viscoelastic Studies

Several studies have shown a significant reduction in maximum clot firmness (clot
strength) in response to gelatin hemodilution; this is attributed to impaired fibrin
polymerization (Egli et al. 1997; Mardel et al. 1998; Fenger-Eriksen et al. 2009; Jin
and Yu 2010). The effect is most pronounced when using a fibrin polymerization
test (e.g., the FIBTEM test in ROTEM®) (Schlimp et al. 2013).
In vitro experiments have shown that hemodilution with gelatin reduces maxi-
mum clot firmness to a greater extent than NS (de Jonge et al. 1998; Mardel et al. 1998).
Mardel et al. compared Haemaccel® and Gelofusine® with RL and found signifi-
cantly lower clot elasticity with both gelatin preparations (26.2 and 22.2 % lower
than RL, respectively) (Mardel et al. 1998). One suggested mechanism is that gelatin
binds with fibronectin and decreases the plasma concentration of this protein (Engvall
et al. 1978; Brodin et al. 1984). Fibronectin contributes to clot stability by forming
covalent cross-links with fibrin. Furthermore, it is suggested that gelatin might be
140 H. Schöchl et al.

incorporated into the clot as it forms, interfering with fibrin architecture and impair-
ing the clot’s strength and stability (Mardel et al. 1998; Kheirabadi et al. 2008).

9.4.3.3 Effects on Platelets

Following infusion, Gelofusine® has been shown to exert a small, transient inhibitory
effect on platelet aggregation (Evans et al. 1998). In the same study, Haemaccel®
showed more significant inhibition of platelet aggregation through the glycoprotein
(GP) IIb/IIIa receptors. Furthermore, gelatin administration decreases plasma levels
of vWF. Aggregation studies have also revealed significant impairment of ristocetin-
induced platelet aggregation, suggesting additional interference via the GP Ib recep-
tor (Tabuchi et al. 1995). Overall, the prolonged bleeding times observed with gelatin
could be a consequence of impaired primary hemostasis (de Jonge et al. 1998).

9.4.3.4 Clinical Studies

It is uncertain whether gelatin infusion increases bleeding tendency. To date, only
one study in cardiac surgery patients has reported increased blood loss following
gelatin infusion, in comparison with albumin (Tabuchi et al. 1995).
Karoutsos et al. studied 42 ASA I patients undergoing total hip or knee replace-
ment. The effects of moderate intraoperative hemodilution with gelatin, HES, or
5 % HA were assessed using TEG. Findings differed from the abovementioned
studies, as they found clear evidence of a state of hypercoagulability in the gelatin
group, with significant decreases in r- and k-time and an increase in alpha angle.
There were no significant between-group differences in intraoperative blood loss
and RBC transfusion (Karoutsos et al. 1999).

9.4.4 Starches

HES are derived from amylopectin and consist of highly branched polysaccharides,
similar to glycogen. HES solutions are available either as iso-oncotic 6 % or hyper-
oncotic 10 % fluids. The volume effect of a 10 % solution exceeds the infused vol-
ume, and it is therefore considered a plasma expander (Westphal et al. 2009).
Compared to gelatin and crystalloids, the initial volume expansion of HES is greater
and lasts longer (Van der Linden and Ickx 2006).
HES are polydisperse fluids with a wide range of MW. HES solutions can be
categorized as high-MW (>400 kDa), medium-MW (200–400 kDa), and low-MW
fluids (<200 kDa) (Jungheinrich and Neff 2005).
The most important physicochemical aspect of HES is the degree of substitution,
defined as the proportion of hydroxyl groups per glucose molecule replaced by
hydroxyethyl subunits. Increased substitution increases the solubility of starch in
water and, more importantly, reduces the rate of destruction by serum amylase
(Kozek-Langenecker 2005). Highly substituted (hetastarch 0.62–0.75), medium-
substituted (pentastrach 0.5), and low-substituted (tetrastarch 0.4) HES preparations
are available.
9 Intravenous Fluids and Coagulation 141

HES substitution is possible at different positions of the glucose molecule, with

the C2 to C6 ratio describing the ratio of hydroxyethyl group substitutions at these
positions. It has been shown that a high C2 to C6 ratio reduces degradation of the
HES molecule by α-amylase and delays elimination from the bloodstream
(Karoutsos et al. 1999). Newer HES preparations have low MW and low substitu-
tion of hydroxyethyl subunits, resulting in rapid metabolism and clearance.
The mechanisms of coagulopathy induced by HES infusion are multifactorial:
slow degradation of HES enables interaction with platelets, the coagulation cas-
cade, and the fibrin polymerization process (Kozek-Langenecker 2005). Thus, it has
been suggested that HES solutions with a prolonged half-life produce more pro-
nounced side effects than those with a short half-life. First- and second-generation
HES solutions were associated with adverse effects on renal function, tissue stor-
age, and coagulopathy. Modern, rapidly degradable HES formulations have less of
an impact on the coagulation cascade, particularly the factor VIII–vWF complex
(Jungheinrich et al. 2004).

9.4.4.1 Effect on Coagulation Factors and Thrombin Generation

Acquired von Willebrand syndrome, together with a decrease in circulating factor
VIII of up to 80 %, has been reported in both healthy volunteers and patients receiv-
ing HES (Kapiotis et al. 1994; Conroy et al. 1996; Jamnicki et al. 2000; Jones et al.
2003; Jungheinrich et al. 2004; Jungheinrich and Neff 2005; Kozek-Langenecker
2005; Van der Linden and Ickx 2006). Kapiotis et al. compared the effect of 6 %
HES 200/0.5 in isotonic saline with 5 % HA using healthy volunteers. The infusion
of 500 ml significantly reduced levels of factor VIII:C in the HES group. However,
there were no significant differences between the study groups regarding other
coagulation and fibrinolytic parameters, such as activated partial thromboplastin
time (aPTT), fibrinogen, thrombin–antithrombin complexes, d-dimers, t-PA, and
PAI-1 (Kapiotis et al. 1994). Recent studies have suggested that rapidly degradable
HES solutions have only minor effects on coagulation. Even high doses of tetra-
starch (50–70 ml/kg) did not impair factor VIII activity (Kasper et al. 2003; Neff
et al. 2003).
Fenger-Eriksen et al. studied cancer patients following 30 % hemodilution with
HES 130/0.4. Fibrinogen, factor II, factor X, and factor XIII decreased significantly
below levels typically expected from dilution. Endogenous thrombin potential,
however, remained unchanged (Fenger-Eriksen et al. 2009).

9.4.4.2 Viscoelastic Studies

The study by Fenger-Eriksen et al. revealed that 30 % hemodilution with HES
130/0.4 had no significant effect on whole-blood clotting time or maximum velocity
of clot formation, compared with baseline observations (Fenger-Eriksen et al. 2009).
However, both in vivo and in vitro studies have reported early, dose-dependent dis-
turbances in fibrin polymerization following HES infusion (Treib et al. 1999; Kozek-
Langenecker 2005). This results in a marked decrease in the velocity of clot formation,
together with a decrease in the α-angle (Schramko et al. 2010; Schlimp et al. 2013).
142 H. Schöchl et al.

More importantly, a pronounced and significant reduction in maximum clot firm-

ness has been observed. In particular, fibrin-based assays, such as FIBTEM, reveal
significantly diminished fibrin polymerization following dilution with HES products
(Fries et al. 2002, 2005; Schramko et al. 2010; Schlimp et al. 2013). Only minor
differences between HES 130/0.4 and HES 200/0.5 have been identified (Jamnicki
et al. 1998; Entholzner et al. 2000; Sossdorf et al. 2009; Casutt et al. 2010).
Some studies suggest that HES solutions might also increase clot lysis
(Mittermayr et al. 2008). In an in vivo study, Jamniki et al. investigated TEG find-
ings following hemodilution with HES 200/0.5 and HES 130/0.4. Clot lysis after
60 min increased significantly after hemodilution with both fluids (Jamnicki et al.
1998).

9.4.4.3 Effects on Platelets

HES solutions have been shown to reduce the platelet contribution to hemostasis.
Several mechanisms have been proposed, such as a decrease in expression and
availability of the GP IIb/IIIa receptors (Stogermuller et al. 2000; Deusch et al.
2003; Thaler et al. 2005). Coating of platelets by HES macromolecules, nonspecific
modification of cytoplasmic membrane structures, and consequent inhibition of
conformational changes to GP IIb/IIIa receptors have all been discussed
(Stogermuller et al. 2000). In vitro studies have identified nonspecific binding of
HES molecules to platelet surfaces as a potential mechanism of HES-induced plate-
let inhibition (Deusch et al. 2003). In healthy volunteers, slowly degradable HES
significantly prolongs PFA-100 closure times (Stogermuller et al. 2000). In addition
to these direct effects, decreased vWF activity may further reduce platelet respon-
siveness after HES administration (Strauss et al. 2002). However, rapidly degrad-
able HES has only minor effects on platelet function (Franz et al. 2001). Further,
HES does not seem to affect intracellular signal transduction of platelets (Gamsjager
et al. 2002).
One study randomly assigned 30 patients with cerebrovascular disease to receive
daily infusions of up to 1.5 l of 6 % HES 200/0.62, 10 % HES 200/0.5, or 6 % HES
40/0.5. Platelet count significantly decreased in all three groups, but the largest drop
was observed in the HES 200/0.62 group. The authors speculate that HES macro-
molecules attach to platelets and are subsequently phagocytosed (Treib et al. 1996).

9.4.4.4 Clinical Studies

Despite their negative side effects on laboratory and viscoelastic parameters, mod-
ern, rapidly degradable HES 130/0.4 solutions have not been shown to increase
blood loss. A double-blind RCT of 42 patients with severe blunt trauma compared
resuscitation using 6 % HES 130/0.4 versus NS. The HES group required signifi-
cantly more blood products than patients receiving NS; however, the mean injury
severity score was significantly higher in the HES group. The effect of HES on
blood loss thus remains unclear (James et al. 2011). Studies in orthopedic and car-
diac surgery patients show that 6 % HES 130/0.4 is associated with lower blood loss
and transfusion requirements than 6 % HES 200/0.5 (Langeron et al. 2001; Niemi
et al. 2005).
9 Intravenous Fluids and Coagulation 143

Studies comparing 3.5 % urea-linked gelatin and 6 % HES 130/0.4 reported no

significant differences in either the number of patients receiving allogeneic blood
products or the volume of RBCs, FFP, or platelets administered (Van der Linden
et al. 2005; Schramko et al. 2010).
Mittermayr and coworkers investigated 61 orthopedic patients who received 6 %
HES 130/0.4, 4 % gelatin, or RL solution. The RL group had the lowest number of
patients receiving allogeneic blood products. The highest number of RBCs was
transfused to the gelatin group. However, significant differences in baseline hemo-
globin levels between the study groups made interpretation of these results difficult
(Mittermayr et al. 2007).

9.5 Hypertonic–Hyperoncotic Solutions

In experimental and preclinical studies, rapid infusion of small amounts (4 ml/kg)

of hypertonic 7.2–7.5 % saline (HS) solutions have proved to be effective in hypo-
tensive patients, with rapid restoration of cardiovascular function and tissue blood
flow (Velasco et al. 1980; Tollofsrud et al. 1998). For the restoration of intravascular
volume, the infusion of 4 ml/kg 7.5 % HS was reported to be as effective as an infu-
sion of 2–3 l of crystalloids. Improvement in cardiovascular function has been
attributed to the redistribution of body water from the extravascular to the intravas-
cular compartment by the osmotic forces of HS (~2,400 mosm/l) (Smith et al.
1985). However, the vascular volume expansion is relatively transient unless an
oncotically effective colloid (e.g., dextran 70 or a starch) is combined with HS to
hold the fluid in circulation. These fluids are called hypertonic–hyperoncotic solu-
tions (HHS) (Angle et al. 1998). Numerous animal studies have revealed attenuated
inflammation, enhanced organ function, and improved survival rates following
hemorrhagic shock and resuscitation with HS/HHS (Smith et al. 1985; Angle et al.
1998).
A recent RCT investigated the effect of out of hospital infusions of HS, HHS,
and NS in hypotensive trauma patients. This study was unable to demonstrate a
clinically significant survival benefit of HS when it was infused during the early
phase of hemorrhagic shock treatment. It is noteworthy that, in the subgroup of
patients who received no blood transfusions in the first 24 h, infusions of HS
increased mortality (Bulger et al. 2011).
Similar results have been found in patients with severe isolated brain injury.
Among patients with severe traumatic brain injury, but not in hypovolemic shock,
initial resuscitation with either HS or HHS provided no benefit over NS, in terms of
6-month neurological outcome (Bulger et al. 2010).

9.5.1 Effects on Coagulation Factors and Thrombin Generation

Several different HS preparations, from 1.6 to 29.9 %, with and without the addition
of artificial colloids, have been used in experimental and clinical studies (Johnson
144 H. Schöchl et al.

and Criddle 2004). However, sound conclusions regarding the influence of HS/HHS
are impossible due to the heterogeneity of the fluids.
Coats et al. investigated the in vitro effect of HHS (including dextran) on coagu-
lation. A mild pro-hemostatic effect was observed up to a dilution of 11 %, but
anticoagulant properties were evident above this level. At 15 % dilution, coagula-
tion was grossly deranged (Coats and Heron 2004).
Wilder et al. reported that HS has strong anticoagulant and antiplatelet effects.
Dilution with HS to a level of only 5 % caused a significant prolongation of PT. In
contrast, there was no significant change in PT following 5 % dilution with hyper-
tonic sorbitol or mixtures based on glycine (Wilder et al. 2002).
A 20 % dilution with 3 % saline resulted in a 52 % reduction of thrombin genera-
tion and 11 % reduction of fibrin formation. Increasing the dilution to 30 %
decreased fibrin formation by 89 % (Brummel-Ziedins et al. 2006).

9.5.2 Viscoelastic Tests

In vitro, 10 % dilution of blood with HHS has been shown to cause significant
impairment of fibrin polymerization (Hanke et al. 2011). Haas et al. studied the
effect of HHS in vivo in an uncontrolled bleeding model in pigs. Median fibrinogen
polymerization was significantly higher among animals receiving HHS, compared
with those receiving 4 % gelatin or 6 % HES 130/0.4. Furthermore, median blood
loss after liver incision was significantly lower in the HHS group (Haas et al. 2008a).

9.5.3 Effects on Platelets

In one study, platelet activation, as determined by α-granule release, decreased by

40 % following 10 % dilution of whole blood with HHS. Complete cessation of
platelet activation was observed after 20 % dilution (Brummel-Ziedins et al. 2006).
The authors suggested that platelets shrink and become dysfunctional, diminishing
the surface required for propagation of thrombin generation (Brummel-Ziedins
et al. 2006).
Wilder et al. reported that platelet function was critically impaired by HS hemo-
dilution at a level of just 5 % (Wilder et al. 2002). Hanke et al. used multiple elec-
trode aggregometry to study platelet function in whole blood following HS and
HHS dilution in vitro. With 5 % dilution, both dilutants impaired platelet aggrega-
tion (Hanke et al. 2011).

9.6 Restoring Coagulation After Dilution Coagulopathy

All artificial colloids interfere with the process of fibrinogen polymerization, reduc-
ing maximum clot firmness in viscoelastic coagulation tests. To overcome this prob-
lem, fibrinogen supplementation has proved effective both in vitro and in vivo (Fries
et al. 2005; Schramko et al. 2009; Grottke et al. 2010; Schlimp et al. 2013). Using a
9 Intravenous Fluids and Coagulation 145

a b c

Fig. 9.3 Electron microscopy scans of blood clots formed from (a) undiluted whole blood,
(b) blood diluted 65 % with gelatin, and (c) blood diluted 65 % with gelatin and the addition of
fibrinogen concentrate (With permission from Fries and Martini (2010))

33 % in vitro dilution model, Schlimp et al. recently showed that fibrinogen concen-
trate was effective in increasing clot firmness in blood samples diluted with either
albumin or gelatin. In samples diluted with HES, however, the effect was poor
(Schlimp et al. 2013). Fries et al. reported improved clot firmness following fibrino-
gen administration in a porcine model of uncontrolled bleeding (Fig. 9.3) (Fries
et al. 2005). Grottke et al. replaced 80 % of blood volume with HES 130/0.4, RL,
and retransfused erythrocytes. The animals randomly received 70 mg/kg fibrinogen
concentrate, 200 mg/kg fibrinogen concentrate, or a placebo before blunt liver
injury was induced. Total blood loss was significantly lower, and survival was sig-
nificantly higher, in both fibrinogen groups as compared to controls. Microscopy
revealed no thrombosis in either group (Grottke et al. 2010).
Factor XIII supplementation, together with fibrinogen, partially restores clot forma-
tion in blood samples diluted in vitro with different colloids (Niemi et al. 2005). Again,
the effect is significantly lower in the HES group compared to albumin and gelatin.
The combination of factor XIII and fibrinogen effectively normalized maximum clot
firmness in blood samples diluted with either albumin or gelatin. Haas and coworkers
further investigated the effect of fibrinogen, factor XIII, and FFP in a 60 % hemodilu-
tion model. Fibrinogen together with factor XIII restored crystalloid-induced impair-
ment of clot strength, while FFP only shortened coagulation times (Haas et al. 2008b).
As shown in elective surgery patients, desmopressin has the potential to reverse
the colloid-induced decreases in levels of factor VIII and vWF (Conroy et al. 1996).
Another potential option for such reversal is the administration of factor VIII/vWF
concentrate, but there are no clinical data to support this strategy.

Conclusion
Crystalloids exert only minor effects on coagulation parameters, apart from the
effects of hemodilution. Artificial colloids impair coagulation and platelet func-
tion to a greater extent than natural colloid albumin. Gelatin and rapidly degrad-
able, short-acting HES seem to have similar effects on blood loss. There is no
conclusive evidence that balanced solutions are superior to non-balanced fluids.
146 H. Schöchl et al.

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Deusch E, Thaler U et al (2004) The effects of high molecular weight hydroxyethyl starch solu-
tions on platelets. Anesth Analg 99(3):665–668
Dunbar NM, Chandler WL (2009) Thrombin generation in trauma patients. Transfusion
49(12):2652–2660
Egli GA, Zollinger A et al (1997) Effect of progressive haemodilution with hydroxyethyl starch,
gelatin and albumin on blood coagulation. Br J Anaesth 78(6):684–689
Engvall E, Ruoslahti E et al (1978) Affinity of fibronectin to collagens of different genetic types
and to fibrinogen. J Exp Med 147(6):1584–1595
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starch (HES 130/0.4) compared to hydroxyethyl starches with higher molecular weight. Acta
Anaesthesiol Scand 44(9):1116–1121
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and plasminogen activator inhibitor-1 (PAI-1) during surgery. Acta Anaesthesiol Scand
39(2):163–166
9 Intravenous Fluids and Coagulation 147

Evans PA, Glenn JR et al (1998) Effects of gelatin-based resuscitation fluids on platelet aggrega-
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148 H. Schöchl et al.

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as a part of a balanced-volume resuscitation in abdominal surgery. Anästhesiol Intensivmed 1:7–18
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McIlroy DR, Kharasch ED (2003) Acute intravascular volume expansion with rapidly administered
crystalloid or colloid in the setting of moderate hypovolemia. Anesth Analg 96(6):1572–1577
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implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients.
J Trauma 55(5):886–891
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istration during major orthopedic surgery: the role of fibrinogen administration. Anesth Analg
105(4):905–917
Mittermayr M, Streif W et al (2008) Effects of colloid and crystalloid solutions on endogenous
activation of fibrinolysis and resistance of polymerized fibrin to recombinant tissue plasmino-
gen activator added ex vivo. Br J Anaesth 100(3):307–314
Mortier E, Ongenae M et al (1997) In vitro evaluation of the effect of profound haemodilution with
hydroxyethyl starch 6%, modified fluid gelatin 4% and dextran 40 10% on coagulation profile
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9 Intravenous Fluids and Coagulation 149

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150 H. Schöchl et al.

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Split Blood Products
10
Theresa M. Boyd, Evelyn Lockhart, and Ian Welsby

10.1 Plasma

10.1.1 Product Description and Selection for Transfusion

Plasma is the acellular fraction of blood, separated from the cellular blood compo-
nents either by centrifugation of citrated whole blood or donor apheresis, with typi-
cal unit volumes averaging from 200 to 300 mL. There are several types of plasma
products used for supplementation or replacement of soluble coagulation factors.
The most widely recognized plasma component is fresh frozen plasma (FFP), which
requires freezing at −18 °C within 6–8 h of collection (AABB 2013a). Plasma fro-
zen within 24 h after phlebotomy (FP24) is similar to FFP in its preparation but
differs in that it may be frozen at or below −18 C within 24 h after collection. Frozen
plasma products prepared for transfusion requires thawing and warming to between
30 and 37 C. This takes 20–30 min, depending upon the equipment used for thawing
and the unit volume. If the prepared plasma is not transfused within the initial 24-h
post-thaw period, it can be relabeled as “thawed plasma” for use within 5 days after

T.M. Boyd, MD
American University of the Caribbean School of Medicine,
Medical Sciences Campus, #1 University Drive at Jordan Road, Cupecoy, Dutch Lowlands,
St. Maarten
e-mail: [email protected]
E. Lockhart, MD
Department of Pathology, Clinical Director of Transfusion Medicine, Duke University Health
System, Rm 1720, Duke North, DUMC 2928, Durham, NC 27710, USA
e-mail: [email protected]
I. Welsby, MBBS, FRCA (*)
Duke University, 2301 Erwin Rd, 3094, Durham, NC 27710, USA
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 151

DOI 10.1007/978-3-642-55004-1_10, © Springer-Verlag Berlin Heidelberg 2015
152 T.M. Boyd et al.

the initial thaw (AABB 2013a; Benjamin and McLaughlin 2012; Eder and Sebok
2007). The utility of thawed plasma is twofold: (1) it provides rapidly available
plasma for the management of massive hemorrhage, and (2) it extends available
plasma inventory by avoiding wastage of plasma suitable for transfusion (Downes
et al. 2001). One rarely used plasma product, available in the USA, is liquid plasma.
Unlike the previously described plasma products, liquid plasma has never been fro-
zen; it is separated from a whole blood unit no later than 5 days before its expiration
date and has a shelf life of 26 days from the date of the source blood collection
(40 days if CPDA-1 is used as the anticoagulant for the parent component) (AABB
2013a; Benjamin and McLaughlin 2012).
Forms of pathogen-reduced plasma are widely available in Europe but until
recently have not been available in the USA. Solvent/detergent-treated plasma (S/D
plasma) is one of the most frequently used pathogen-reduced plasma products.
Pooled plasma composed of a given ABO type undergoes viral inactivation with
solvents (i.e., 1 % tri(n-butyl) phosphate) and detergents (i.e., 1 % Triton-X 100),
which are subsequently extracted by oil and affinity ligand chromatography for
selective binding of prion proteins (PrPSc). This treatment significantly inactivates
lipid-enveloped viruses such as HIV and Hepatitis C as well as cellular pathogens
such as bacteria and protozoa. While the pathogen inactivation process is ineffective
against non-lipid-enveloped viruses such as hepatitis A (HAV) and parvovirus B19,
product specifications identify minimum levels of B19 and hepatitis E virus (HEV)
genetic material permissible, as well as minimum levels of neutralizing antibodies
directed against HAV and B19 (Benjamin and McLaughlin 2012). This product had
not been approved for use in the USA until January 2013, when the FDA approved
Octaplas® (Octapharma, Austria) for transfusion (FDA 2013; Riedler et al. 2003;
Ozier et al. 2011; Sachs et al. 2005; Sinnott et al. 2004).
Methylene blue (MB)-treated plasma is another pathogen-reduced product
available in Europe. Methylene blue is an aniline dye which, upon light activation,
generates reactive oxygen species that inactivate enveloped and some nonenvel-
oped viruses, with lesser activity directed against protozoa and bacteria (Benjamin
and McLaughlin 2012). Unlike S/D plasma, MB plasma is a single donor
component.
Plasma contains ABO isoagglutinins, the naturally occurring antibodies directed
against ABO antigens, and therefore must be ABO compatible with the recipient’s
red cells (see Table 10.1); however, cross-matching is not required. Group AB
plasma, which lacks antibodies directed against A and B antigens, is compatible
with all blood types and is used as emergency release plasma when there is insuffi-
cient time for determining the recipient’s blood type (Wehrli et al. 2009). The Rh
(D) type is not always matched because immunization to Rh (D) antigen has rarely
been reported as a result of transfusion of Rh (D)-positive plasma to Rh (D)-negative
individuals. Hemolytic reactions as a consequence of infusion of an undetected anti-
body directed toward recipient RBC antigens are rarely seen, as is alloimmunization
to RBC antigens (Ching et al. 1991).
10 Split Blood Products 153

Table 10.1 ABO compatibility of blood components

Recipient ABO-compatible blood components

blood Recipient Whole Packed
group alloantibodies blood red cells Plasma Cryoprecipitate Platelets
A Anti-B A A or O A or AB A or AB A or AB
(preferred) (preferred)
B Anti-A B B or O B or AB B or AB B or AB
(preferred) (preferred)
AB Nil AB O, A, B, AB AB (preferred) AB (preferred)
or AB
O Anti-A and O O A, B, AB, Any Any
anti-B or O
For platelet transfusions given to small pediatric or infant patients, the donor plasma should be
ABO compatible with recipient red cells. Note the rare AB group is the universal plasma donor,
while the common O group is the universal PRBC donor. ABO compatibility is required for plasma
but may be waived in some circumstances for adult patients receiving cryoprecipitate or platelets

10.1.2 Indications

Notable variation exists in published guidelines for plasma transfusion (ASA 2006;
Ferraris et al. 2011; Iorio et al. 2008; O’Shaughnessy et al. 2004; Fuller and Bucklin
2010; Roback et al. 2010), although there is agreement on its indication for replace-
ment of coagulation factors in bleeding or surgical patients, particularly those suf-
fering from disseminated intravascular coagulation (DIC) or undergoing massive
transfusion. Many guidelines recommend using the international normalized ratio
(INR) at or greater than 1.5 as an indication for plasma transfusion (O’Shaughnessy
et al. 2004). However, a consensus on laboratory value “triggers” for plasma trans-
fusion has not been reached. For massive hemorrhage, empiric transfusion of plasma
in set ratios to RBC units is widely practiced in the USA (Holcomb et al. 2013; Dzik
et al. 2011). Retrospective and observational studies on massive transfusion in mili-
tary and civilian trauma have reported associations between higher plasma/RBC
transfusion ratios and improved survival (Holcomb et al. 2013; Borgman et al. 2007;
Shaz and Hillyer 2010), although definitive data on optimal use of plasma in this
setting has yet to emerge (Holcomb et al. 2013).
Plasma is also indicated as a replacement fluid in therapeutic apheresis for throm-
botic thrombocytopenia purpura (TTP) (Szczepiorkowski et al. 2010) and for coagu-
lation factor replacement in patients with congenital deficiencies of single factors
(such as FV and FXI), but should not be used for factor replacement in congenital
factor deficiencies if factor concentrates are readily available (i.e., FVIII concen-
trates in hemophilia A patients). Additional indications include rapid warfarin rever-
sal in an actively bleeding patient, although guidelines are emerging preferentially
recommending prothrombin complex concentrates as a first-line agent (Ageno et al.
2012; Keeling et al. 2011; Morgenstern et al. 2010; Ansell et al. 2008). Plasma is not
appropriate to use as a nutritional supplement or as a source of immunoglobulin and
154 T.M. Boyd et al.

should not be used as a volume expander when blood volume can safely and ade-
quately be replaced with other agents such as colloids (AABB 2013).

10.1.3 Dose and Therapeutic Effect

In a nonpregnant individual, 1 mL of plasma contains approximately 1 unit of coag-

ulation factor activity. Nonpathogen-reduced plasma products contain slightly less
than 1 U/mL clotting factors due to approximately 10 % dilution from anticoagulant
solution and naturally occurring variability in factor levels between individual
donors (Benjamin and McLaughlin 2012; Eder and Sebok 2007). Administration of
a 10–20 mL/kg dose of plasma typically increases circulating coagulation factor
levels by 20–30 % (Spector et al. 1966). Standardization of clotting factors in S/D
plasma manufacturing allows for more precise dosing; a dose of 12–15 mL/kg
should raise most coagulation factors levels by up to 25 %. Plasma doses exceeding
15 mL/kg present increasing risks for volume overload in the recipient unless given
in context of ongoing blood loss or therapeutic plasmapheresis (Murad et al. 2010;
Popovsky 2004). Standard dosing protocols are appropriate for FFP and FP24, as
well as for liquid plasma as these three products are considered essentially hemo-
statically equivalent for almost all clotting factors except for FV and FVIII—despite
slight variations between clotting factors existing between these products (Benjamin
and McLaughlin 2012; Eder and Sebok 2007; Downes et al. 2001; Sidhu et al. 2006;
Yazer et al. 2008, 2010; Gosselin et al. 2013) (see Table 10.2). The process of sol-
vent detergent treating of plasma also results in a decrease in FV and FVIII (Buchta
et al. 2004). While remaining within regulatory requirements, declines in procoagu-
lant levels may be clinically significant and require patient monitoring (Benjamin
and McLaughlin 2012; Buchta et al. 2004).
Liquid plasma dosing is the same as that for FFP and FP24. Additional recom-
mendations in the literature are that liquid plasma should be used in conjunction
with either thawed FFP or FP24 and limited to a shelf life less than 15 days. A study
by Gosselin et al. demonstrated significant drops in the levels of FV, FVIII, vWF,
protein S, and endogenous thrombin activity (the thrombin generation potential of
the product) at 30 days (Gosselin et al. 2013). Because of the decreased levels of
both clotting and antithrombotic factors, liquid plasma is recommended only for
massive transfusion support in patients with life-threatening hemorrhage and sig-
nificant coagulation factor deficiencies (AABB 2013a).
In the USA, earlier forms of S/D plasma retained clotting factor levels close to
those in other licensed plasma products, though reductions in protein C, protein S
(Flamholz et al. 2000), antiplasmin, and antitrypsin activity were noted (Theusinger
et al. 2011; Pock et al. 2007). In the early 2000s, reports of thrombotic adverse
events and increased fibrinolysis after the use of S/D plasma prompted withdrawal
of the product from the US markets (Flamholz et al. 2000; de Jonge et al. 2002).
Currently, the manufacturer of FDA-approved Octaplas® claims to have all coagula-
tion factors within their known references ranges and the same hemostatic activity
as FFP (Heger et al. 2006). The only exception is the inhibitor α-2 antiplasmin,
which is below the cited reference range. Protein S levels are lower in S/D plasma
10 Split Blood Products 155

Table 10.2 Average values of coagulation factors found in different plasma and cryoprecipitate
preparations
Thawed Thawed
plasma from plasma from Cryo from FP24
FFP (Downes FP24 (Yazer (cryo24) (Yazer Liquid plasma
Factors et al. 2001) et al. 2008) et al. 2010) (Gosselin et al. 2013)
Ref. range
(U/mL) Day 1 Day 5 Day 1 Day 5 Standard Cryo24 Day 1 Day 15 Day 30
Factor V 0.70 0.66 1.40 0.87 1.10 0.77 0.50
(0.70–1.50)
Factor VII 0.90 0.72 1.09 0.96 0.97 0.78 1.08
(0.60–1.60)
VWF:Ag 448.1 505.9 0.73 0.50 0.40
(340–820)
Factor VIII 1.07 0.63 0.60 0.69 2.16 2.52 0.72 0.56 0.50
(0.60–1.50)
FX 0.85 0.80 1.10 1.11 1.12
FIX (0.60–1.50) 1.20 1.26 0.86 0.84 0.76
Antithrombin III 0.89 0.92
(0.80–1.20)
Protein C 1.05 0.96 0.88 0.89 0.86
(0.70–1.40)
Protein S 0.70 0.52 0.90 0.91
(0.58–1.28)
Protein S activity 0.90 0.48 0.22
(0.76–1.35 IU/
mL)
Fibrinogen 225 225 320 318 455.8 575.8 2.92 2.76 2.75
(150–350 mg/dL)
Further details including the variability of these levels can be found in the individual references
(Downes et al. 2001; Yazer et al. 2008; Gosselin et al. 2013; Yazer et al. 2010)

as compared with FFP; as such, the use of S/D plasma is not recommended for use
in patients with severe protein S deficiency (Theusinger et al. 2011).
MB-treated plasma, however, may have markedly reduced hemostatic (Pock
et al. 2007) and antithrombotic (Alvarez-Larran et al. 2004) efficacy; other photo-
chemical pathogen reduction treatments of plasma, such as amotosalen, are also
being evaluated and appear more equivalent to FFP (de Alarcon et al. 2005; de
Valensart et al. 2009; Mintz et al. 2006a, b).

10.2 Cryoprecipitate and Plasma, Cryoprecipitate Reduced

10.2.1 Product Description and Selection for Transfusion

Cryoprecipitated antihemophilic factor (cryoprecipitate) is the cold-precipitated pro-

tein fraction collected by centrifugation from a frozen plasma component thawed at
1–6 °C. A single 10–15 mL cryoprecipitate unit is enriched in high-molecular-weight
proteins including vWF, FVIII, fibrinogen, fibronectin, and FXIII (AABB 2013a).
156 T.M. Boyd et al.

Cryoprecipitate is stored at −18° C or below, and preparation time prior transfu-

sion includes 30 min or more to thaw and pool individual units into one dose. Unlike
plasma, cryoprecipitate cannot be stored in a thawed form and causes the longest
preparation delay when used as a component of a massive transfusion protocol.
Cryoprecipitate administration in adults does not need to be ABO compatible; how-
ever, the transfusion of large volumes of ABO-incompatible cryoprecipitate in to
any single recipient may cause positive direct antiglobulin test results and, rarely,
mild hemolysis (Dzik et al. 2011; Nascimento et al. 2011). Rh compatibility does
not need to be considered for pre-transfusion product selection (Downes and
Schulman 2011).
The stability of FVIIIC, vWF antigen, and fibrinogen between standard cryopre-
cipitate and cryoprecipitate made from FP24 plasma has been demonstrated (Yazer
et al. 2010). Cryoprecipitates derived from pathogen-inactivated plasma treated
with psoralens, however, contain significantly reduced levels of fibrinogen, FVIII,
and ADAMTS-13 (an enzyme degrading vWF), although the vWF quantity and
quality are well preserved (Cid et al. 2013).
The plasma supernatant remaining after the preparation of cryoprecipitate is
termed “plasma, cryoprecipitate reduced” also known as “cryo-poor plasma” or
cryosupernatant. Compared with other plasma products, this blood fraction is
depleted of vWF, FVIII, FXIII, and fibrinogen. However, many of the remaining
clotting factors are found in levels similar to that in FFP or FP24, including factors
II, V, VII, IX, X, and XI (AABB 2013a; Benjamin and McLaughlin 2012; Wehrli
et al. 2009).

10.2.2 Indications, Dosage, and Therapeutic Effect

Cryoprecipitate was originally developed as a FVIII concentrate for the treatment of

hemophilia A, but the availability of safer, purified, or recombinant FVIII concen-
trates has largely supplanted its use in these patients. The primary indication for
cryoprecipitate in modern transfusion practice is as a fibrinogen concentrate (Callum
et al. 2009). Cryoprecipitate is the most frequently used fibrinogen concentrate in
the USA and is the only one approved for use in the USA for treatment of acquired
fibrinogen deficiency such as surgical blood loss, trauma, or postpartum hemor-
rhage. Pasteurized fibrinogen concentrates are increasingly replacing cryoprecipi-
tate for treatment of both congenital and acquired fibrinogen deficiencies (Franchini
and Lippi 2012; Kozek-Langenecker et al. 2013; Wikkelso et al. 2013). In the USA,
each unit of cryoprecipitate is expected to contain >80 IU FVIII and >150 mg fibrin-
ogen, with typical adult doses ranging from 6 to 10 pooled units. The following
formula is recommended for calculating cryoprecipitate dosage: body weight (in
kg) × 0.2 = number of cryoprecipitate units to raise fibrinogen by 50–100 mg/dL
(AABB 2013a). Therapeutic recovery of transfused fibrinogen from cryoprecipitate
may be reduced by consumption in ongoing hemorrhage or fibrinolysis. A recent
retrospective review of plasma fibrinogen increments following cryoprecipitate
transfusion in the setting of trauma found a mean increase of 55 mg/dL after an
10 Split Blood Products 157

average transfusion of 8.7 units (±1.7) (Stanworth 2007). Cryoprecipitate remains a

second-line therapy for von Willebrand disease and hemophilia A, as well as bleed-
ing secondary to uremia (Hedges et al. 2007). Additionally, the 2013 European
Society for Anaesthesia perioperative bleeding guidelines suggest that the use of
cryoprecipitate for the treatment of hypofibrinogenemia is indicated if fibrinogen
concentrates are not available (Kozek-Langenecker et al. 2013).
The depletion of FVIII, fibrinogen, vWF, and FXIII in cryosupernatant limits its
utility and renders it unsuitable as a substitute for other forms of plasma.
Cryosupernatant has been used most widely as a replacement fluid during therapeu-
tic apheresis for the treatment of thrombotic thrombocytopenic purpura (AABB
2013a). Both cryosupernatant and cryoprecipitate have potential utility for treating
acquired coagulation factor deficiency in Jehovah’s Witness (JW) patients. While
typically refusing transfusion, the JW community leadership has allowed for indi-
viduals to consider accepting “processed” fractions of blood products as a matter of
individual conscience (Hughes et al. 2008; Sniecinski et al. 2007).

10.3 Platelet Concentrates

10.3.1 Product Description

Platelets are small (2–3 μm in diameter) anucleate cell fragments which bind to sites
of injury, providing the phospholipid surface for coagulation enzymes to assemble
and generate thrombin (Hoffman and Monroe 2001). In addition, they contribute
key protein and molecular elements for fibrin clot formation as well as exerting a
contractile force that draws together the margins of injury. Platelet concentrates are
obtained either from whole blood or by collection from donors via apheresis.
Platelet concentrates derived from a single 450–500 mL whole blood collection
contain greater than 5.5 × 1010 platelets per unit, with a typical adult dose formed by
pooling 4–6 concentrates (AABB 2013a). Apheresis platelets contain over 3 × 1011
platelets per unit, and contrary to other platelet concentrates, they have the advan-
tage that they represent only a single donor exposure per transfusion, reducing the
risk of transfusion-transmitted infections. While some in vitro differences have been
observed between platelets derived from the different collection methods
(Vasconcelos et al. 2003), these have little clinical consequence, and these products
are interchangeable (Slichter 2007; Chambers and Herman 1999).
One notable characteristic of platelet components is their cold intolerance. The
exposure of platelet concentrates to temperatures of 4 °C or less results in platelet
shape change, functional defects, and increased circulatory clearance rates
(Hoffmeister et al. 2003; Rao and Murphy 1982). Platelets also have the shortest
shelf life of any transfused product: the time from collection to expiration is 5 days;
attempts to extend the approved storage time have failed (Dumont et al. 2010). This
is due in part to the relatively short functional life of platelets (7–10 days in the
circulation) but also to the risks of bacterial proliferation due to storage at room
temperature (Palavecino et al. 2010).
158 T.M. Boyd et al.

Platelets, whether in the form of platelet concentrate or apheresis platelets, are a

plasma-rich product and should, ideally, be ABO compatible with the recipient to
avoid the infusion of ABO isoagglutinins. However, inventory shortages often
prompt the use of ABO-incompatible platelets; these are typically well tolerated,
but hemolytic transfusion reactions have been reported in rare instances (Slichter
2007; Fung et al. 2007; Josephson et al. 2010). The highest risk ABO-incompatible
platelet transfusions are those from group O single donor products administered to
group A or B recipients, due to the tendency of group O individuals to form high
titer anti-A and anti-B antibodies (Chambers and Herman 1999). Lastly, although
platelets do not bear RhD antigens, trace red blood cell content in platelet products
has driven the practice of transfusing RhD-negative donor platelets to RhD-negative
recipients to avoid alloimmunization. Should inventory shortages necessitate trans-
fusion of RhD-positive platelets to RhD-negative recipients—particularly women
of child-bearing age or female pediatric patients with child-bearing potential—
treatment with anti-RhD immunoglobulin is recommended to avoid RhD alloim-
munization (British Committee for Standards in Haematology 2012).

10.3.2 Indication, Dose, and Therapeutic Effect

Platelet transfusion is indicated (1) as prophylaxis against hemorrhage in severely

thrombocytopenic patients (most widely defined as <10 × 109/L platelets) and (2)
for the treatment of bleeding in patients with thrombocytopenia or platelet dysfunc-
tion (AABB 2013a; ASA 2006; Slichter 2007; Slichter et al. 2010). Therapeutic
platelet transfusion in the context of massive transfusion or DIC should be adminis-
tered with the aim of keeping the recipient’s platelet count at >50 × 109/L (British
Committee for Standards in Haematology 2012). The transfusion of one unit of
platelets typically increases platelet count by 20−40 × 109/L.
The majority (86 %) of platelets are given to patients with hematologic malig-
nancies; 68 % are given for bleeding prophylaxis and 32 % to treat acute bleeding
episodes (McCullough et al. 1988). Other indications include dilutional thrombocy-
topenia after massive transfusion, qualitative platelet disorders, rare congenital dis-
orders of platelet function such as Glanzmann thrombasthenia, or drug-induced
platelet dysfunction. Aspirin-, clopidogrel-, abciximab-, or prasugrel-related plate-
let dysfunction should respond to platelet transfusion although high circulating
plasma levels of eptifibatide or clopidogrel also render transfused platelets dysfunc-
tional (Vilahur et al. 2007). Little data are available for ticagrelor, but due to its
reversible binding to the P2Y12 receptor, transfused platelets can be inhibited by
redistribution of ticagrelor from native to the transfused platelets.
The current recommended transfusion trigger for prophylaxis in oncology
patients is 10 × 109/L (Rebulla et al. 1997). For patients who are bleeding or
undergoing invasive procedures the trigger is typically higher (National Institutes
of Health Consensus Conference 1987; ASA 2013). While the American Society
of Anesthesiologists (2006) proposes a platelet count of 50 × 109/L as a trigger
for platelet transfusion prior to an invasive procedure (ASA 2013), a target closer
to >100 × 109/L is often favored for neurosurgical interventions as historically
10 Split Blood Products 159

bleeding time was shown to steadily increase below this level (Slichter and
Harker 1978).
Pathogen-inactivated, photochemically treated (PCT) platelets offer the promise
to minimize transfusion-related infection with a broad range recognized and emerg-
ing bacteria, viruses, and protozoa (McCullough et al. 2004). Synthetic psoralens
intercalate with microbial DNA or RNA and, upon exposure to ultraviolet light,
cross-link pyrimidine bases to prevent microbial replication. While equivalent
hemostatic efficacy was seen in clinical trials of standard versus PCT platelets
(McCullough et al. 2004; Cid et al. 2012), the in vivo recovery of PCT platelets was
lower and others dispute their efficacy (Kerkhoffs et al. 2010). PCT platelets are
approved for use in Europe, but not in the USA.
Platelets require a supportive milieu derived from the plasma they are stored in;
most apheresis units are stored in 100 % plasma with ACD-A anticoagulant.
Reduction of plasma volume allows diversion of the plasma for other uses and may
reduce the risk of plasma-associated TRALI occurring on transfusion of plasma-
containing platelets. The use of platelet additive solutions (PAS) such as InterSol®
(Fenwal Inc., Zurich, IL) allows plasma reduction to be tolerated by supplementing
electrolytes and buffers. PAS platelets demonstrate in vivo recovery and survival
that exceed FDA requirements (van der Meer et al. 2010; Dumont et al. 2013).
Future developments in available platelet products include reconstituted, cryo-
preserved platelets. The in vivo survival of transfused thawed, resuspended, cryo-
preserved platelets met FDA criteria (Dumont et al. 2013), and in vivo hemostatic
activity appears adequate (Khuri et al. 1999). However, while the relevance to
hemostasis is unclear, adequate 24-h in vivo recovery remains a regulatory hurdle.

10.3.3 Whole Blood as a Source of Platelets

While fresh whole blood may be viewed as ideal treatment for trauma resuscitation,
there are several logistical and functional limitations. First, it would limit availabil-
ity of other blood components, and second, if not used when fresh, how long could
it be stored and how rapidly do storage lesions develop? The longer whole blood
remains in storage, the more platelets and white cells aggregate in the product,
increasing the risks of adverse reactions following transfusion. Erythrocytes pro-
mote aggregation and activation of platelets within the product, thereby defeating
one of the therapeutic benefits of using whole blood. Although some in vitro mea-
sures support the hemostatic function for whole blood refrigerated for up to 21 days
(Pidcoke et al. 2013). Many issues would have to be addressed before whole blood
can be licensed by the FDA and readily available for transfusion.

10.4 Complications of Transfusion

Transfusion-related complications originate from immunologic complications or

contamination with infectious agents (Eder and Chambers 2007; Kleinman et al.
2003). A comprehensive review of all adverse transfusion reactions is beyond the
160 T.M. Boyd et al.

scope of this chapter, particularly the infectious complications, but will be reviewed
briefly.

10.4.1 Transfusion-Transmitted Infections

All blood components bear the risk of transmitting infectious diseases, despite care-
ful screening of blood donors and (in many countries) universal testing of the blood
supply for infectious disease markers. Pooled products such as pooled platelets or
cryoprecipitate, which have not undergone pathogen inactivation, present increased
risks due to the multiple donor exposures. Existing and emerging infectious agents
are of greatest local or regional importance in endemic areas, but international travel
increases exposure to pathogens. If all pathogens are not included in existing screen-
ing mechanisms in a traveler’s native country, travel may increasingly limit suitable
blood donors. Rigorous donor screening, serologic testing, and nucleic acid ampli-
fication testing have proven extremely effective in reducing the risk of transfusion-
transmitted infections in developed nations (Bowden and Sayers 1990), but
transfusion-transmitted infection remains a serious concern throughout the develop-
ing world.
In 2009, the American Association of Blood Banks Transfusion-Transmitted
Diseases Committee made up of volunteer members with expertise in infectious
disease convened to publish a supplement to the journal Transfusion on the threat to
the North American blood supply from emerging infectious diseases (Stramer et al.
2009). They prioritized specific agents into categories: red agents had the highest
priority, followed by orange, yellow, and white. For further understanding of the
classification system, readers are directed to the reference (Stramer et al. 2009).
Red agents include human variant Creutzfeldt-Jakob disease, dengue viruses,
and Babesia species. Orange agents include Chikungunya virus, St. Louis encepha-
litis virus, Leishmania species, Plasmodium species, and T. cruzi. Yellow agents
include chronic wasting disease prions, human herpes virus 8, HIV variants, human
parvovirus B19, influenza A virus subtype H5N1, simian foamy virus, Borrelia
burgdorferi, and hepatitis A virus. White agents include hepatitis E and Anaplasma
phagocytophilum (Stramer et al. 2009).

10.4.2 Bacterial Contamination

Bacterial contamination of blood components can be asymptomatic or induce sepsis

with a high mortality. It is especially relevant to platelet products as they are the
only component to not undergo refrigerated storage. Incidences approximate
5–30 in 10,000 units of random donor-pooled platelets, 0.5–23 in 10,000 units of
apheresis platelets stored at room temperature, 0.25 in 10,000 units of packed RBCs
stored at 4 °C, and, rarely, in FFP or cryoprecipitate contaminated during thawing
in water baths (Kleinman et al. 2003). Bacterial contamination of platelet products
is acknowledged as the most frequent infectious risk from transfusion (Blajchman
and Goldman 2001; Brecher and Hay 2005). Along with TRALI and clerical errors
10 Split Blood Products 161

resulting in ABO mismatch, it is considered one of the most common causes of

death from transfusion, with mortality rates ranging from 1:20,000 to 1:85,000
donor exposures (Hillyer et al. 2003).
Clinically recognized septic reactions have been reported at a rate of 1 in 2,500
to 1 in 11,400 for whole blood-derived platelet concentrate pools and 1 in 15,400 for
apheresis platelets. Symptoms occurred after 17–42 % of contaminated platelet
transfusions, with a 17 % mortality rate (Kleinman et al. 2003; Brecher and Hay
2005). The incidence of severe septic episodes has not been clearly established but
is probably approximately 200/million platelet units transfused (50 % sensitivity)
(Blajchman and Goldman 2001; Walker 1987). Given the 5-day storage life and the
persistent risk of platelet shortage, in September 2005, the FDA trialed the use of
7-day apheresis platelets under the surveillance program PASSPORT to determine
the safety of extending the storage life. The study was discontinued early after 2
true-positive cultures were detected in 2,571 day 8 platelets (778/million) (Dumont
et al. 2010). However, based on risk modeling, overall recipient risk may not have
been improved by the reduced inventory caused by withdrawal of 7-day apheresis
platelets. From an inventory management standpoint, platelet pools would have
replaced them, potentially increasing infection risk and delaying a TRALI risk
reduction strategy (Kleinman et al. 2009). Pathogen reduction strategies may fur-
ther renew enthusiasm for 7-day storage.

10.4.3 Acute Hemolytic Transfusion Reaction

Acute hemolytic transfusion reactions are one of the most serious complications of
transfusion and remain as one of the leading causes of transfusion-related mortality
worldwide (Eder and Chambers 2007; Vamvakas and Blajchman 2010). These
reactions result from RBC lysis or accelerated clearance by the reticuloendothelial
system resulting from RBC transfusion into a recipient with preformed antibodies
directed against donor erythrocytes. Rarely, plasma-rich blood products have been
implicated in hemolytic reactions by passive transfer of antibodies directed against
recipient erythrocytes (Fung et al. 2007). Antibodies directed against ABO antigens
are the most frequent source of incompatibility (Ching et al. 1991; Josephson et al.
2010), for example, transfusion of O platelets containing anti-A and anti-B. Pre-
transfusion plasma reduction and ABO matching easily avoid this complication.

10.4.4 Febrile Nonhemolytic Transfusion Reaction

Febrile nonhemolytic transfusion reactions (FNHTR) represent an essentially

benign, albeit unpleasant, transfusion reaction most notable for development of
fever, defined as a temperature elevation of >1 °C above pre-transfusion tempera-
ture. Patients may also experience chills, rigors, nausea, and vomiting. Occasionally
patients will manifest such signs and symptoms in the absence of fever. FNHTRs
are caused by pyrogenic cytokines, such as IL-1, Il-6, or TNF-α, which accumulate
in blood products during storage. The onset of symptoms usually occurs during
162 T.M. Boyd et al.

transfusion but may present toward the end of the transfusion process or even within
1–2 h afterward due to the increasing level of cytokine exposure. The diagnosis of
FNHTR is one of exclusion, having ruled out other causes of febrile reactions such
as hemolytic transfusion reactions, septic reactions, or contributions from comor-
bidities or medications. Treatment is supportive, including antipyretics such as acet-
aminophen (Heddle 2007).

10.4.5 Allergic Reactions/Anaphylaxis

Allergic transfusion reactions are one of the most common adverse transfusion reac-
tions, with incidence rates estimated between 1 and 3 % (Vamvakas 2007; Domen
and Hoeltge 2003). Clinical presentation varies, but most manifests solely with
cutaneous symptoms such as urticaria, pruritus, erythema, and angioedema (Domen
and Hoeltge 2003). These minor allergic reactions are thought to be most often
mediated by preexisting recipient IgE or IgG targeting plasma protein antigens.
Passive transfer of IgE directed against recipient plasma allergens or other environ-
mental allergens has also been observed. Accordingly, allergic reactions occur most
frequently with plasma-rich products (including platelets) but may also occur in
plasma-deplete products such as red cell units. Antihistamines such as diphenhydr-
amine or famotidine form the cornerstone for treatment of minor allergic transfu-
sion reactions with corticosteroids reserved for more severe reactions.
Rarely, severe allergic reactions may rapidly progress to anaphylactic shock within
minutes after symptom onset. These reactions are characterized by bronchospasm,
hypotension, nausea and vomiting, chest pain, and tachycardia. IgA-deficient patients
who have developed class-specific anti-IgA are at risk; however, this group only
represents a fraction of anaphylactic transfusion reactions (AABB 2013a). Causative
agents vary widely from anti-haptoglobin antibodies to passive transfer of allergens to
which a patient is already sensitized, such as recently ingested foods (i.e., peanuts)
(Jacobs et al. 2011). Ultimately, anaphylaxis is an unpredictable and potentially fatal
transfusion outcome requiring swift action to prevent an adverse outcome. Severe
allergic reactions or anaphylaxis should be managed in a similar fashion to anaphy-
laxis from other causes, with administration of epinephrine (with or without other
vasopressors as needed) and corticosteroids, maintenance of a patent airway, and vol-
ume infusion to maintain hemodynamic stability. Testing for associated DIC and post-
poning procedures requiring further transfusion should also be considered.

10.4.6 Transfusion-Related Acute Lung Injury (TRALI)

10.4.6.1 Pathophysiology
Transfusion of plasma-containing blood products—which include all blood products
other than washed cellular blood products—may result in a syndrome of non-
cardiogenic pulmonary edema and acute respiratory distress. Clinical findings defining
TRALI include (1) onset during or within 6 hours of transfusion; (2) severe hypoxemia,
10 Split Blood Products 163

such as less than 90 % oxygen saturation on room air; (3) diffuse bilateral pulmonary
infiltrates on chest x-ray; (4) absence of volume overload; and (5) no preexisting acute
lung injury (Kleinman et al. 2004). TRALI may also be associated with fever, chills,
hypotension, and transient leukopenia. The primary pathophysiologic mechanism is
believed to be a reaction between donor anti-leukocyte antibodies and recipient leuko-
cytes, which results in leukocyte activation (Marques et al. 2005), sequestration, and
infiltration into the pulmonary capillary bed (Fung and Silliman 2009). Leukocyte acti-
vation results in pulmonary microvascular injury and capillary leakage with an influx
of proteinaceous fluid into the alveolar space (Bux and Sachs 2007). A “two-hit”
hypothesis for the pathogenesis of TRALI holds that the first hit is due to recipient
neutrophils primed for activation by virtue of the patient’s underlying clinical condi-
tion. The second hit involves activation of these neutrophils by anti-leukocyte antibod-
ies or biological response modifiers contained in the transfused product (Silliman
2006). In rare cases, the transfused product may provide both hits (Kelher et al. 2009).
Female donors sensitized to human leukocyte antigens (HLA) by pregnancy are
most frequently implicated as the source of blood products which have been linked to
TRALI cases (Densmore et al. 1999; Powers et al. 2008; Triulzi et al. 2009). The
frequency of anti-HLA antibodies ranges from 1.7 % for never pregnant females to
32.2 % for four or more pregnancies, whereas males and previously transfused donors
all showed very low frequency of anti-HLA antibodies (in the range of 1–2 %) (Triulzi
et al. 2009; Kakaiya et al. 2010). As a result, many blood collection agencies in the
USA and Europe limit or prohibit collection of plasma-rich blood products from
female donors (Eder et al. 2010; Funk et al. 2012; Jutzi et al. 2008; Keller-Stanislawski
et al. 2010; Lucas et al. 2012; Middelburg et al. 2010; van Stein et al. 2010).
The best available, current TRALI incidence estimate comes from a prospective
study surveilling hypoxemia after transfusion of over 450,000 units between 2006
and 2009. Ninety-one TRALI cases were identified with an incidence of 1 in
3,141 in 2006 compared with 1 in 12,346 in 2009 after the introduction of gender-
based mitigation strategies (Toy et al. 2012).

10.4.6.2 Diagnosis and Management

The diagnosis of TRALI is clinical and not based on the results of laboratory inves-
tigations for the presence of anti-leukocyte antibodies in the donor (Popovsky and
Moore 1985; Goldberg and Kor 2012). Although cognate leukocyte antibody-antigen
matches are often seen in TRALI cases, their absence does not rule out TRALI
(Kopko et al. 2003; Stafford-Smith et al. 2010). Careful patient evaluation of sus-
pected TRALI should involve both the clinical team and the transfusion service and
include posttransfusion chest x-rays, measures of oxygenation, and evaluation for
volume overload. Once TRALI is suspected, the transfusion must be immediately
discontinued and the blood bank informed (Su and Kamel 2007). The details of the
transfusion workup are beyond the scope of this chapter. Briefly, following all cases
of TRALI and some cases of possible TRALI, the blood bank and the blood collec-
tion facility should investigate all donors associated with TRALI or possible TRALI
cases for the presence of antihuman leukocyte antigen (HLA) and possibly antihu-
man neutrophil antigen (HNA) antibodies (Reil et al. 2008). Few laboratories (mostly
164 T.M. Boyd et al.

in Europe) also perform leukocyte cross-matching as part of the evaluation. The

extent of these investigations varies depending upon the availability of donor sam-
ples (usually not a problem), the availability of neutrophil antibody testing, and the
availability of a recipient sample for HLA antigen typing (Kopko et al. 2001, 2003).
A donor with HLA antibodies matching an affected recipient is classified as an
implicated donor and is deferred from future plasma apheresis or platelet apheresis
donation. If a donor has the highly morbid anti-HNA 3a antibodies, most blood
banks will defer the donor from any type of blood donation (Davoren et al. 2003).
The management of the patient with TRALI/possible TRALI is supportive, with
oxygen supplementation for the correction of hypoxemia and hemodynamic support
for hypovolemia and associated hypotension (Wallis 2007). Most patients who
develop TRALI or possible TRALI will require endotracheal intubation and ventila-
tory support (approximately 70–80 %) (Popovsky and Moore 1985; Vlaar et al.
2010; Gajic et al. 2007a; Wallis 2003). Early reports described a mean duration of
ventilatory support of approximately 40 h (Popovsky and Moore 1985), while more
recent evidence points to longer period of respiratory support (approximately 3–10
days) (Vlaar et al. 2010; Gajic et al. 2007a). TRALI is not responsive to diuretics,
and the role of corticosteroids remains unclear (Peter et al. 2008); the majority of
patients recover with supportive care.

10.4.6.3 Prevention
It has been well established that donors implicated in TRALI cases are more likely
to be female and multiparous (Toy et al. 2012; Gajic et al. 2007b). While not all
studies support the benefit of avoiding female plasma (Welsby et al. 2010), the over-
whelming evidence supports the implementation of gender-based policies for reduc-
ing TRALI incidence from plasma transfusion. These factors resulted in the
implementation of a new TRALI risk mitigation policy during the mid- to late 2000s
throughout most of Europe and the USA, in which plasma units were predominantly
obtained from male donors, thereby avoiding the transfusion of plasma units from
female donors. This policy is feasible for plasma transfusion because the number of
plasma units collected from whole blood or apheresis collections meets, or is in
excess of, demand. In contrast, this policy is challenging for group AB platelet and
plasma components (Reesink et al. 2012), where restriction of units to male donors
jeopardizes supply (see Table 10.3). Despite that, in 2013 the AABB announced
new TRALI risk mitigation standards requiring high-plasma volume components
come from males, females who have not been pregnant, or females who have been
tested since their most recent pregnancy to rule out the presence of anti-HLA anti-
bodies, regardless of ABO group. These new standards are to go into effect in 2014
(AABB 2013b).
Some blood centers have implemented a policy of testing selected populations of
platelet apheresis donors for anti-HLA antibodies or resuspending apheresis plate-
lets in platelet additive solution (PAS) (Lucas et al. 2012; Reesink et al. 2012;
Kleinman et al. 2010) although there are inadequate data to evaluate its effect on the
incidence of TRALI following platelet transfusion (Kakaiya et al. 2010; Reesink
et al. 2012).
10 Split Blood Products 165

Table 10.3 Following implementa- Component Cases (n) TRALI rates per 106
tion of the American Red Cross
A, B, O plasma 9 1.9
TRALI mitigation strategies, the
AB plasma 12 24.9
incidence of TRALI cases 2008–2010
fell for all but group AB plasma RBC 39 2.2
where female donors still comprise Apheresis platelets 19 8
40 % of the group AB donor pool Adapted from Reesink et al. (2012)

The use of solvent/detergent-treated plasma has also been promoted as a TRALI

risk reduction strategy. In contrast to a TRALI incidence from single donor plasma
units of 1 in 31,000 units, observational data (Riedler et al. 2003) and hemovigi-
lance data from France between 2007 and 2008 (Ozier et al. 2011) identify a zero
incidence of TRALI with this product with undetectable HLA antibodies (Sachs
et al. 2005).
While hemovigilance data may be subject to biased reporting, these international
data present compelling evidence supporting the global implementation of gender-
based TRALI risk reduction strategies, provided inventory or organizational imped-
iments are not restrictive.

10.4.7 Volume Overload

10.4.7.1 Pathophysiology
Transfusion-associated circulatory overload (TACO) will cause transfusion-related
respiratory insufficiency and is thought to occur when the rate of transfusion exceeds
the recipient’s cardiovascular adaption to the additional workload. The rapid infu-
sion of excessive volume can result in dyspnea, hypoxemia, elevated central venous
pressure, and pulmonary edema (Eder and Chambers 2007).
TACO is typically reported in elderly patients and small children, due to their
relatively small circulating volume but can occur in all age ranges. Compromised
cardiac function, positive fluid balance, and rapid blood product administration are
additional risk factors for TACO, which appears to occur more frequently in opera-
tive or intensive care settings, where large fluid volumes and blood are administered
(Li et al. 2011).
While the primary mechanism of TACO centered around fluid overload
(Popovsky 2004; Li et al. 2010), this has recently been questioned as the median
transfusion volume in patients who develop TACO is only 3 (2–7) units (Li et al.
2011) and a large proportion of reported TACO cases occur after a single blood unit
exposure (Popovsky et al. 1996). Similarly, Roubinian et al. reported no statistically
significant differences in hourly fluid balance or the number of blood component
units transfused in the 24-h interval preceding the TACO or TRALI episode
(Roubinian et al. 2012).
TACO is also typically associated with increased systemic blood pressure
(Popovsky 2010; Klein and Anstee 2006), which exceeds that expected from the
166 T.M. Boyd et al.

volume challenge alone, suggesting a possible effect of vasoconstricting substances

in the transfused blood product (Donadee et al. 2011). While most likely associated
with RBC transfusion, a sudden increase in the systemic vascular resistance has the
clear potential to compromise left ventricular function resulting in the elevated left
atrial pressures and ultimately hydrostatic pulmonary edema characteristic of
TACO.

10.4.7.2 Diagnosis and Management

Distinguishing TRALI from TACO is important but often difficult (Skeate and
Eastlund 2007; Popovsky 2009). Generally, TRALI is more likely to be associated
with fever, hypotension, and exudative pulmonary infiltrates and less likely to
respond to diuresis, whereas TACO is more likely to be associated with volume
overload (e.g., positive fluid balance, elevated jugular venous pressure) or poor car-
diac function (e.g., history of congestive heart failure, reduced left ventricular ejec-
tion fraction, or diastolic dysfunction). Similarly, elevated systolic blood pressures
near the time of dyspnea onset, cardiomegaly, and/or increased circulating levels of
brain natriuretic peptide (BNP) or N-terminal (NT)-pro-BNP support a diagnosis of
TACO rather than TRALI (Popovsky 2009; Zhou et al. 2005; Tobian et al. 2008; Li
et al. 2009; Rice et al. 2011; Ely et al. 2001).
Differentiating TRALI from TACO can be a significant challenge, particularly as
both may coexist (Popovsky 2009, 2010; Gajic et al. 2006). Related to this, approxi-
mately 30 % of ALI/ARDS patients show evidence of left atrial hypertension
(Wheeler et al. 2006), increasing the difficulties of differential diagnosis and
explaining a degree of diuretic responsiveness associated with TRALI.
While chest x-ray findings of bilateral infiltrates are similar to TRALI, TACO
shows symptomatic improvement with diuresis. Patients with suspected TACO
should have any ongoing transfusion paused to establish the diagnosis, with diuret-
ics and supportive care given as indicated before attempting further transfusion.
Resumption of transfusion should be approached with a slower infusion rate and
careful vigilance for recurrent symptoms.

10.4.8 Metabolic Complications and Hypothermia

As all blood products are collected and stored in citrate-based anticoagulants, large
volume transfusions may be complicated by hypocalcemia (Eder and Chambers
2007). Citrate binds divalent cations such as calcium and magnesium and is rapidly
metabolized by the liver. Whereas citrate is easily cleared during nonurgent transfu-
sions, citrate load during massive transfusion may overwhelm this clearance mecha-
nism (Sihler and Napolitano 2010). In the awake patient, hypocalcemia presents
initially with chills, tingling, dizziness, and tetany; continued progression of citrate
toxicity can lead to prolonged QT interval, decreased left ventricular function, and
cardiac arrhythmias. While hypocalcemia can be managed by slowing the rate of
transfusion, in ongoing massive transfusion, and in patients with liver dysfunction
or under general anesthesia, calcium replacement therapy should be guided by the
patient’s ionized calcium concentration.
10 Split Blood Products 167

Hypothermia can lead to multiple systemic derangements, including peripheral

vasoconstriction, cardiac dysfunction, acidosis, and coagulopathy (Moffatt 2013).
The effects of hypothermia and acidosis on coagulation have been observed both
clinically and in vitro. Decreases in core temperature <34 °C and pH <7.1 after mas-
sive transfusion are predictive for the development of coagulopathy (Eder and
Chambers 2007). The activity of tenase (FVIIa/tissue factor) and prothrombinase
(FXa/FVa) complexes is directly dependent on temperature, with both showing a
1.1-fold loss of activity at 33 °C as compared to 37 °C (Meng et al. 2003). Even
more dramatically, FVIIa/tissue factor and FXa/FVa show sharp decreases in activ-
ity in acidic environments, with activity decreasing by 55 and 70 % at pH 7.0,
respectively (Viuff et al. 2008). Blood products transfused in this setting may be less
effective, and, similarly, transfusion of chilled blood products especially in large
volumes is absolutely contraindicated.

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Coagulation Factor Concentrates
11
Lars M. Asmis

11.1 Introduction

Perioperative management of coagulation involves the use of blood products. Patients

have typically been transfused whole blood or derivatives of whole blood, including
red blood cell (RBC) concentrates, platelet concentrates (PC), and plasma. Fractionated
plasma products, in the form of single and combined coagulation factor concentrates,
have been available for decades. Following isolated human coagulation factors,
recombinant coagulation factors eventually became a part of standard medical
practice. Both isolated and recombinant types of coagulation factor preparations can
contain nonactivated or activated coagulation factors. A third group of drugs used to
manage perioperative bleeding includes medications that alter either the activity
(e.g., tranexamic acid) or the plasma levels (e.g., desmopressin) of coagulation-related
proteins. The latter group of drugs will be discussed in Chap. 12.
The transfusion of any blood product requires a thorough risk–benefit evaluation
(Dunbar et al. 2012; Hardy 2012; Berseus et al. 2013; Shaw et al. 2013). From the
very beginnings of transfusion medicine, it has been known that the use of cell-
containing transfusion products, such as RBC concentrates, is associated with
potential side effects. Transfusion reactions, due to blood group incompatibility in
RBC transfusion, are potentially lethal treatment complications. Due to the way
they are produced, platelet concentrates may harbor a significant risk of sepsis.
Storage at room temperature is conducive to bacterial growth in these products that
may lead to patient harm (Stroncek and Rebulla 2007). Fresh frozen plasma (FFP)
was originally considered a “cell-free” product. As a cell-free product containing
physiological coagulation factors and inhibitors, it was assumed to be safe. It has

L.M. Asmis
Unilabs Coagulation Laboratory, Centre for Perioperative Thrombosis and Hemostasis,
Hufgasse 17, Zurich CH 8008, Switzerland
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 177

DOI 10.1007/978-3-642-55004-1_11, © Springer-Verlag Berlin Heidelberg 2015
178 L.M. Asmis

since been shown that FFP may be contaminated with fragments of cellular origin,
termed as microparticles, as well as soluble mediators including antibodies and
interleukins (George et al. 1986; Theusinger et al. 2011). These contaminants can
potentially lead to adverse effects. A rare but dangerous complication of FFP trans-
fusion is transfusion-related acute lung injury (TRALI) that is associated with
increased mortality (Inaba et al. 2010).
The ongoing quest for efficient and safe transfusion products has resulted in the
development of isolated coagulation factor concentrates (i-CFC) and recombinant
coagulation factor concentrates (r-CFC). This chapter focuses on isolated (single)
and combined coagulation factor concentrates. Based on differences in regulation
and approval procedures in various countries, there are relevant geographical differ-
ences in the availability and use of coagulation factor products. Indications for the
various products vary significantly from country to country. Substitution of i-CFC
in acquired coagulation factor deficiencies represents on-label use in some coun-
tries, while it is off label in others. This chapter discusses the most frequently used
coagulation factor concentrates.

11.2 Coagulation Products

11.2.1 Fibrinogen Concentrate

11.2.1.1 Background
Fibrinogen was the first coagulation factor to be discovered. In an open wound, the
white aggregates of fibrin strands can be seen with the naked eye. In the nineteenth
century, Home coined the term “fibrin,” and Virchow postulated that there was a
precursor molecule, which he called “fibrinogen.” In 1905, fibrinogen was already
defined as a coagulation factor I (FI) in a review by Morawitz (1905). Hiippala and
colleagues established fibrinogen’s key role in perioperative hemostasis and demon-
strated that it was the first coagulation factor to reach critical levels in massive
bleeding (see “Indications”, below) (Hiippala et al. 1995).

11.2.1.2 Description
Fibrinogen, synthesized in the liver, is an abundant plasma protein with concentrations
typically ranging between 1.5–4.0 g/l and 6–13 µmol/l. Fibrinogen’s molecular
weight is approximately 340 kDa. It is a heterodimer with two sets of α, β, and γ
chains. The six chains are N covalently linked in the central E domain. Two sets of α,
β, and γ chains extend from the E domain to form 2 so-called D domains at their
distal ends. Thrombin (FIIa) cleaves activation peptides from the central (E domain)
end of the α and β chains, releasing two sets of fibrinopeptides, A and B, thereby
exposing polymerization sites. After the release of these fibrinopeptides, the mole-
cules are called fibrin or fibrin monomers. The fibrin monomers aggregate to form
soluble fibrin strands that form by the interaction of the D and E domains of neigh-
boring molecules. Initially, the interaction between fibrin monomers is reversible; the
11 Coagulation Factor Concentrates 179

BA
AB
D E D
BA
AB

D E D D E D D E D
D E D
D E D D E D D E D
BA
AB

D E D FIIa FIIIa
Soluble fibrinogen Soluble fibrin monomers Insoluble fibrin strand

Fig. 11.1 Model of fibrinogen polymerization. Thrombin (FIIa)-induced cleavage of the fibrino-
peptides A and B from soluble fibrinogen molecules leads to the generation of soluble fibrin mono-
mers that reversibly aggregate into a soluble fibrin monomer gel. Activated factor XIII (FXIIIa)
can irreversibly stabilize the monomers into an insoluble and stable fibrin strand through covalent
cross-linking

resulting fibrin strand can potentially disintegrate again. Only once factor XIII
(FXIII) has covalently cross-linked the individual fibrin monomers does the fibrin
strand become irreversibly interconnected (Nieuwenhuizen 1995; de Maat and
Verschuur 2005; Sorensen et al. 2011b; Levy et al. 2012) (see Fig. 11.1).
The three polypeptide chains (Aα, Bβ, and γ) are encoded by three distinct genes,
all residing on chromosome 4. The three genes contain interleukin 6 (IL-6) response
elements, which explains why fibrinogen is an acute phase reactant.
Fibrinogen is a glycoprotein that has a plasma half-life of approximately 100 h
(Blomback et al. 1966). Liver disease and sepsis increase turnover. In liver cirrhosis,
glycosylation may be altered, leading to acquired dysfibrinogenemia, characterized
by circulating fibrinogen molecules with reduced biological activity. Degradation of
soluble fibrinogen is mediated by “normal protein degradation, the coagulation
process, and unknown pathways.” Stabilized fibrin (and soluble fibrinogen) degra-
dation occurs by plasmin-induced proteolysis (de Maat and Verschuur 2005).
Fibrinogen has at least four major biological functions: it is a substrate of coagu-
lation; it is a cross-linker in platelet aggregation; it is a coagulation inhibitor as
“antithrombin I”; and it is a substrate for interaction with other proteins (Weisel and
Litvinov 2013). Most other coagulation factors are serine proteases capable of spe-
cifically recognizing target molecules and activating many of them. For example,
one activated molecule of factor X (FXa) can activate more than 1,000 prothrombin
molecules (FII), while one thrombin molecule can activate more than 1,000 mole-
cules of fibrinogen. Enzymatically active coagulation factors can continue to inter-
act with many other target molecules while fibrinogen, in its role as substrate, will
be consumed. One activated molecule of fibrinogen will give rise to one molecule
of fibrin in the resulting clot. Fibrinogen’s second role is that of the cross-linker in
platelet aggregation. Once platelets have been activated “outside in,” an “inside-
out” activation will occur that leads to an altered structure of the glycoprotein IIb/
IIIa (GP IIb/IIIa) receptor on the platelet surface. This structural change permits the
interaction of one fibrinogen molecule with several GP IIb/IIIa receptors on several
180 L.M. Asmis

platelets, leading to the formation of platelet aggregates. The third role involves
fibrinogen’s ability to bind thrombin (Sorensen et al. 2011b). Finally, there is FXIII,
which is reported to covalently link α2-plasmin inhibitor (α2-PI) on to fibrinogen
(Richardson et al. 2013). This reaction is important for the stability of the resulting
fibrin clot (see below).

11.2.1.3 Indications
11.2.1.3.1 Acquired Fibrinogen Disorders
Hiippala’s pioneering work identified the clinical relevance of fibrinogen in massively
bleeding patients (Hiippala et al. 1995). He studied 60 massively bleeding patients
and measured platelet counts and coagulation factor levels. Based on “critical
levels,” or thresholds, which he took from a prominent coagulation textbook of the
time, he observed that the fibrinogen threshold of 1.0 g/l was reached at 142 % of
blood loss. Other parameters he monitored only fell below their respective thresh-
olds considerably later: platelet count at 230 %, FII at 201 %, FV at 229 %, and
FVII at 236 %.
Others corroborated the finding that fibrinogen will be the first factor to reach
critical levels in massive bleeding (Martini et al. 2005; Fenger-Eriksen et al. 2009c).
Acquired hypofibrinogenemia is thus a frequently observed problem in massively
bleeding patients. Suggested treatment thresholds lie ≥1.5 g/l (Fenger-Eriksen et al.
2009a). A less frequent problem is acquired dysfibrinogenemia. This may occur in
end-stage liver cirrhosis as a consequence of an altered glycosylation of fibrinogen
molecules that interferes with the plasma assembly of fibrin monomers. The laboratory
hallmark of this disorder is longer thrombin time and a reduced ratio of functional
to antigenic fibrinogen tests (<0.7).

11.2.1.3.2 Congenital Disorders of Fibrinogen

Congenital disorders of fibrinogen are registered indications for fibrinogen substitu-
tion in many countries. There are various such disorders, including afibrinogenemia
(no measurable protein), hypofibrinogenemia (<1.5 g/l), and dysfibrinogenemia.
Afibrinogenemia and dysfibrinogenemia are orphan diseases with frequencies of
approximately 1:1,000,000 (Peyvandi et al. 2012a). Experienced physicians should
manage prophylaxis and treatment of acute bleeding in these patients as these
diseases can also manifest a thrombotic phenotype depending on the molecular
pathophysiology. Suggested treatment thresholds lie in the area of 0.5–1.0 g/l
(Bolton-Maggs et al. 2004; Acharya and Dimichele 2008).

11.2.1.4 Monitoring
Tests for fibrinogen were proposed in the middle of the last century: the Schulz
method in 1955 and the Clauss method in 1957 (Schulz 1955; Clauss 1957;
Nieuwenhuizen 1995; Lowe et al. 2004). Interestingly, Hartert had published his
work on thromboelastography several years before that, in 1948, but functional
fibrinogen tests for viscoelastic point-of-care (POC) devices (including functional
“fibrinogen” tests on ROTEM, TEG, and related devices) were only standardized
and validated much later (Hartert 1948).
11 Coagulation Factor Concentrates 181

The Schulz method is an antigenic test performed in citrate plasma: fibrinogen is

heat denatured and the precipitable protein is measured in a graded tube. One of the
pitfalls of this test is the presence of other precipitable proteins, not related to fibrin-
ogen, which falsely increase outcomes. Turnaround time is approximately 60 min.
The Clauss method is a functional test of fibrinogen in which a coagulation time
is measured in prediluted plasma, rendering fibrinogen the rate-limiting reagent.
The addition of (bovine) thrombin is the start signal and formation of soluble fibrin
is the stop signal. This coagulation time can be converted into a fibrinogen concen-
tration. Strong inhibitors of thrombin (including direct anti-FIIa inhibitors), exces-
sively high levels of fibrin degradation products (including D dimers), and other
inhibitors may falsely lengthen the coagulation time resulting in falsely low fibrino-
gen results. Turnaround time is approximately 40 min.
Fibrinogen tests in viscoelastic POC devices represent functional tests. The addition
of tissue factor induces whole blood to coagulate. Platelet function is inhibited by
specific inhibitors. The maximum clot firmness, or maximum amplitude, is mea-
sured after a defined time. The results are not only dependent on the fibrinogen
concentration, but may be influenced by hematocrit, FXIII, heparin, hydroxyl-ethyl
starch, gelatin, and albumin (Solomon et al. 2011; Ogawa et al. 2012; Schlimp et al.
2013). None of these tests is standardized, and the international, gold standard test
is currently debated.

11.2.1.5 Efficacy and Safety

To date, there is only limited evidence from three, small randomized controlled
trials (RCTs) evaluating fibrinogen concentrate in acutely bleeding patients.
A cystectomy trial (n = 20), a coronary artery bypass grafting (CABG) trial
(n = 20), and an elective thoracic/thoracoabdominal aneurysm trial have been
published. The cystectomy trial showed that fibrinogen concentrate increased
maximum clot firmness and reduced postoperative transfusion in patients whose
blood loss was substituted by hydroxyl-ethyl starch (Fenger-Eriksen et al.
2009b). In the CABG trial, patients were randomized to 2 g of fibrinogen con-
centrate preoperatively or placebo. This raised fibrinogen levels by 0.6 g/l. No
adverse effects of fibrinogen substitution were observed (Karlsson et al. 2009).
The largest trial, including 62 patients scheduled for elective thoracic/thoracoab-
dominal surgery, showed that thromboelastography-guided hemostatic therapy
using fibrinogen concentrate was more effective than placebo to control bleed-
ing. Fibrinogen substitution was also compared with cycles of FFP/platelets and
found to be superior to one cycle and at least as effective as two cycles of the
prespecified transfusion protocol. This trial’s approximate target level of fibrino-
gen was 3.6 g/l (Rahe-Meyer et al. 2013a).
The RCT cited above are too small to draw any conclusions regarding safety.
In the Rahe-Meyer RCT, one patient in the treatment group died after cardiorespira-
tory arrest, potentially of thromboembolic origin. In the placebo group, there were
four deaths and two thromboembolic events. Based on the limited evidence, reviews
describe fibrinogen concentrate as being safe (Fenger-Eriksen et al. 2009a; Levy
et al. 2012; Warmuth et al. 2012).
182 L.M. Asmis

The manufacturer of fibrinogen concentrate conducted a post-marketing pro-

gram of pharmacovigilance between 1986 and 2008. More than one million
grams of fibrinogen were administered, with 48 adverse events reported and 9
cases of arterial or venous thromboembolism. Of these nine patients, seven had
congenital fibrinogen disorders and two had acquired fibrinogen disorders
(Fenger-Eriksen et al. 2009a). The numbers cited suggest an estimated incidence
of thromboembolic events of less than 1 per 10,000. Allergic reactions occurred
at a frequency of less than 1 per 10,000. Underreporting of adverse events in the
post-marketing phase is a well-known problem, so these numbers need to be
interpreted with caution and corrected when data from large RCT become
available.

11.2.1.6 Dosing
The following dosing regimen has been suggested in the context of classic coagula-
tion testing: dose (g) = desired increase in g/l × plasma volume (plasma vol-
ume = 0.07 × (1-hematocrit) × body weight (kg)) (Acharya and Dimichele 2008). In
the context of thromboelastographic/metric testing, 2 g of fibrinogen in a 70-kg
patient generally increase the FIBTEM by 4 mm (Rahe-Meyer et al. 2009). The
manufacturer of fibrinogen concentrate recommends 30–60 mg/kg or 2–4 g in a
70-kg patient (Fenger-Eriksen et al. 2009a). This dose will increase plasma fibrino-
gen by approximately 1 g/l (Solomon et al. 2010). Threshold and target values for
fibrinogen have changed considerably in the recent years (see Sect. 11.3) (Sorensen
et al. 2011b). In the recent Rahe-Meyer RCT, the target post-substitution fibrinogen
level was 3.6 g/l or a maximum cloth firmness (MCF) of 22 mm in ROTEM in
patients undergoing major aortic replacement surgery.

11.2.1.7 Key Points and Prospects

Preliminary evidence from these three RCTs indicates that fibrinogen concentrates
can play an important role in the management of perioperative bleeding. Further
research is needed to confirm the treatment’s efficacy and safety for this
indication.

11.2.2 Factor XIII Concentrate

11.2.2.1 Background
Factor XIII (FXIII) was the last coagulation factor to be discovered. First indica-
tions of its existence date back to the 1920s. Fibrin clots that formed in the pres-
ence of calcium became insoluble in the presence of weak bases (Barkan 1923). A
similar experiment was performed in 1944 with purified fibrinogen. The authors
concluded that an additional “stabilizing factor” to calcium was necessary to
explain their findings (Robbins 1944). Duckert first described human FXIII defi-
ciency in 1960 (Duckert et al. 1960). The protein was attributed with its current
name in 1963 by the International Committee on Blood Clotting Factors (Muszbek
et al. 2011).
11 Coagulation Factor Concentrates 183

11.2.2.2 Description
FXIII is a transglutaminase, an enzyme that cross-links proteins. This clearly distin-
guishes it from the classic coagulation factors that are serine proteases – enzymes
that cleave proteins. In plasma, FXIII bound to fibrinogen forms a tetramer with two
catalytic A domains and two inhibitory B domains. Cellular FXIII, present in plate-
lets, monocytes, and bone marrow-derived cells, has two catalytic A domains
(Muszbek et al. 2011; Levy and Greenberg 2012).
The catalytic A domain is an 83 kDa protein that can be activated by proteolytic
activation (by thrombin) or non-proteolytic activation (in the presence of high calcium
concentrations).
The FXIIIA encoding genes reside on chromosome 6 (6p24-25). It is expressed
in bone marrow-derived cells including megakaryocytes, macrophages/monocytes,
and in hepatocytes. The B domain, which lacks enzymatic activity, is an 80 kDa
protein. The FXIIIB gene is located on chromosome 1 (1q31-32.1) and is expressed
primarily in hepatocytes (Hsieh and Nugent 2008).
In the context of the fibrin clot, FXIII has two functions with fibrin and fibrino-
gen as its main substrates. FXIII-mediated cross-linking of soluble fibrin monomers
results in the generation of an insoluble or stabilized fibrin strand that is essential for
in vivo hemostasis. Furthermore, FXIII mediates the cross-linking of fibrinolysis
inhibitors to fibrinogen, e.g., the α2-plasmin inhibitor (α2-PI, also called
α2-antiplasmin) (Mosesson et al. 2008; Fraser et al. 2011). Fibrinogen circulating in
a context of sufficient FXIII will be rich in α2-PI cross-linked to it. This type of
fibrinogen will eventually give rise to fibrin strands rich in α2-PI. The presence of
the fibrinolysis inhibitor in the fibrin strands hypothetically assures an increased
stability of the hemostatic plug. Fibrinogen with low α2-PI supposedly gives rise to
fibrin strands that are more prone to plasmin’s fibrinolytic activity and may thus be
associated with an increased risk of bleeding.

11.2.2.3 Indications
11.2.2.3.1 Acquired FXIII Deficiency
Acquired FXIII deficiency has been described in a variety of clinical settings due to
consumption of the coagulation factor and due to inhibition by acquired inhibitors
(Levy and Greenberg 2012). Consumption of FXIII can occur in massive bleeding,
but its incidence is not very well defined in the literature. A study in 1,004 adult
patients in a university hospital setting showed a prevalence of 21 % of patients with
values below the reference range. A 62 % incidence of acquired FXIII deficiency was
found in a population of patients with acute leukemia. In view of this high frequency,
some published algorithms for bleeding management incorporate FXIII. Conditions
associated with large wound areas, such as chronic inflammatory bowel disease
(IBD: ulcerative colitis and Crohn’s disease), massive burns, extensive orthopedic
surgery of the spine, etc., are known to be associated with low FXIII levels. However,
whether low levels of FXIII are associated with a clinical bleeding diathesis in the
context of IBD, for example, is contested (Van Bodegraven et al. 1995; Chamouard
et al. 1998). Acquired deficiency due to autoantibody formation is an extremely rare
event, with less than 100 reported cases to date (Boehlen et al. 2013).
184 L.M. Asmis

11.2.2.3.2 Congenital FXIII Deficiency

The prevalence of congenital FXIII deficiency is estimated at 1 per million. Areas
with high rates of consanguinity have higher incidences. Treatment of the rare
patients who require FXIII substitution in this context should be carried out in spe-
cialized centers. Heterozygote carriers of FXIII deficiency, with FXIII levels below
the reference range (in the range of 50 %), will generally not present with a bleeding
tendency under normal circumstances. Under special conditions, including postpar-
tum bleeding, major trauma, and severe perioperative bleeding, FXIII levels may
fall to levels that are conducive to a clinically relevant coagulopathy (Hsieh and
Nugent 2008) (and personal observation).

11.2.2.4 Monitoring
FXIII monitoring can be done using functional and antigenic tests. The usual test is
clot solubility in monochloroacetic acid solution, but this functional test is neither
standardized nor quantitative. Quantitative FXIII activity tests use activated FXIII
to assay its transglutaminase activity. This can be done in two main ways: (1) mea-
surement of ammonia released as an early byproduct of the transglutaminase reac-
tion (ammonia release assays) and (2) measurement of amine substrates that are
covalently linked to another substrate (amine-incorporation assays). More commer-
cial kits use the first method than the second. As there are non-FXIII-dependent
ammonia-releasing reactions that can account for up to 15 % of the measured activ-
ity, FXIII measurements <20 % should be interpreted with caution and confirmed in
an experienced laboratory. It should be noted that high ammonia concentrations in
severe hepatic dysfunction can interfere with ammonia release assays. Antigenic
tests can be directed against subunit A, subunit B, or the combination of both (Hsieh
and Nugent 2008; Karimi et al. 2009). In the context of perioperative FXIII moni-
toring, any automated, rapid, reproducible, and precise test is suitable. Knowing the
lower detection limit and test range used in one’s institution is important. Peyvandi’s
review shows that FXIII correlates badly with clinical bleeding (Peyvandi et al.
2012b).
Some literature suggests that, due to absent or inadequate testing strategies,
acquired FXIII deficiency goes largely undetected (Lawrie et al. 2010). Classic
global coagulation tests, including prothrombin time (PT) and activated partial
thromboplastin time (aPTT), are “blind” to FXIII (see Fig. 11.2). Specialized tests,
such as thrombin time and fibrinogen according to Clauss, do not incorporate FXIII
activity. The common stop signal for all the coagulation time-based tests is the
appearance of soluble fibrin monomers in the test vial. Fibrin monomers can be
detected optically or mechanically. Whatever the method, coagulation time mea-
surements stop prior to the onset of FXIII’s action.

11.2.2.5 Efficacy and Safety

Two RCTs evaluating human FXIII concentrate have been published to date. Rasche
et al. compared FXIII substitution versus placebo in 60 patients with acute leukemia
(Rasche et al. 1982). Although FXIII treatment resulted in increased FXIII levels,
11 Coagulation Factor Concentrates 185

PK

HK
FXII
aPTT FVII PT/Quick

FXI Tissue factor (FIII)

FIX Ca++
Ca++
FVIIIa PL

FX Ca++
FVa PL
FXIII

Prothrombin Thrombin (FIIa) Ca++

Fibrinogen Fibrins Fibrini

Fig. 11.2 The cascade model of coagulation and coagulation tests. Coagulation factors are
depicted as circles. Yellow circles indicate enzymatically active coagulation factors (exception:
fibrinogen, which is not enzymatically active, but a substrate). Yellow circles with a pink insert
represent activated coagulation factors. Orange circles indicate cofactors. Tissue factor is depicted
in blue, as it normally does not circulate in plasma. The factors involved in the activated partial
thromboplastin time (aPTT) and prothrombin time according to Quick (PT) are circled by light
blue and purple polygons, respectively. It is important that both FXIII and von Willebrand factor
(not depicted) are not assayed in the so-called standard coagulation tests. Prothrombin complex
concentrates contain FIX, FX, and FII and FVII to a variable degree. Substitution with PCC thus
influences both PT and aPTT. Abbreviations: Ca 2+ calcium, Fibrins soluble fibrin, Fibrini insoluble
fibrin, HK high molecular weight kininogen, PL phospholipids, PK prekallikrein

there were no statistically significant differences in the number of bleeding compli-

cations or transfusions.
Korte et al. investigated maximal clot firmness using ROTEM measurement as
the primary outcome in 22 cancer patients undergoing abdominal surgery. Patients
were randomized to receive 30 IU/kg of human FXIII or placebo within the first
15 min of surgery. The trial was halted prematurely (prespecified primary outcome
difference at interim analysis) because of an 8 % decrease in MCF in the treatment
group compared with a 38 % decrease in the placebo group – a statistically significant
difference (Korte et al. 2009).
186 L.M. Asmis

11.2.2.6 Dosing
No prospectively evaluated treatment thresholds or target values have been estab-
lished for the frequently acquired FXIII deficiencies.
In cases of congenital deficiency and in patients at a high risk of bleeding, 10 IU/kg
of FXIII are given at 4–6 week intervals (Bolton-Maggs et al. 2004) for prophylaxis.
This translates into 500–1,000 IU per application. In settings of acute bleeding,
10–20 IU/kg are recommended. This corresponds to single doses of 750–1,500 IU/kg
for a patient of approximately 75 kg.

11.2.2.7 Key Points and Prospects

Similarly to fibrinogen, there are only preliminary data on the efficacy and safety of
FXIII in the perioperative setting.

11.2.3 Von Willebrand Factor/Factor VIII Concentrates

11.2.3.1 Background
Von Willebrand factor (vWF) is named after the Finnish internist Erik A von
Willebrand, who first described a family with the disease in 1926 (von Willebrand
1926; Federici et al. 2006). The family came from the Åland Islands in the Baltic
Sea. In contrast to the hemophilias, both sexes were affected. The disease was char-
acterized by a prolonged bleeding time, despite a normal platelet count, normal PT,
(described by Quick in 1935), and normal-to-increased aPTT (described by Langdell
in 1953). The disease’s description was published under the designation “hereditary
pseudohemophilia.” In the 1950s, it became possible to measure FVIII and the first
cases of “pseudohemophilia” were described in patients of both sexes who had
reduced FVIII levels. In 1963, reduced platelet adhesiveness in affected patients
became detectable (Salzman 1963). In 1971, using a specific antibody against FVIII,
Zimmermann was able to show that there was another protein responsible for the
phenotype (Zimmerman et al. 1971), initially called FVIII-related protein. In 1971,
Howard and Firkin showed that an antituberculosis agent, ristocetin, could trigger
platelet agglutination in normal subjects, but not in patients with von Willebrand’s
disease (Howard et al. 1973). Von Willebrand factor was finally isolated in 1972
(Bouma et al. 1972), and as there are several distinct underlying pathophysiological
mechanisms, von Willebrand syndrome (vWS) is the recommended designation.

11.2.3.2 Description
VWF is a multimeric glycoprotein with monomers approximately 2,050 amino
acids long. These monomers are assembled into dimers, which are subsequently
polymerized into multimers of 2–20 units with a molecular weight of up to
20 × 106 D. VWF is encoded on the short arm of chromosome 12. It is primarily
expressed and stored in endothelial cells (Weibel–Palade bodies) and megakaryo-
cytes (α granules). Endothelial cells express DDAVP receptors that can induce vWF
secretion. DDAVP stimulation can lead to three- to five-fold increase in plasma
levels of vWF. Platelet activation and degranulation will also lead to a release of
stored vWF (Laffan et al. 2004).
11 Coagulation Factor Concentrates 187

The vWF monomer has 4 N terminal D domains (D1, D2, D’, D3), then 3 A
domains (A1, A2, A3) followed by another D domain (D4), a B domain, and three
terminal C domains (C1, C2, CK). VWF has three main functions, the first of which
is binding and stabilizing FVIII. FVIII binds to the vWF N terminal D′-D3 domains.
Its second function is interaction with platelets through glycoprotein GP Ibα expressed
on the platelet surface. Platelet GP Ibα interacts with the vWF A1 domain. Third,
vWF can bind to collagen in the subendothelium. Collagen-binding sites on vWF are
in the A3 or A1 domains (Schneppenheim and Budde 2011). The vWF-cleaving
protease, ADAMTS13, cleaves vWF in the A2 domain (Crawley et al. 2011).
VWF is a key molecule in hemostasis as it interacts with all three of its subsys-
tems. It interacts with vascular wall collagen in cases of trauma or other causes of
denudation of the vascular lining; it provides the landing strips for platelets by bind-
ing to their GP 1bα, thereby immobilizing them in the subendothelial matrix; and it
stabilizes plasmatic FVIII. Similarly to fibrinogen, vWF plays a role in both pri-
mary and secondary hemostasis.
Endothelial cells release vWF as long chains of covalently linked dimers. These
multimers are degraded by ADAMTS13 as they circulate. As the molecules decrease
in size, they become less “sticky” (Schneppenheim and Budde 2011).

11.2.3.3 Indications
11.2.3.3.1 Acquired Deficiency
Unlike other coagulopathies, such as fibrinogen or FXIII deficiencies, where
acquired deficiencies are more frequent than inherited forms, acquired vWS is less
frequent than its congenital variant. By 2000, fewer than 200 cases had been reported
(Sucker et al. 2009). Based on those figures and the author’s personal experience,
underreporting is very likely. Acquired vWS has been described in association with
underlying disorders including myeloproliferative disorders (where affected cells
may bind and consume vWF), lymphoproliferative disorders (autoantibodies against
vWF), other neoplasms, autoimmune disorders, cardiovascular disorders (vWF
consumption due to aortic stenosis, i.e., Heyde syndrome), and drug effects
(hydroxyl-ethyl starch is reported to reduce vWF antigen (vWF:AG), but interfer-
ence with vWF function is also possible) (Mohri 2006; Federici et al. 2013). A high
frequency of a new form of acquired vWS has been associated with patients using
ventricular assist devices. The supposed mechanism is the mechanical destruction
(versus the action of ADAMTS13) of the molecule (Dassanayaka et al. 2013).
Interestingly, in the context of acute bleeding, consumption of vWF without any of
the underlying disorders cited above is a rarely reported problem. This clearly
distinguishes vWF from fibrinogen, which is the first molecule to reach critical
levels in acute bleeding. This is possibly due to vWF’s multiple production sites
(megakaryocytes in bone marrow, endothelial cells) and storage pools (platelets,
endothelial cells).

11.2.3.3.2 Congenital Deficiency

VWS is the most frequent congenital bleeding disorder, with a population frequency
of approximately 1 % (Schneppenheim and Budde 2011). It can be categorized into
three subtypes (Federici 2009a; Favaloro 2011):
188 L.M. Asmis

• Partial quantitative deficiency or type I vWS

• Qualitative vWF deficiency or type II vWS (several type II forms are
distinguished)
• Virtually complete quantitative deficiency or type III vWS
Regarding the perioperative assessment of bleeding risk and prophylactic measures,
a distinction needs to be made between “real” vWS patients and those with low
vWF levels related to other factors, including the association of low vWF with
blood group O. However, in the context of acute bleeding, all these patients may
potentially benefit from vWF substitution.

11.2.3.4 Monitoring
Perioperatively, vWF testing should be based on pretest probability. If a validated
bleeding questionnaire is positive, then preoperative hemostasis testing is indicated
(Tosetto et al. 2006). VWF:AG, vWF ristocetin cofactor (vWF:RCo), and their ratio
are sufficient to detect most of the clinically relevant manifestations of vWS.
Historically, vWF:AG was the first to be measured. This can be done manually
using ELISA technology, but also using modern tests. The discovery that ristoce-
tin could agglutinate platelets was used to design the first functional vWF:RCo
test. Large vWF molecules tend to have vWF:RCo to vWF:Ag ratios of close to 1.
When vWF consumption increases, due to a stenotic heart valve, for example,
there is an increased proportion of smaller, less “sticky” vWF molecules, and the
vWF:RCo to vWF:Ag ratio will drop. Ratios of less than 0.70 are considered
indicative of acquired vWS or forms of congenital type II vWS, characterized by
qualitative vWF defects.
Exact subtyping of vWS can be done by specialized laboratories capable of mea-
suring vWF collagen-binding capacity (vWF:CB), vWF FVIII-binding capacity
(vWF:FVIII), and performing vWF multimer (vWF:MM) analysis (Laffan et al.
2004; Sucker et al. 2009).

11.2.3.5 Efficacy and Safety

In the perioperative setting, there are no RCT-based treatment algorithms available
for either congenital or acquired vWF deficiencies. With regard to safety, it must be
noted that vWF concentrates contain both vWF and FVIII. When substituting vWF,
it must be remembered that over substitution of vWF may be associated with an
increased risk of venous and arterial thromboembolism (VTE and ATE).
Furthermore, in a vWF-deficient patient who is substituted using concentrates, the
previously normal or even increased FVIII level (FVIII is an acute phase reactant)
will be boosted by the concentrate. This may result in supranormal levels of FVIII,
which are similarly associated with VTE and ATE (Federici 2009a, b). The relative
content of vWF:RCo to FVIII varies depending on the product. For Haemate P®, the
ratio is 2.5 to 1. The ratio is lower for other concentrates, with a minimum ratio of
1.1 to 1 (Federici 2005).
In the 1980s, cryoprecipitate and DDAVP were the only available treatment
options for vWS patients. Cryoprecipitate is poorly standardized, and not all
patients are responsive to DDAVP; thus, initial attempts were made toward
11 Coagulation Factor Concentrates 189

standardizing factor concentrates. The mid-1980s catastrophe of plasmatic prod-

ucts contaminated with hepatitis B, hepatitis C, and human immunodeficiency
virus shocked both patients and treating physicians alike (Alter et al. 1972; Evatt
et al. 1985; Kuo et al. 1989). The catastrophe led to the introduction of viral inactiva-
tion methods (Alter and Klein 2008), followed by donor screening in the 1990s
(Vamvakas and Blajchman 2009). These steps dramatically reduced the risks associ-
ated with plasmatic products down to current levels of less than 2 cases per 100,000
(Legler et al. 2000).

11.2.3.6 Dosing
Treatment of vWS aims to correct the deficient adhesion of platelets to the subendo-
thelium and to redress FVIII deficiency if necessary. Dosing recommendations are
mostly based on similarities to congenital vWF deficiency contexts and some lim-
ited experience with acquired vWS (AvWS) (Federici 2005; Franchini 2008; Tiede
et al. 2011). As a rule of thumb, substitution of 1 IU of vWF (RCo) per kg body-
weight will raise vWF activity by approximately 2 %. VWS acquired due to severe
aortic stenosis (Heyde syndrome) or other valvular defects is probably one of the
most frequent forms of AvWS. Either no substitution or a single preoperative dose
of Haemate P® 500–1,000 IU IV can be considered (not evidence based, in line with
(Mohri 2006; Federici et al. 2013) and personal experience). Once a defective heart
valve has been replaced, vWF levels return to normal and within hours the bleeding
diathesis will disappear. As in other indications, the severity of the AvWS, the clini-
cal context (active bleeding or not, previous bleeding complications), and potential
treatment complications, particularly thromboembolism, must be taken into consid-
eration. Treatment thresholds and targets are discussed later in Sect. 11.3. There are
differing vWF concentrates on the market. They can be categorized according to
purification method, viral inactivation, vWF:RCO to vWF:AG ratio, vWF:RCO to
FVIII ratio, and vWF MM content (Franchini 2008). The one for which most expe-
rience exists is Haemate P®. The pharmacokinetics of concentrates may also show
interindividual variability (Kessler et al. 2011).

11.2.3.7 Key Points and Prospects

There is a lack of RCT data for vWF concentrates in the perioperative setting.

11.2.4 Prothrombin Complex Concentrates

11.2.4.1 Background
Prothrombin complex concentrates (PCC) were historically also referred to as PPSB.
This latter abbreviation summarized the four coagulation factors: prothrombin (FII),
proconvertin (FVII), Stuart–Prower factor (FX), and antihemophilic factor B (FIX).
The first description of PCC dates back to more than 50 years ago when Didisheim
described the preparation of this human plasma fraction and its potential application
in humans (Didisheim et al. 1959). Surgenor described the original isolation proce-
dure – barium sulfate elution – in 1959, and methodology improved over the
190 L.M. Asmis

following years. In 1965, Tullis reported on the clinical use of prothrombin com-
plexes in the New England Journal of Medicine (Tullis et al. 1965). First reports on
the adverse thromboembolic effects of PCC led to the addition of heparin (Kasper
1975; Menache 1975). When cases of PCC-associated transmission of hepatitis B
and further thromboembolism-associated deaths were described, an international
task force was convened. This led to products being retracted from the market, stron-
ger regulation regarding isolation procedures, product surveillance regarding the con-
tamination by activated coagulation factors, the addition of inhibitors (antithrombin,
protein C, and protein S) to the products, viral inactivation procedures, and a formal
recommendation by the European Medicines Agency (EMEA) regarding minimal
and desired potencies for the various factors (Hellstern 1999; Hellstern et al. 1999).

11.2.4.2 Description
PCC are subdivided into two major categories based on their composition: three-
factor concentrates (containing FII, FIX, and FX – some contain traces of FVII) and
four-factor concentrates (containing all four factors, FII, FVII, FIX, and FX). PCC
were originally intended for the treatment of hemophilia B or hereditary deficiency
of FIX. In view of this, PCC were “labeled” according to their FIX content. Most
current PCC contain 500 or 600 IU of FIX per vial and thus have this figure in their
brand name. Procedures aimed at increasing product safety are frequently carried
out (and an appropriate suffix added to the product name), such as nanofiltration
(N or NF or F), pasteurization (P), solvent detergent treatment (SD or D), and vapor
and/or heat (VH or T). It is important to know that PCC from different producers
differ significantly in their relative and absolute content of the various coagulation
factors (Samama 2008; Sorensen et al. 2011a). Based on the variable yield achieved
during production, different lots from the same producer also vary in composition,
which is the reason why their factor content is generally indicated as a range and not
a single figure.
A further categorization of PCC is possible based on whether or not activated
coagulation factors are included in the formulation. Current PCC, registered for
most of the indications noted below, are nonactivated PCC. Activated PCC (aPCC)
represent a formulation that was designed and intended for use with hemophilia
patients who had acquired antibodies directed against the coagulation factor that
they had a deficiency for – so-called inhibitor patients. Factor eight inhibitor bypass-
ing agent (FEIBA) is the only registered plasma-based aPCC. It contains FII, FIX,
and FX, primarily but not solely in their nonactivated forms, and FVII largely in its
activated form (FVIIa) (Cromwell and Aledort 2012).

11.2.4.3 Indications
11.2.4.3.1 Acquired Disorders
Most coagulation factors are synthesized in the liver, including FII, FVII, FIX, and
FX. After synthesis in the hepatocyte, they are modified prior to secretion into
the blood stream. One of the modification steps is mediated by γ carboxylase, the
vitamin K-dependent enzyme that is the site of action of vitamin K antagonists.
11 Coagulation Factor Concentrates 191

Acquired deficiencies of FII, FVII, FIX, and FX can occur for several reasons,
including (1) coagulation inhibition due to vitamin K antagonists (VKA), (2)
coagulation factor consumption in the context of coagulopathy or uncontrolled
bleeding, (3) inhibition of coagulation by direct anticoagulants, and (4) other rare
causes.
The most frequent cause of an acquired prothrombin complex deficiency is the
use of VKA. Approximately 1 % of the population is estimated to be anticoagulated
at any given time. In randomized trials for atrial fibrillation, the bleeding risk of
patients treated by VKA ranged from 1.3 to 4.2 % per year (Wiedermann and
Stockner 2008).
Coagulation factor consumption in uncontrolled bleeding will lead to a critical
prothrombin complex factor deficiency after loss of approximately 200–240 % of
the calculated blood volume (Hiippala et al. 1995). Coagulation factor consumption
can also occur in the absence of active blood loss, e.g., in disseminated intravascular
coagulopathy.
While the reversal of VKA effects on coagulation is a well-established indication
for PCC, the data on PCC use to reverse the effects of novel oral anticoagulants
(NOAC), including direct FIIa inhibitors (dabigatran) and direct FXa inhibitors
(including apixaban, edoxaban, rivaroxaban, and others), is only now emerging
(Eerenberg et al. 2011). The FEIBA aPCC has recently been included in European
guidelines for the treatment of NOAC-related bleeding (Kozek-Langenecker et al.
2013). However, to date, no RCTs have been published on PCC or aPCC use in
actively bleeding patients (Siegal and Cuker 2013).
Rare causes of acquired deficiencies involving one or more factors of the pro-
thrombin complex include severe nutritional vitamin K deficiency, an acquired
inhibitor (antibody) directed against FIX in hemophilia B patients, a propeptide
mutation of the FIX gene leading to pseudohemophilia B in patients treated with
VKA (Ulrich et al. 2008), absorption of FX to amyloid protein in systemic AL amy-
loidosis, and inhibitors directed against thrombin (FIIa) in patients with the same
disease (Thompson et al. 2010).

11.2.4.3.2 Congenital Disorders

The deficiency of FIX, or hemophilia B, as one of the “more” frequent congenital
bleeding disorders has a frequency of 1:60,000. Since the licensing of FIX concen-
trates, these products have largely replaced PCC as first-line treatment of hemo-
philia B. In principal, however, they remain a treatment option for hemophilia B
replacement therapy. In several countries, individual concentrates for “rare” coagu-
lation disorders (less frequent than hemophilia A or B) including severe FVII defi-
ciency (frequency 1:0.3–0.5 × 106), FX deficiency (frequency 1 × 106), and FII
deficiency (frequency 1:2 × 106) are not readily available or do not exist. For these
conditions, three- and four-factor PCC remain relevant treatment options for man-
aging bleeding (Bolton-Maggs et al. 2004).
The FEIBA aPCC is indicated in hemophilia patients, particularly those who
have developed inhibitors (Aledort 2008).
192 L.M. Asmis

11.2.4.4 Monitoring
Factors II, VII, and X are key factors in determining PT; thus PT will detect deficien-
cies of these factors and is suitable for PCC monitoring (see Fig. 11.3). The activity
and antigen levels of these three factors can also be used for this purpose.
Characteristics including plasma half-lives are given in Table 11.1. FIX is a vitamin
K-dependent (VKD) factor, as are the three mentioned above. However, it is not a
key determinant of PT. For FIX, aPTT and FIX determinations are the sensitive tests
necessary to monitor substitution.
Point-of-care (POC) technologies including rotational thromboelastometry
(ROTEM) and thromboelastography (TEG), as well as other systems, can assay

a
6
[Fibrinogen] (g/l)

5
4
3
2
1

1 2 3 4 5 6 7
Time (days)
b
6
[Fibrinogen] (g/l)

5
4
3
2
1

1 2 3 4 5 6 7
Time (days)

Fig. 11.3 The threshold and target question. (a) Depicts the time course of plasma fibrinogen
concentration in a fictive patient, e.g., with hereditary afibrinogenemia (yellow curve). After (one
big) substitution, the concentration increases into the normal range (depicted by dark blue area)
and drops off with a half-life of approximately 72–100 h over the following days. (b) Illustrates the
time course of a fictive perioperatively bleeding patient (red curve). The transfusion threshold in
this example is set at 1.0 g/l (lower border of dark blue box) and the transfusion target at 2.0 g/l
(upper limit of light blue box). Initially multiple (small) substitutions are needed to reach the trans-
fusion target value. After two more instances of substitution, the fibrinogen levels stabilize as the
fictive patient ceases to bleed. Note that in the acutely bleeding patient, the observed half-life of
fibrinogen is initially much shorter than 72 h and only later approaches the value described under
physiological conditions
11 Coagulation Factor Concentrates 193

Table 11.1 Factors relevant for coagulation

MW
Name Abbreviation Function (kDa) μg/ml μmol/l IU/ml t1/2 (h)
Fibrinogen FI Substrate of 340 3,000 8.8235 n.a. 72–100
coagulation: forms
fibrin
Prothrombin FII Serine protease 72 100 1.3889 0.60–1.40 60
(VKD): multiple
targets
Labile factor FV Cofactor to FX 330 10 0.0303 0.60–1.40 15
Stable factor FVII Serine protease 50 0.5 0.0100 0.60–1.40 5
(VKD): activates
FX (and FIX)
Antihemophilic FVIII Cofactor to FIX 185 0.1 0.0005 0.50–2.00 12
factor
Christmas FIX Serine protease 56 5 0.0893 0.60–1.40 18
factor (VKD): activates
FX
Stuart–Prower FX Serine protease 56 10 0.1786 0.60–1.40 30
factor (VKD): activates
FII
Plasma FXI Serine protease: 160 5 0.0313 0.60–1.40 45
thromboplastin activates FIX
antecedent
Hageman FXII Serine protease: 80 30 0.3750 0.60–1.40
factor activates FXI
Fibrin- FXIII Cross links soluble 320 60 0.1875 0.50–1.50 216
stabilizing fibrin monomers
factor (fibrins) to insoluble
fibrin strand (fibrini)
von Willebrand vWF Mediates platelet 225xn 10 n.a. 0.50–2.00 10
factor adhesion to
collagen, stabilizes
and transports FVIII
Tissue factor FIII Main initiator of 45 n.a. n.a. n.a. n.a.
coagulation in
vivo: cofactor to
FVII/FVIIa
Coagulation factors I–XIII and von Willebrand factor are listed together with their abbreviation,
function, molecular weight (MW), mean concentration in μg/ml and in μmol/l, reference range in
IU/ml, and plasma half-life (under physiological conditions). Plasma half-life may be considerably
shorter in the presence of bleeding. Tissue factor, the main initiator of coagulation in vivo, is prin-
cipally a membrane-bound protein expressed on subendothelial cells. Under pathophysiological
conditions it may (1) circulate bound to microparticles or monocytes, (2) circulate in truncated
form as a free protein, or (3) be ectopically expressed on endothelial and other cells. Vitamin
K-dependent (VKD)

FII-, FVII-, FIX-, and FX-dependent pathways. Tests targeting the “extrinsic” system
(using tissue factor as the starting reagent) are available for thromboelastometric/
graphic test systems. PCC influence the clotting times of such tests, including
EXTEM and RapidTEG. However, as anticoagulated patients may present normal
194 L.M. Asmis

clotting or R times in these whole blood tests, sensitivity is an issue. POC testing
systems have the advantage of shorter turnaround times than routine coagulation
tests. However, the fact that they generally use whole blood can have a negative
impact on their sensitivity toward VKA, other anticoagulants, and possibly PCC.

11.2.4.5 Efficacy and Safety

Only a few RCTs have been published regarding the use of PCC in different settings.
A French study with 59 patients evaluated two dosing regimens for urgent VKA
reversal (Kerebel et al. 2013). An interesting study monitoring coagulopathic cardiac
surgery patients showed reduced allogenic blood transfusion in 100 patients random-
ized to POC-based monitoring or standard care. The predefined treatment algorithm
included PCC (Weber et al. 2012). Most of the data stems from cohort studies
(Makris et al. 1997; Lubetsky et al. 2004; Riess et al. 2007; Pabinger et al. 2008).
PCC trials in an anticoagulant reversal setting have reported rates of thromboem-
bolism, possibly related to PCC, in the percent range: approximately 1 % for VTE
and up to 3 % for ATE (Majeed et al. 2012). A meta-analysis of 27 trials by Dentali
reported a mean thromboembolism rate for PCC (three- and four-factor PCC com-
bined) of 1.4 % (95 % CI 0.8–2.1 %) (Dentali et al. 2011). Sorensen reported throm-
boembolism in 1.5 % of PCC study patients (Leissinger et al. 2008; Sorensen et al.
2011a). The review also discusses the pathophysiology potentially related to the
accumulation of coagulation factors with long half-lives, FII in particular. However,
these thromboembolic complications may also be related to the underlying causes
that mandate anticoagulation in the first place (Sorensen et al. 2011a). Nevertheless,
thromboembolism in these settings appears to be more frequent than is observed in
settings of fibrinogen or FXIII substitution.

11.2.4.6 Dosing
Clinical trials have not been able to resolve questions about the optimal dose of
PCC. Doses reported in the studies cited above range from 7 to more than 80 IU/kg
bodyweight. As RCT data is lacking, guidelines and other official dosing informa-
tion are helpful (Makris et al. 1997; Mannucci and Douketis 2006; Weber et al.
2013). Algorithms dependent on the international normalized ratio (INR) exist.
In perioperative bleeding, 20–30 IU/kg bodyweight has been suggested by a group
of Austrian experts (OEGARI). The numerous confounding factors include differ-
ing target values for the INR; the fact that dosing algorithms are often based on
pharmacological models which may or may not be applicable to a given patient; the
question of whether the product is applied to an actively bleeding or non-bleeding
patient; and the clinical context in which PCC are prescribed. Whenever possible,
dosing should be standardized within institutions or clinics and should follow an
evidence-based algorithm appropriate to the patient’s clinical context (van Aart
et al. 2006).
Factors reported to be associated with adverse outcome include repeated dosing
(with potential accumulation of coagulation factors with a long half-lives, such as
FII), coadministration with other coagulation products, and nonobservance of
recommended infusion speeds (Pabinger et al. 2010).
11 Coagulation Factor Concentrates 195

11.2.4.7 Key Points and Prospects

There remains a paucity of RCT evidence on PCC. The evidence available points to
a potential safety issue regarding thromboembolic events in the range of 1–3 %.

11.2.5 Recombinant Activated Factor VII

11.2.5.1 Background
Recombinant human activated factor seven (rFVIIa) was developed more than 20
years ago for hemophilia patients suffering from inhibitor formation. Antibodies
directed against FVIII, or inhibitors, may complicate the treatment of hemophilia
patients who are treated by FVIII products. The inhibitors may then neutralize the
patient’s own and the exogenous FVIII, leading to severe bleeding complications.
Bypassing agents that circumvent the FIX/FVIII complex can stop bleeding in these
patients. Pure plasma-derived FVIIa showed clinical efficacy in proof-of-principle
experiments. Subsequently, recombinant FVIIa was developed and tested in clinical
trials (Hedner 2007, 2012).
Distinguishing the clinical setting in which patients are treated with FVIIa appears
relevant. On-label indications include only hypocoagulable patients. In off-label
indications patients may be normo- or even hypercoagulable.

11.2.5.2 Description
FVIIa circulates in plasma and comprises approximately 1 % of the circulating
plasma FVII pool. The precursor single-chain FVII molecule is synthesized in the
liver and is one of the vitamin K-dependent coagulation factors. FVII is a 50 kD pro-
tein that has the shortest plasma half-life among coagulation proteins (see Table 11.1).
The activation of FVII to two-chain FVIIa involves cleavage at a single peptide bond.
This activation can be mediated by FXa, FVIIa itself, and other coagulation factors.
By binding to surface-bound tissue factor, the enzymatic activity of FVIIa is dramati-
cally increased. The cell surface-bound complex of calcium/tissue factor/FVIIa is
capable of activating FX and FIX (Hedner and Brun 2007; Vadivel and Bajaj 2012).
Two mechanisms of action have been postulated for rFVIIa. The first is the
tissue factor-mediated process described above on the surface of cells expressing
tissue factor. The second is tissue factor independent and believed to occur by
direct binding of FVIIa to the surface of activated platelets (Hoffman 2003;
Logan and Goodnough 2010).

11.2.5.3 Indications
On-label indications include hemophilia A or B with inhibitors, congenital FVII
deficiency, and acquired hemophilia. The treatment of these rare disorders goes
beyond the scope of this chapter and will not be discussed in detail. Off-label indi-
cations for which clinical trial evidence exists, include body trauma, brain trauma,
cardiovascular surgery, intracerebral hemorrhage, upper GI bleeding in the context
of cirrhosis, liver transplantation, and hematopoietic stem cell transplantation
(Logan and Goodnough 2010).
196 L.M. Asmis

11.2.5.4 Monitoring
Monitoring of FVIIa treatment requires specialized coagulation tests. Classic coag-
ulation tests including prothrombin time, activated partial thromboplastin time, and
FVIII or FIX activity are unsuitable for this purpose. Some specialized tests, includ-
ing thrombin generation tests, thromboelastography/rotational thromboelastometry,
and aPTT waveform analysis, have been used (Hoffman and Dargaud 2012).

11.2.5.5 Efficacy and Safety

In the trauma setting two main studies have been published. The multicenter blunt
trauma study (n = 70) showed a significant decrease of red blood cell transfusion and
a reduced frequency of acute respiratory distress syndrome. Mortality did not differ
between FVIIa and placebo in either study (Beste et al. 2012).
In the cardiovascular surgery context, two RCTs could show a significant
decrease in RBC transfusion (Diprose et al. 2005; Gill et al. 2009).
In coagulopathic patients with liver disease, most RCTs showed negative results;
only one study could show a reduction in RBC transfusion requirements (Bosch et al.
2004; Lodge et al. 2005; Planinsic et al. 2005; Pugliese et al. 2007; Bosch et al. 2008).
Thromboembolic complication rates of up to 11 % have been reported in the off-
label setting of normo- and hypercoagulable patients (Levi et al. 2010).

11.2.5.6 Dosing
Off-label use of FVIIa requires an individualized risk–benefit assessment, with a
particular focus on thromboembolic complications.
Reported dosing schemes in the on-label context range from 15 to 30 μg/kg every
4–6 h to 90 μg/kg every 2 h IV. In the off-label context, doses ranging 5–200 μg/kg
were studied (Warren et al. 2007; Logan and Goodnough 2010). In cases where an
off-label use appears unavoidable, it is the author’s opinion that the lowest possible
dose should be used (van de Garde et al. 2006; Narayan et al. 2008).

11.2.5.7 Key Points and Prospects

For on-label indications the evidence suggests efficacy and safety.
For off-label indications, few RCTs have been able to show clinical benefit.
Safety is a relevant issue with thromboembolic events up to 11 %.

11.3 The Threshold and Target Question

One of the big unanswered questions in perioperative coagulation management is

that of the treatment threshold. Which level is appropriate for a given parameter?
For example, at which fibrinogen concentration is it indicated to substitute the
patient? Some recent transfusion guidelines either do not define a threshold at all or
give a wide range of thresholds (Dzik et al. 2011; Sniecinski et al. 2012).
One widely held misconception is that a test’s reference range holds the answer
to the threshold question. This is false: a reference range is defined in a population
of healthy individuals. Ideally, the number of individuals tested is large (>20) and
11 Coagulation Factor Concentrates 197

the population covers both sexes and all relevant age groups. The reference range
reflects the distribution of normal values for a given parameter and typically includes
the central 95 or 99 % of individuals. There is no evidence to suggest that values
below the lower limit of this range are associated with bleeding or that they might
represent a useful threshold for transfusion in the perioperative setting.
If the reference range is not the appropriate tool to define the parameter’s thresh-
old, another procedure must be agreed upon. To address this issue, there is a need
for large RCTs that show reduced mortality in transfused or substituted patients and
that define thresholds. Currently, such studies are not available. In their absence,
threshold levels are best defined locally. What are the important factors to consider
when defining a threshold?
The threshold question is test dependent on at least three levels. Classic coagula-
tion tests measure coagulation factor antigen or activity levels. Antigen assessments
are defined by weight per volume, while activity assays test a biological function in
relation to the amount of coagulation factor contained in 1 ml of plasma. It is unclear
which value is the more reliable for use in a transfusion algorithm. Moreover, for a
given test type, e.g., functional fibrinogen, test results can vary depending on which
test kit is used. Furthermore, fibrinogen measured using the same test can vary
between individual laboratory platforms.
The clinical context is another relevant factor to be considered when setting a
coagulation factor threshold; threshold levels for different indications may vary. For
hereditary disorders, such as afibrinogenemia or FXIII deficiency, guidelines and
experts propose 0.5 g/l and 5–10 % as levels generally sufficient for hemostasis
(Ciavarella et al. 1987; Anwar et al. 2002; Mannucci 2010). Recent data show that
these numbers are not appropriate in states of acquired deficiency. Instead, in the
setting of hypofibrinogenemia induced by acute bleeding, fibrinogen levels from 0.8
to 2.0 g/l have been proposed (Spahn et al. 2007; Rossaint et al. 2010).
Another relevant clinical factor is the hemostatic state. An actively bleeding patient
with acquired fibrinogen deficiency below a given cutoff may require treatment. In the
absence of bleeding, the treatment is likely to be different. Transfusion thresholds for
bleeding (therapeutic intention) and non-bleeding patient populations (prophylactic
intention) need to be established. If the volume of blood loss is used as the transfusion
trigger, then target concentrations should be defined. In fact, Rahe-Meyer et al. pub-
lished a randomized trial in major aortic surgery where the threshold for fibrinogen
transfusion was defined by the volume of blood loss; the target concentration was
defined for a FIBTEM MCF of 22 mm, corresponding approximately to a fibrinogen
level (Clauss) of 3.6 g/l (Rahe-Meyer et al. 2013b).
The timing of testing is another complicating factor. Classic coagulation tests are
performed in citrate plasma. The centrifugation of whole blood and the production
of cell-free citrate plasma necessitate time. Between drawing the blood, centrifuga-
tion, and producing the test result, a turnaround time of 30–40 min is common.
However, within this time span, an acutely bleeding patient’s coagulation status can
change dramatically, undergoing multiple transfusions and substitutions. To mini-
mize turnaround time in acutely bleeding patients, whole blood tests have been
designed utilizing POC testing devices. Fibrinogen tests exist for such POC test
198 L.M. Asmis

devices (FIBTEM for ROTEM and functional fibrinogen for TEG). These fibrino-
gen tests are performed on whole blood and measure other aspects of fibrinogen
than the classic coagulation tests. Because of their design as whole blood tests,
POC-based tests have a higher degree of outcome variability (Okuda et al. 2003;
Theusinger et al. 2010).
Large outcome-based studies are necessary to properly answer the transfusion
threshold question. These studies are scarce or nonexistent for isolated coagulation
factor products. In the absence of appropriate evidence, institutions should stan-
dardize their approach and define test procedures in order to optimize treatment
efficacy and patient safety. Locally defined thresholds should be reevaluated regu-
larly and changed in response to new evidence.

11.4 Conclusions and Prospects

Isolated coagulation factor concentrates including fibrinogen, FXIII, vWF, and PCC
represent some of the therapeutic options for patient management in perioperative
settings. Evidence based on RCT is only beginning to emerge. Safety signals include
thromboembolic rates in the range of 1–3 % for PCC. These risks appear to be less
important for other isolated coagulation factor concentrates. Besides safety, health-
care cost needs to be integrated into the final risk–benefit evaluation of the use of
coagulation products. RCTs designed for perioperative settings and investigating
predefined treatment algorithms will help define the evidence-based strategies of
the future.

Key Points
With current knowledge and in the absence of RCT-based strategies, an individual-
ized risk–benefit evaluation should be performed for every patient prior to the
use of isolated coagulation factor concentrates.
Transfusion thresholds and targets depend on the clinical context (congenital versus
acquired hemostatic disorders, active bleeding versus no bleeding).
Transfusion thresholds and targets need to be validated locally.
Transfusion thresholds and targets need to be established in an evidence-based
context.

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11 Coagulation Factor Concentrates 203

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Procoagulant Drugs
12
Rainer B. Zotz, Nikola Zotz, and Christoph Sucker

12.1 Procoagulant Drugs

Procoagulant drugs are non-transfusional agents that are primarily used when
bleeding is the consequence of a specific defect of hemostasis. In this chapter, the
pharmacological properties and uses of desmopressin, antifibrinolytics, and vitamin K
will be reviewed. Desmopressin, with its various procoagulant pharmacological
effects, is used in the prevention and treatment of bleeding related to congenital
and acquired coagulation factor deficiencies or platelet function disorders.
Antifibrinolytics (inhibitors in particular steps of fibrinolysis) are the treatment of
choice in bleeding caused by hyperfibrinolysis. Because of their low cost and their
mild side effects, desmopressin and antifibrinolytics are also used as blood-saving
agents in surgery. Vitamin K is given in states of vitamin K deficiency which lead to
vitamin K deficiency bleedings. This is relevant to patients taking vitamin K antago-
nists in cases of urgent invasive procedures, asymptomatic and excessively elevated
INR values, and bleeding.

12.2 Desmopressin

12.2.1 Description

Desmopressin is an analogue of the naturally occurring human antidiuretic hormone,

vasopressin. It was first synthesized in 1967 by removing the N-terminal amino

R.B. Zotz (*) • N. Zotz

Centrum für Blutgerinnungsstörungen und Transfusionsmedizin (CBT),
Immermannstrasse 65 a, Düsseldorf 40210, Germany
e-mail: [email protected]
C. Sucker
LaboMed Gerinnungszentrum Berlin, Tauentzienstrasse 7 b/c, Berlin 10789, Germany
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 205

DOI 10.1007/978-3-642-55004-1_12, © Springer-Verlag Berlin Heidelberg 2015
206 R.B. Zotz et al.

group and substituting l-arginine with d-arginine (DDAVP, desamino-d-arginine

vasopressin; full name, 1-desamino-8-d-arginine vasopressin). This modification
leads to an extensive loss of the molecule’s vasopressive effect, while the duration
of its antidiuretic activity is significantly prolonged. These clinically useful attri-
butes made it the drug of choice for the treatment of central diabetes insipidus
(Vavra et al. 1968; Kohler and Harris 1988; Mannucci 2008). In the 1970s, it was
observed that desmopressin also raises the level of plasma coagulation factor VIII
when infused into healthy volunteers (Cash et al. 1974; Mannucci et al. 1975).
This effect is due to the selective binding of desmopressin to the vasopressin recep-
tor subtype 2 (V2R). When endothelial V2R are activated, they cause cyclic adenos-
ine monophosphate (cAMP)-mediated signaling, leading to the exocytosis of
Weibel-Palade bodies, where von Willebrand factor (vWF) is stored and then
released. After the administration of desmopressin, a fast increase of vWF levels in
plasma can be observed. The details of the simultaneous increase of factor VIII
levels in plasma are still not fully understood, although the mechanism can be
explained as an indirect increase due to vWF secretion, making more factor VIII
binding sites available.
The Weibel-Palade bodies also store tissue plasminogen activator (t-PA), which
is released in the same way as vWF. This leads to profibrinolytic activity, as t-PA
converts plasminogen to plasmin and thus initiates fibrin degradation. This activity
is enhanced by fibrin binding (Irigoyen et al. 1999; Kaufmann and Vischer 2003).
For that reason, the concurrent administration of tranexamic acid is discussed.
In addition to the increased vWF, factor VIII, and t-PA levels in plasma, other
procoagulant mechanisms are induced by desmopressin, e.g., its effect on platelet
function. It was possible to show that desmopressin enhances platelet adhesion to the
subendothelium. This is unaffected by the vWF concentration in plasma. Therefore,
other agonists must facilitate the adhesion of platelets; however, the mechanism of
their response to desmopressin is not fully understood (Sakariassen et al. 1984;
Lethagen 1997; Balduini et al. 1999). Several findings suggest that intercellular
messengers, secreted by monocytes, may play a role in the hemostatic effects of
desmopressin. As a consequence of the vWF release, P-selectin, a component of the
membrane of Weibel-Palade bodies and an important cell adhesion molecule for
thrombocytes and monocytes, is integrated in the membrane of the endothelial cells.
This enhances platelet adhesion and adhesion of monocytes to the extracellular
matrix of endothelial cells. Furthermore, the monocytes upregulate the expression
of tissue factor through a simultaneous expression of inflammatory cytokines
(Galvez et al. 1997; Pereira et al. 2003).

12.2.2 Clinical Uses

The different procoagulant pharmacological effects of desmopressin make it an oft

used drug for the treatment of several congenital and acquired bleeding disorders
(Mannucci 1998). It is also being evaluated as a blood-saving agent in surgery or
trauma (Mannucci and Levi 2007), as recent studies have shown that red blood
12 Procoagulant Drugs 207

cell transfusion is significantly associated with infection, ischemic postoperative

morbidity, prolonged hospital stays and increased associated costs, and decreased
long-term survival (Murphy et al. 2007).

12.2.2.1 Desmopressin in Inherited Bleeding Disorders

(von Willebrand Disease, Hemophilia A, Factor XI Deficiency,
Platelet Function Disorders)
The chief virtue of desmopressin – the direct release of vWF – has two main functions
in hemostasis. VWF is an adhesion protein that redirects circulating platelets to sites
of vascular injury, particularly through larger multimers, which is essential for platelet
plug formation. Furthermore, in plasma it forms a complex with coagulation factor
VIII, thereby protecting it from inactivation and clearance (Weiss et al. 1977; Wise
et al. 1991; Sadler 1998). This accounts for its most established applications in several
inherited bleeding disorders, first of all von Willebrand disease (vWD) and mild
hemophilia A. The mainstay of treatment in these patients is the replacement of the
deficient protein at the time of spontaneous bleeding such as hemarthrosis or mucosal
bleeding or before invasive procedures are performed (Franchini 2007).
VWD is categorized into three major types with several subtypes (Favaloro
2011). In patients with type 1 vWD and baseline vWF and factor VIII levels higher
than 10 IU/dL, desmopressin is most effective (Mannucci 1997). In vWD types 2A,
2M, and 2N, a variable response pattern occurs, and the decision to use desmopres-
sin should be made based on the results of a test infusion. Its use in vWD type 2B is
traditionally considered contraindicated because of the transient appearance of
thrombocytopenia, but there are a few case reports where it has been used safely.
Patients with vWD type 3 are usually unresponsive to desmopressin (Gralnick et al.
1986; Casonato et al. 1994; Mannucci 2001).
The magnitude of the response of factor VIII to desmopressin usually varies in
patients with hemophilia A as well and is not always linked to the basal levels of
factor VIII coagulant activity (FVIII:C). However, an effective application of des-
mopressin is only reasonable in patients with mild hemophilia A (FVIII:C >5 %).
A test infusion should be carried out to assess the efficacy in each patient to be
treated. Therapeutic indications must, furthermore, take into account the type of
bleeding episode or surgical procedure and the factor VIII levels that must be
attained and maintained. Patients with severe hemophilia A do not respond to des-
mopressin at all (Castaman 2008).
A number of patients with vWD and hemophilia A are unresponsive or display
adverse effects to desmopressin. In these cases recombinant interleukin-11 is being
tested as an alternative hemostatic agent (Ragni et al. 2013).
Although limited, data from the available literature suggest a potential role for
desmopressin in patients with milder factor XI defects for the treatment of bleeding
episodes and the prevention of postoperative bleeding (Franchini et al. 2009).
The increase in adhesiveness of platelets to the subendothelial matrix and the aug-
mentation of platelet aggregation by means of desmopressin has been proved to be
efficacious in platelet function disorders (Cattaneo 2002). Independently of their clas-
sification (Podda et al. 2012), these are characterized by impaired platelet-dependent
208 R.B. Zotz et al.

hemostatic functions, associated with bleeding diatheses of varying severity, and

manifested in mild to severe mucocutaneous bleeding. Due to the rarity and heteroge-
neity of these disorders, results of the treatment with desmopressin are only reported
in a few case series and have not been corroborated by means of thorough clinical
trials (Coppola and Di Minno 2008). The types of inherited platelet function disorder
for which some evidence of the efficacy of desmopressin has been shown include
delta-storage pool diseases, disorders of granule secretion, signal transduction disor-
ders, thromboxane receptor deficiency, and May-Hegglin anomaly. Weaker evidence
has been provided for Bernard-Soulier syndrome, Hermansky-Pudlak syndrome, and
arachidonate metabolism defects. In severe platelet dysfunctions, such as Glanzmann’s
thrombasthenia, which is characterized by a missing or dysfunctional glycoprotein
(GP) IIb/IIIa receptor on platelets, desmopressin has no clinically relevant efficacy
(Nurden et al. 2012).

12.2.2.2 Desmopressin in Acquired Bleeding Disorders

(Acquired vWD or Hemophilia A, Liver Cirrhosis,
Uremia, Drug-Induced Platelet Disorders)
Desmopressin has been used in several acquired bleeding disorders, most impor-
tantly in acquired von Willebrand disease (AvWD) and acquired hemophilia A.
AvWD occurs in association with a variety of underlying disorders, most fre-
quently in lymphoproliferative and myeloproliferative disorders, other malignan-
cies, and cardiovascular disease. The bleeding pattern and the laboratory findings
are similar to the congenital form of vWD. Classification, diagnosis, and the mecha-
nism of the vWF deficiency in patients with AvWD are largely influenced by the
underlying disorder or causative agent. Treatment should pursue two strategies:
treating the underlying disorder if possible and treating AvWD itself (Sucker et al.
2009; Tiede et al. 2011). Desmopressin can be used to prevent and control bleeding
in some patients with AvWD. However, success rates depend on the underlying
disorder: they were low in cardiovascular (10 %) and myeloproliferative disorders
(21 %), but higher in autoimmune (33 %), lymphoproliferative (44 %), and other
neoplastic disorders (75 %) (Federici et al. 2013).
Acquired hemophilia A is a rare bleeding disorder in which patients present with
bleeding episodes that are often spontaneous and life-threatening. It is caused by
autoantibodies to factor VIII. While a minority of cases are associated with a variety
of conditions, e.g., pregnancy, autoimmune disorders, cancers, and drugs, it occurs
mostly in patients without concomitant diseases. Predictors of a clinical response to
desmopressin include a low inhibitor titer (<5 Bethesda units) and a residual FVIII:C
level greater than 5 % (Franchini and Lippi 2011). Current registry data reveal a
good response in acquired hemophilia treated with desmopressin as a first-line
agent (Baudo et al. 2012).
Desmopressin can also be used in patients with acquired platelet function disor-
ders such as uremia, a complex metabolic disorder with a platelet dysfunction being
the main factor responsible for hemorrhagic problems (Mannucci et al. 1983; Lee
et al. 2010). In patients with liver cirrhosis who need invasive procedures, a benefit
from treatment with desmopressin was shown several times (Burroughs et al. 1985;
12 Procoagulant Drugs 209

Mannucci et al. 1986; Agnelli et al. 1995), but could not be confirmed in later trials
(Wong et al. 2003; Pivalizza et al. 2003).
Finally, drug-induced bleeding disorders, especially if caused by antiplatelet
agents, can be treated successfully with desmopressin (Levi et al. 2011).
Theoretically, desmopressin could also be used in an attempt to control acute bleed-
ing caused by novel anticoagulants (Brem et al. 2013).

12.2.2.3 Desmopressin as a Blood-Saving Agent in Surgery

Since it was first suggested in the mid-1980s that desmopressin could reduce blood
loss and transfusion requirements in surgery (Salzman et al. 1986), numerous stud-
ies and several meta-analyses have proved, and failed to prove, a positive effect
from its administration. One of the two latest analyses concluded that there was no
convincing evidence that desmopressin minimizes transfusion or blood loss in sur-
gical patients who do not have congenital bleeding disorders (Carless et al. 2004).
The other analysis concluded that desmopressin reduces blood loss and transfusion
requirements only slightly, but without a reduction in the proportion of patients who
received transfusions (Crescenzi et al. 2008). Stratifying these trials into patients
with a high risk of bleeding due to aspirin intake and/or a surgical intervention with
expected high blood loss on the one hand and patients with a low risk of bleeding on
the other, it can be shown that the use of desmopressin significantly reduces blood
loss and the number of red blood cell units transfused in the high-risk group. In
contrast, in subjects with low risk of bleeding, no significant benefit from using
desmopressin was found (Zotz 2009).

12.2.3 Administration and Dosage

Desmopressin is usually administered by intravenous infusion and should be diluted

in saline solution and slowly infused over the course of approximately 30 min. To
obtain a maximum response from factor VIII and vWF, the optimal dose is 0.3 μg/
kg. After 1 h the peak plasma levels are 3–5 times higher than baseline for factor
VIII and almost 3–5 times higher than baseline for vWF. Half-life varies as well: in
the ranges of 2–5 h for circulating factor VIII and of 6–9 h for vWF. A subcutaneous
injection of 0.3 μg/kg produces a similar response, but peak plasma levels are
reached more slowly. The recommended dose for children is similar to that for
adults. When body weight is greater than 10 kg, the drug should be diluted in 50 mL
of fluid, whereas in young patients weighing less than 10 kg, the volume of fluid
should be 10 mL (Villar et al. 2002). In children under the age of 1 year, desmopres-
sin should be used with caution because of adverse effects (see below).
The preferred route for home treatment is intranasal administration with an
optimal dose of 300 μg in two puffs; in children this should be reduced to one puff.
As intranasal administration elicits a slower and less marked response (maximum
factor VIII level of approximately 2.5 times higher than baseline value), subcutane-
ous or intravenous routes of administration should be chosen if the maximum
response is desired (Villar et al. 2002).
210 R.B. Zotz et al.

Repeated doses of desmopressin over short intervals of time are associated with
a phenomenon known as tachyphylaxis – the progressively lower rises in the factor
VIII and vWF levels. This must be taken into account when planning treatment for
a prolonged period of time, e.g., in surgery with treatment lasting 7 days or longer.
The factor VIII level should be checked daily, and blood samples should be taken
1 h after the completion of the infusion. In such cases it is particularly important to
monitor the plasma sodium level (Vicente et al. 1993).

12.2.4 Side Effects and Contraindications

Desmopressin can cause side effects in about 30 % of patients, but in the vast major-
ity of cases, these are transient and mild. Administration is frequently accompanied
by headache, facial flushing, and a mild decrease in blood pressure and heart rate
(Mannucci 1998). More severe, but rarer, are episodes of fluid overload, severe
hyponatremia, and seizures due to the modest antidiuretic effect of the hemostatic
agent. This affects mostly very young patients after the administration of several
doses or patients receiving hypotonic fluids. Thus, desmopressin should be used
with caution in small children and patients with congestive heart failure or renal
insufficiency. Fluid intake should also be regulated.
There are reports of the occurrence of arterial thrombotic episodes associated
with the use of desmopressin, but no significant difference in the frequency of
venous and arterial thrombosis could be shown in cardiac, orthopedic, or other
major surgeries. Nevertheless, in patients with a history of cardiovascular events or
diffuse atherosclerosis, caution should be exercised when considering desmopressin
treatment (Castaman 2008).
Finally, desmopressin is not contraindicated in an uncomplicated pregnancy.
A recent review determined it had a good safety record and was effective in selected
cases in reducing bleeding complications associated with pregnancy and childbirth
(Trigg et al. 2012). However, as with all drugs, in this indication desmopressin
should be used with caution.

12.3 Antifibrinolytics

12.3.1 Description

Antifibrinolytics work by inhibiting particular steps of fibrinolysis. There are three

agents that have antifibrinolytic activity in humans: the kallikrein inhibitor, apro-
tinin, and two synthetic derivates of the amino acid lysine, tranexamic acid and
aminocaproic acid. As aprotinin has been withdrawn from the world market because
of safety issues (Fergusson et al. 2008), this chapter focuses on the lysine analogues
that are effective alternatives and may be safer for patients (Hutton et al. 2012).
Most of the clinical and efficacy data concern tranexamic acid, as it is the only avail-
able antifibrinolytic agent in some places. It also has a favorable risk-benefit ratio,
12 Procoagulant Drugs 211

and it has been used for years in cases of most types of bleeding or surgery in
patients with congenital or acquired bleeding disorders (Schulman 2012).
The antifibrinolytic amino acids tranexamic acid (trans-4-(aminomethyl)cyclo-
hexane carboxylic acid) and aminocaproic acid (6-aminohexanoic acid) both oper-
ate by blocking the lysine binding sites on plasminogen molecules, inhibiting the
formation of plasmin and therefore inhibiting fibrinolysis. Tranexamic acid is about
ten times more potent than aminocaproic acid and binds to both the strong and weak
sites of the plasminogen molecule to a higher extent (Mannucci 1998). The mechanism
also has a protective effect on thrombocytes, because the inhibited conversion of
plasminogen to plasmin prevents the plasmin-induced cleavage of several receptors
on thrombocytes (Quinton et al. 2004).

12.3.2 Clinical Uses

Because of their mode of action, antifibrinolytic amino acids are used in disease
patterns with an expected local or generalized hyperfibrinolysis. This is relevant for
nonsurgical and surgical bleeding. Recent studies and reviews have shown evidence
that tranexamic acid reduces blood transfusion particularly in patients undergoing
nonelective surgery.

12.3.2.1 Antifibrinolytic Amino Acids in Nonsurgical Bleeding

(Upper Gastrointestinal Bleeding, Bleeding in the Urinary
Tract, Menorrhagia, Congenital and Acquired Bleeding
Disorders)
For patients with upper gastrointestinal bleeding, clinical trials testing tranexamic
acid have presented differing results. A meta-analysis from 1989 including
patients with peptic ulcers, mucosal erosions, and other causes of bleeding found
considerable reductions in recurrent bleeding, the need for surgery, and mortality
(Henry and Oconnell 1989). When compared with a placebo, a recently prepared
review demonstrated a beneficial effect of tranexamic acid on mortality, but not on
bleeding or transfusion requirements (Gluud et al. 2012). As no randomized clini-
cal trials on the benefits and harms of antifibrinolytic amino acids for upper gas-
trointestinal bleeding in patients with liver diseases have been conducted so far,
their use in these patients can neither be recommended nor advised against
(Marti-Carvajal et al. 2012).
Bleeding in the urinary tract may occur after prostatectomy resulting in hematuria.
In clinical trials tranexamic acid or aminocaproic acid reduced blood loss in patients
who had undergone prostatectomy by up to 50 %, as compared with a placebo.
There was no reduction in mortality or the need for transfusion. In patients with
bleeding from the upper urinary tract, this kind of treatment is contraindicated
because of the risk of residual clots in the ureter and bladder (Mannucci 1998).
In women with heavy menstrual bleeding not induced by organic causes,
tranexamic acid reduces blood loss by about 40–50 % (Bonnar and Sheppard 1996;
Lukes et al. 2010).
212 R.B. Zotz et al.

Patients with congenital or acquired bleeding disorders may also benefit from the
use of antifibrinolytic amino acids in cases of epistaxis, gingival bleeding, or men-
orrhagia. Furthermore, these agents are useful for the prevention of bleeding follow-
ing minor surgical procedures or dental extractions (Seligsohn 2012).

12.3.2.2 Antifibrinolytic Amino Acids in Surgical Bleeding (Cardiac

Surgery, Total Knee and Hip Arthroplasty, Orthotopic Liver
Transplantation, Trauma)
Antifibrinolytic drugs are widely used in surgery. A 2011 review confirmed relevant
reductions in blood loss and the use of allogeneic red cell transfusion when com-
pared with placebo in adult patients scheduled for nonurgent surgery. There were no
serious adverse events (particularly vascular occlusion, renal dysfunction, or death)
when antifibrinolytic acids were applied (Henry et al. 2011).
The use of antifibrinolytic amino acids in surgery has been studied most thor-
oughly for cardiac surgery. In a meta-analysis from 2009, including 49 trials where
all 3 antifibrinolytic agents were evaluated, the need for transfusion was reduced
with tranexamic acid, aminocaproic acid, and aprotinin. Although aprotinin did not
increase the risk of death, compared with a placebo, the point estimate was higher
in the indirect comparison with tranexamic acid, there was a strong statistical trend
in the direct comparison with tranexamic acid, and there were similar numbers in
the direct comparison with aminocaproic acid. There was no increase in the risk of
myocardial infarction with these agents (Henry et al. 2009).
In total hip and knee arthroplasty, there are currently 50 published peer-reviewed
studies that evaluate the effectiveness of tranexamic acid. Meta-analyses of this lit-
erature have demonstrated that the use of tranexamic acid leads to significant reduc-
tions in both perioperative blood loss and the proportion of patients requiring
postoperative transfusion (Watts and Pagnano 2012).
There is some evidence that antifibrinolytic drugs show efficacy in reducing
red blood cell requirements in patients undergoing orthotopic liver transplanta-
tion. The effect depends not only on the patient’s preoperative condition but also
on the donor’s liver quality as well as surgical conditions during the hepatectomy
and anhepatic stages. Therefore, it will be important to identify patients who
could benefit from prophylactic treatment in further evaluations (Sabate et al.
2012).
Along with its inhibiting function on fibrinolysis and its protective effect on
thrombocytes, tranexamic acid has also been shown to modulate the inflammatory
response to injury. However, the exact mechanism in surgery and trauma is as yet
poorly understood (Rappold and Pusateri 2013). Studies on the use of tranexamic
acid in trauma populations have only been conducted for the last few years.
A recently published retrospective review (MATTERs study), including critically
injured combat victims treated with tranexamic acid, demonstrated that unadjusted
mortality was reduced in the group receiving tranexamic acid and the survival
advantage was greatest in patients who received massive transfusions. The use of
tranexamic acid was also, in an adjusted analysis, independently associated with
survival (Morrison et al. 2012). A 2010 randomized prospective trial in patients
12 Procoagulant Drugs 213

after traumatic injury (CRASH-2 trial) reported a reduction of in-hospital mortality

in the group that received tranexamic acid. Furthermore, when tranexamic acid was
given within 3 h of injury, mortality attributable to bleeding was reduced (Shakur
et al. 2010; Roberts et al. 2011). In patients with traumatic brain injury, neither
moderate benefits nor moderate harmful effects can be excluded (CRASH-2
Collaborators (Intracranial Bleeding Study) 2011). There is evidence that tranexamic
acid reduces blood transfusions in patients undergoing emergency or urgent surgery
(Perel et al. 2013).

12.3.3 Administration and Dosage

The half-lives of tranexamic acid and aminocaproic acid are 2.3 and 2 h, respec-
tively. They can be administered orally (in the form of tablets or as an oral solution)
or intravenously.
For the treatment of acute bleeding syndromes, due to elevated fibrinolytic activity,
it is suggested that 5 g of aminocaproic acid be administered during the first hour of
treatment, followed by a continuous rate of 1 g/h. This method of treatment should
be continued for about 8 h or until the bleeding situation is under control. In trials
regarding the reduction of perioperative blood loss, dose regimens for aminocaproic
acid varied significantly. Loading or bolus doses ranged from 75 to 150 mg/kg;
maintenance doses ranged from 1 to 2 g/h or 12.5 to 30 mg/kg/h infused over vary-
ing time periods (Henry et al. 2011).
The dosage recommendations for tranexamic acid are as follows: as intravenous
injection in local fibrinolysis, 0.5–1 g two to three times daily, and in generalized
hyperfibrinolysis, 1 g (15 mg/kg) every 6–8 h. The general recommendations for oral
application are 3–4 g daily. In trials regarding the reduction of perioperative blood
loss, dose regimens for tranexamic acid differed significantly with varying doses and
time frames for drug administration. In trials involving cardiac surgery, the loading
or bolus doses ranged from 2.5 to 100 mg/kg. The maintenance doses for these car-
diac trials ranged from 0.25 to 4.0 mg/kg/h delivered over 1–12 h. A similar variation
was observed in trials not involving cardiac surgery (Henry et al. 2011). Dosing of
tranexamic acid must be reduced in patients with renal dysfunction.

12.3.4 Side Effects and Contraindications

The side effects of tranexamic acid and aminocaproic acid are dose dependent. They
usually involve the gastrointestinal tract (nausea, vomiting, abdominal pain, and
diarrhea). Headache and dizziness can also be observed. Sometimes allergic reac-
tions may occur. No striking increase in the risk of thrombosis was observed when
the drugs were used during operations (Mannucci 1998; Henry et al. 2011). The use
of tranexamic acid in moderate (24 mg/kg) to high doses (≥100 mg/kg) is associ-
ated with convulsive seizures after cardiopulmonary bypass (Kalavrouziotis et al.
2012; Koster et al. 2013).
214 R.B. Zotz et al.

12.4 Vitamin K

12.4.1 Description

Vitamin K was discovered by chance in 1929 and was immediately associated with
blood coagulation. Vitamin K is a group of structurally similar, fat-soluble vitamins
that cannot be synthesized by the human body, but are provided via nutrition and
gastrointestinal bacterial flora. This group of vitamins includes two natural vita-
mers: vitamin K1 and vitamin K2. Vitamin K1 – also known as phylloquinone, phy-
tomenadione, or phytonadione – is synthesized by plants, and the highest
concentration is found in leafy green vegetables. Vitamin K2 – also known as mena-
quinone – constitutes the main storage form in animals and has several subtypes
which differ in isoprenoid chain length. Vitamin K enables the posttranslational
γ-carboxylation of coagulation factors II (prothrombin), VII, IX, and X and pro-
teins C, S, and Z. Prothrombin and factors VII, IX, and X represent the classic
vitamin K-dependent plasma clotting factors and participate in the formation of a
fibrin clot. In contrast, proteins C, S, and Z are inhibitors of the procoagulant sys-
tem. Protein C exerts its inhibitory activity by inactivating factors Va and VIIIa and
enhances fibrinolysis with protein S as a cofactor. Protein Z serves as a cofactor for
the inhibition of factor Xa by protein Z-dependent protease inhibitor (Ferland
2012).

12.4.2 Clinical Uses

The only verified area of application of vitamin K is the therapy and prevention of
states of vitamin K deficiency which lead to vitamin K deficiency bleedings that
cannot be cured by nutrition. This includes vitamin K prophylaxis in neonates
immediately after delivery. The prophylactic administration of vitamin K to preg-
nant women treated with anticonvulsives, antituberculosis drugs, or coumarin deri-
vates does not seem to prevent deficiency in the newborn infants (Puckett and
Offringa 2009). Vitamin K deficiency bleeding has a low incidence in neonates and
infants as well as in adults. Reasons for vitamin K deficiency in adults include
chronic liver disease, short bowel syndrome, chronic inflammatory bowel disease,
and biliary tract obstruction leading to poor nutrition and malabsorption of fat-
soluble vitamins (De Simone and Sarode 2013). Until now, no randomized clinical
trials have been conducted to assess the benefits and harms of vitamin K use for
upper gastrointestinal bleeding in patients with acute or chronic liver disease. Its use
in this treatment can neither be recommended nor advised against (Marti-Carvajal
and Sola 2012). Impaired vitamin K synthesis can also be caused by a disturbance
of gut flora by a broad-spectrum antibiotic therapy.
The most frequent reason for severe vitamin K deficiency bleeding in adults is
the intake of vitamin K antagonists (coumarin derivates). Intracranial hemorrhage,
for instance, is seen in up to 2 % of patients receiving these drugs and has a mortal-
ity rate as high as 79 %. Patients with superwarfarin poisoning represent special
12 Procoagulant Drugs 215

cases. Superwarfarin, available as rodenticide, is 100 times more potent than

medicinal vitamin K antagonists and has a half-life of 20–62 days (De Simone and
Sarode 2013).

12.4.3 Administration and Dosage

Vitamin K can be taken orally and parenterally by means of intramuscular, intrave-

nous, or subcutaneous injection.
A 2009 review demonstrated that a single dose (1.0 mg) of intramuscular vita-
min K after birth is effective in the prevention of classic vitamin K deficiency
bleeding in neonates. Oral vitamin K has not been tested in randomized trials for
its effect in this indication, neither as a single nor as a multiple dose (Puckett and
Offringa 2009).
In patients treated with vitamin K antagonists, there is a need for strategies to
reverse the effect of the oral anticoagulation. This is the case when an urgent inva-
sive procedure is required, when an asymptomatic patient presents with excessively
elevated international normalized ratio (INR) values, or in bleeding patients.
Therapeutic options include interruption of treatment with vitamin K antagonists,
administration of vitamin K, and the administration of blood derivatives such as
fresh frozen plasma, prothrombin complex concentrates, or even recombinant acti-
vated factor VII. The dosage of vitamin K in these indications consists of oral intake
or a slow infusion of 5–10 mg of vitamin K, repeated after 12 h if necessary. This
leads to an increase in coagulation factor activities within 8–16 h. The half-lives of
the various vitamin K antagonists are different: 9 h for acenocoumarol, 6–42 h for
warfarin, and 90 h for phenprocoumon. In phenprocoumon, additional doses of vita-
min K after 3–4 days may be necessary to avoid new increases in INR and bleeding
(Ageno et al. 2012). In patients with superwarfarin poisoning, major acute bleeding
should be treated with prothrombin complex concentrates and intravenous vitamin K
(10 mg daily for several days) followed by the administration of high doses of long-
term oral vitamin K (25–50 mg daily over several months until the superwarfarin
efficacy has faded away) (De Simone and Sarode 2013).

12.4.4 Side Effects and Contraindications

The side effects and contraindications of vitamin K depend on the route of admin-
istration. The main disadvantages of oral administration are that complete absorp-
tion is not certain and can be adversely affected by vomiting or regurgitation. With
regard to intramuscular vitamin K administration, hematomas are possible.
Intravenous vitamin K administration carries the risk of allergic and anaphylactic
reactions, which might be lower when slow administration in saline solution is
used, e.g., over 30 min. Subcutaneous administration exhibits a lower risk of hema-
toma or anaphylaxis; however, drug absorption has been shown to be inconsistent
(Burke 2013).
216 R.B. Zotz et al.

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Patient Blood Management
13
Oliver M. Theusinger, Stephanie L. Kind,
and Donat R. Spahn

13.1 Introduction

Although blood transfusions may be lifesaving in critical bleeding, treatment with

allogeneic blood products has been shown to be associated with increased mortality
and morbidity in all surgical specialties, as well as in intensive care medicine.
Ischemic complications in particular, can lead to increased morbidity after blood
transfusion (Vincent et al. 2002; Malone et al. 2003; Corwin et al. 2004; Koch et al.
2006; Surgenor et al. 2006, 2009; Murphy et al. 2007; Jakobsen et al. 2012; Jans et al.
2012). The World Health Organization (WHO) urges member states to search for and
apply transfusion alternatives, and to introduce individualized patient blood manage-
ment programs (http://apps.who.int/gb/ebwha/pdf_files/WHA63/A63_R12-en.pdf)
(Spahn et al. 2008). Existing evidence supports the use of low-hemoglobin transfusion
triggers, even in patients with cardiovascular disease (Carson et al. 2012a), and shows
a reduction in in-hospital mortality without influencing hospital or intensive care
length of stay (Carson et al. 2012a).
Blood transfusion is one of the most expensive treatments in medicine (Shander
et al. 2007, 2010; Morton et al. 2010). Summing all transfusion related costs, includ-
ing long-term side effects, blood transfusion accounts for up to 5 % of the health care

O.M. Theusinger, MD (*) • S.L. Kind, MD

Institute of Anesthesiology, University Hospital Zurich,
Raemistrasse 100, CH – 8091, Zurich, Switzerland
e-mail: [email protected]
D.R. Spahn, MD, FRCA
Institute of Anesthesiology, University Hospital Zurich,
Raemistrasse 100, CH – 8091, Zurich, Switzerland
Medical Section Anesthesiology, Intensive Care Medicine, OR-Management University,
Zurich, Switzerland

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 221

DOI 10.1007/978-3-642-55004-1_13, © Springer-Verlag Berlin Heidelberg 2015
222 O.M. Theusinger et al.

Table 13.1 The basics of patient blood management

Patient blood management
Detect and correct preoperative anemia and iron deficiency
Iron (i.v.) + ESA perioperatively
Reduce perioperative RBC loss
Meticulous surgical technique
Acute normovolemic hemodilution
Cell salvage and re-transfusion
Avoidance of coagulopathy with an individualized, goal-directed coagulation algorithm and the
use of antifibrinolytics and factor concentrates
Low CVP, no hypertension, normothermia
Harness and optimize physiogical reserve of anemia
Tolerate low hemoglobin values
Administer high FiO2
Minimize metabolic demand
ESA erythropoiesis stimulating agent, CVP central venous pressure, FiO2 inspired oxygen fraction

budget of developed countries (Morton et al. 2010). The known and hidden costs,
including the treatment of side effects, have been estimated close to USD 2,000 per
red blood cell (RBC) unit in the USA (Shander et al. 2010; Ferraris et al. 2012). As
blood donations are generally decreasing and previously regular blood donors grow
older, a shortage of blood products is predicted (Borkent-Raven et al. 2010).
The Society for the Advancement of Blood Management defines patient blood
management as “the appropriate use of blood and blood components, with a goal of
minimizing their use”.
The aim of patient blood management is to preoperatively identify patients at
risk and offer individualized therapy to decrease the likelihood of transfusion
(Williams and McCarthy 2003; Goodnough and Shander 2007; Spahn et al.
2008; Gombotz et al. 2011b), thereby improving outcome, and reducing side
effects and overall costs. Avoiding RBC transfusion completely by introducing
a patient blood management program is not possible, nevertheless a decrease in
provided and used blood products has been shown after implementation (Wells
et al. 2002; Cobain et al. 2007; Gombotz et al. 2007; Moskowitz et al. 2010;
Kotze et al. 2012).
Patient blood management is a multi-disciplinary approach built upon three
pillars: treatment of preoperative anemia, minimizing intraoperative blood loss,
and increasing tolerance of anemia (Gombotz et al. 2011a; Spahn et al. 2012)
(Table 13.1). Ideally, improvements in all three are strived for, but optimizing even
one pillar reduces transfusion needs drastically. In 94 % of elective interventions,
intraoperative RBC transfusion needs can be predicted from the preoperative hemo-
globin level, possible blood loss, and individual transfusion triggers (Gombotz et al.
2007; Gombotz 2011). In May 2010, the WHO recognized patient blood manage-
ment as a significant means to improve transfusion safety, and since then it has
promoted its implementation in order to improve patient care.
13 Patient Blood Management 223

The following chapter provides an overview of all the aspects that have to be
taken into consideration and suggests what such a program could, or should,
look like.

13.2 The Adverse Effects of Blood Transfusion (Table 13.2)

One unit of RBCs transfused to adults increases the hemoglobin level by approxi-
mately 1 g/l and the hematocrit by about 3 % (Liumbruno et al. 2009, 2011).
Blood products are frequently administered to older and sicker patients, there-
fore causing more serious complications and various side effects. Current esti-
mates of viral transmission via blood products are 1:280,000–1:357,000 for
hepatitis B, 1:1,149,000 for hepatitis C, and 1:1,467,000 for human immunodefi-
ciency virus (HIV) (Epstein and Holmberg 2010). Although viral and bacterial
transmission via RBC units is considered to be under control in developed coun-
tries (Pomper et al. 2003; Goodnough 2005), RBC transfusion increases morbid-
ity and mortality several fold (Klein et al. 2007; Murphy et al. 2007; Spahn et al.
2008; Jakobsen et al. 2012). Effects on mortality are most commonly seen close
to the time of transfusion, but effects have been shown up to 5 years after the

Table 13.2 Complications of blood transfusion

Complications Author Year
RBC’s Viral transmission Epstein and Homberg 2010
Cancer recurrence Amato and Pescatori 2006
Postoperative infections
TRALI Rana et al. 2006
Khan et al. 2007
Chaiwat et al. 2009
Non Hodgkin Lymphoma Castillo et al. 2010
Chronic lymphotic leukemia
Small lymphotic lymphoma
Alzheimer’s disease Morales et al. 2011
de Calignon et al. 2012
Multi organ failure Moore et al. 1997
Thromboembolic events
Myocardial infarction
Renal dysunction Rogers et al. 2006
Sepsis Ferraris et al. 2012
FFP’s Allergic reaction Dara et al. 2005
TRALI, TACO Buddeberg et al. 2008
Infections Toy et al. 2005
Platelets Infections Norda et al. 2006
RBC red blood cells, FFP fresh frozen plasma, TRALI transfusion related acute lung injury, TACO
transfusion-associated circulatory overload
224 O.M. Theusinger et al.

initial transfusion (Reeves and Murphy 2008a, b; Jakobsen et al. 2012). Because
of transfusion-related immunomodulation (TRIM), a higher incidence of postop-
erative infection and cancer recurrence is observed (Amato and Pescatori 2006 ).
Immunosuppression is caused by a decreased activity of T-cells, macrophages,
and other natural killer cells. Blood transfusion is also associated with an increased
risk of developing non-Hodgkin lymphoma (NHL), chronic lymphocytic leuke-
mia, and small lymphocytic lymphoma, up to 15 years after transfusion (Castillo
et al. 2010). Furthermore, it is assumed that protein misfolding diseases such as
Alzheimer’s disease might be transmitted through blood transfusions, however
further studies need to be performed (Morales et al. 2011; de Calignon et al.
2012).
Besides an increased frequency of MOF, thromboembolic events such as myo-
cardial infarction and stroke are correlated to blood transfusion (Moore et al. 1997).
Overall, around 4 % of RBC transfusions are associated with transfusion-related
complications.
It is therefore fundamental to accept intraoperative hemoglobin levels of between
6 and 7 g/dl in order to reduce possible side effects (Spahn and Madjdpour 2006;
Spahn et al. 2008). Perioperative anemia does not increase postoperative mortality
or morbidity in cardiac surgery, whereas restrictive transfusion recommendations
decrease complications (Moskowitz et al. 2010).
Adverse effects are directly dependent on the number of units transfused and the
mean storage time (Offner 2004; Shorr et al. 2004; Koch et al. 2008; Spinella et al.
2009; Ness 2011; Tung et al. 2012). Even transfusion of a single unit has been asso-
ciated with increased mortality, renal dysfunction, and sepsis (Rogers et al. 2006;
Ferraris et al. 2012). Longer stored erythrocytes have significantly more harmful
effects, such as increased in-hospital mortality, increased 1 year mortality, renal
failure, and sepsis (Spahn et al. 2008; Belizaire et al. 2012). Ventilator associated
pneumonia is increased by 1 % per day of mean storage time (Shorr et al. 2004;
Bernard et al. 2009). This is due to the time-dependent metabolic, biochemical, and
molecular changes undergone by stored RBCs. These include: adenosine triphos-
phate (ATP) depletion; bioactive generation of histamine, cytokines, and lipids;
reduction of nitric oxide; and a decrease of 2.3-diphosphoglycerate leading to a
left-shift of the oxyhemoglobin dissociation curve (Chin-Yee et al. 1997; Offner
2004; Raat et al. 2005). Further, stored RBCs have a higher inflammatory potential,
due to increased vascular endothelial growth factor levels; they are also stiffer.
Increased hemolysis of aged RBCs after massive transfusion has recently been
shown in a guinea pig model. Cell-free, plasma hemoglobin led to vascular injury
and renal insufficiency (Upile et al. 2009; Urner et al. 2012). Hemoglobin toxicity
was prevented by co-infusion of haptoglobin, showing possible protective effects
(Urner et al. 2012).
Unfortunately it is not yet clear exactly when negative effects occur, though a
storage time over 14 days has been associated with negative outcomes such as
increased in-hospital mortality, renal failure, sepsis, and intubation prolonged
beyond 72 h (Koch et al. 2008; Blasi et al. 2012).
13 Patient Blood Management 225

Correlation between RBC transfusion and increased postoperative incidence of

infections has been shown in all surgical fields (Hill et al. 2003).
Whereas the transmission of hepatitis and HIV has decreased in developed
countries over the last 10 years, nosocomial infections have increased and are
enhanced by 9.7 % with each unit transfused (Claridge et al. 2002; Taylor et al.
2006). The median onset of infection is around 5 days after transfusion (Rachoin
et al. 2009).
Gram-positive and Gram-negative organisms were both detected more frequently
in transfused patients than in non-transfused ones. Acinetobacter – a Gram-negative
coccobacillus – is frequently identified (Rachoin et al. 2009).
Transfusion-related acute lung injury (TRALI) occurs once in every 1,000–4,000
units transfused (Rana et al. 2006; Khan et al. 2007; Chaiwat et al. 2009), thus being
the leading cause of death correlated with blood therapy (Vamvakas and Blajchman
2010). The reaction usually starts within 6 h of transfusion. TRALI is defined by
acute onset of non-cardiogenic pulmonary edema, dyspnea, fever, and hyperten-
sion. A mortality rate of 5–10 % has been reported (Popovsky et al. 1992; Gude
2012).
A great number of TRALIs are caused by antibody carrying blood products of
female blood donors with a positive pregnancy history. Therefore, plasma is only
accepted from female donors who have either a negative pregnancy history or nega-
tive HLA- and HNA-antibody results (Nguyen et al. 2011).

13.3 The Three Pillars of Patient Blood

Management (Fig. 13.1)

13.3.1 Detection and Treatment of Preoperative Anemia:

Pillar One

13.3.1.1 Definition and Risk of Perioperative Anemia

The WHO defines anemia as hemoglobin (Hb) levels below 12 g/dl in women and
below 13 g/dl in men, or hematocrit (Hct) levels lower than 36 % in woman and less
than 39 % in men (Goodnough 2007; Theusinger et al. 2007).
Preoperative anemia is seen in 5–75 % of patients scheduled for elective surgery
(orthopedic, cardiac, visceral), depending on age, the underlying pathology, and the
definition of anemia (Shander et al. 2004; Patel and Carson 2009; Gombotz et al.
2011a; Musallam et al. 2011). A reduced preoperative circulating erythrocyte mass,
as estimated by the patient’s hemoglobin concentration (Cosgrove et al. 1985), is
also a major risk factor for perioperative RBC transfusion, and is associated with
increased mortality, morbidity, and length of hospital stay (Khanna et al. 2003;
Murphy et al. 2007; Isbister et al. 2011; Leichtle et al. 2011). Moreover, preopera-
tive anemia is an independent risk factor for increased 30-day mortality in cardiac
and non-cardiac surgical patients (Glance et al. 2011; Musallam et al. 2011). Even
preoperative hemoglobin levels between 10 and 12 g/dl lead to a 40 % increase in
 226

Evaluation of current consumption → adjusted ordering

Set individual restrictive transfusion triggers

1. Pillar 2. Pillar 3. Pillar

Optimizing erythrocyte volume Minimizing blood loss Increase and fully utilize tolerane of anemia
- Recognition of anemia - Estimate and reduce risk of bleeding - Compare expected blood loss to tolerable
- Identify underlying disease - Minimize diagnostic and interventional loss of individual blood loss
- Treatment of underlying disease and other blood - Estimate individual risk factors and tolerance
deficiency symptoms - Interdisciplinary planning of the surgery of anemia
- Optimize physiologic reserve of anemia
- Set individual restrictive transfusion triggers

Preoperative
- Timing of surgical intervention depending on - Careful hemostasis and surgical technique - Optimize cardiac output
the concentration of preoperative erythrocytes - (minimal invasive) - Optimize mechanical ventilation
- Use of measures to avoid allogeneic blood - Strict indication for blood transfusion
- Hemostasis and coagulation monitoring
- Use of hemostats

Intraoperative
- Stimulation of erythropoiesis with iron and/or - Monitor bleeding and prevent post-bleeding - Optimize reserve of anemia
EPO - Hemostasis and coagulation monitoring - Optimize O2-supply
- Be aware of drug interaction that can increase - Minimize diagnostic and interventional loss of - Reduction of O2-consumption
anemia blood - Avoidance and prompt treatment of infections
- Prophylaxis of upper gastrointestinal bleeding - Strict indication for blood transfusion
- Avoidance and prompt treatment of infections

Postoperative
- Autologous blood conservation methods

Re-evaluation

Fig. 13.1 Strategies for Pre-, per- and postoperative Patient Blood Management
O.M. Theusinger et al.
13 Patient Blood Management 227

mortality and a 30 % increase of morbidity. This risk is doubled when blood products
are transfused (Musallam et al. 2011).
Postoperative anemia is common. Moderate postoperative anemia does, however,
not influence rehabilitation (Carson et al. 2011; Vuille-Lessard et al. 2012). In
order to minimize the degree of postoperative anemia or to reduce its incidence,
patient blood management focuses on the detection and treatment of preoperative
anemia and the reduction of RBC loss during surgery (Westenbrink et al. 2011).

13.3.1.2 Screening and Treatment of Preoperative Anemia

In addition to an in-depth coagulation history, preoperative laboratory tests need to
be performed in order to detect anemia or a coagulation disorder ahead of surgery
(Pfanner et al. 2007). Preferably, elective surgery is rescheduled if anemia, coagu-
lopathy, or any other concomitant disease needs to be treated.
According to the National Blood Authority of Australia, preoperative tests
include full blood count, iron studies including ferritin levels, C-reactive protein
(CRP), and renal function tests. Ferritin can be elevated in malignancy, liver dis-
ease, and inflammation, therefore a thorough investigation is essential in these
cases. Furthermore, gastrointestinal bleeding needs to be ruled out in patients with
unexplained iron deficiency.
Correction should be achieved with intravenous iron, erythropoietin (EPO), and
Vitamin B12 and/or folic acid at least 2 weeks before elective surgery. Oral iron is
not absorbed during inflammatory processes due to the presence of hepcidin and
patient compliance is low due to side effects (Goodnough et al. 2010). Intravenous
iron, however, can be administered in much higher doses (Chang et al. 2002;
Mircescu et al. 2006; Auerbach and Rodgers 2007).
Optimally, patients should be seen 4 weeks before surgery in order to increase
hemoglobin levels (Gombotz et al. 2011a; Goodnough et al. 2011) up to around
15 g/dl at the time of surgery, nevertheless short-term therapy is possible and better
than no therapy at all (Weltert et al. 2010; Na et al. 2011; Yoo et al. 2011). Avoiding
higher hemoglobin levels is advisable in order to prevent possible thromboembolic
complications (Cuenca et al. 2004). In patients with carcinoma and chronic kidney
failure, hemoglobin levels should not exceed 11 g/dl (Addeo et al. 2009; Brookhart
et al. 2010); this requires a close cooperation between primary care physicians and
hospital staff.
Autologous donations are not very cost effective (Etchason et al. 1995; Bierbaum
et al. 1999) and are associated with serious side effects such as possible mistaken
identity, storage lesions, and bacterial contamination (Tokuno et al. 2012). In addi-
tion, most patients arrive at the hospital anemic after their prior donation, forcing
early re-transfusion of their own RBCs (Spahn 2010). Autologous predonation has
thus been abandoned in most centers, except for patients with extremely rare blood
groups or multiple anti-bodies.
In summary, the first pillar calls for individual preoperative therapy to optimize
the RBC mass and consequently tolerance of blood loss. Existing preoperative
228 O.M. Theusinger et al.

anemia influences the course of diseases negatively (Endres et al. 2009). Preoperative
iron treatment, as well as the use of EPO in orthopedic surgery, reduces the rate of
allogeneic blood transfusions and infections (Spahn 2010). Today, 90 % of existing
preoperative anemia is not treated prior to surgery with expected significant blood
loss, resulting in a three to fourfold increase in the transfusion rate (2nd Austrian
Benchmark study; http://www.bmg.gv.at).

13.3.2 Avoiding Intraoperative Coagulopathy: Pillar Two

13.3.2.1 Intraoperative Techniques

Optimizing intraoperative hemostasis is a multi-disciplinary task: surgical tech-
niques and anesthesiological management are equally important. Using a harmonic
scalpel, argon beam coagulation, fibrin glue, or bone wax to reduce intraoperative
blood loss and thereby allogeneic blood transfusions, are just some of the surgical
possibilities (Cuenca et al. 2004; Freischlag 2004; Madjdpour and Spahn 2005;
Munoz et al. 2005; Spahn 2010; Emmert et al. 2011). Minimal invasive surgery is
also considered to be blood saving. The patient’s body position plays an important
role too, as arterial and venous pressure during surgery should be kept to a mini-
mum (Australian Patient Blood Management Guidelines). Additionally, coagulopa-
thy due to blood loss increases the risk of mortality and morbidity (Spahn and
Rossaint 2005; Hess et al. 2008).
Fluid resuscitation using Ringer’s lactate and placing the patient in the
Trendelenburg position are major aspects of ideal anesthesiological perioperative
management. In addition, maintaining body temperature above 35 °C (to prevent
coagulopathy), and controlled hypotension with a mean arterial pressure of
50–55 mmHg also reduce intraoperative blood loss (Fukusaki et al. 1997; Fukusaki
and Sumikawa 2000; Theusinger et al. 2012). Maintaining postoperative mean arte-
rial pressure between 60 and 70 mmHg is recommended (Emmert et al. 2011).
Normovolemic hemodilution reduces the total amount of intraoperative RBC loss.
It should be considered in patients undergoing surgery in which substantial RBC
loss is anticipated (Australian Patient Blood Management Guidelines).

13.3.2.2 Pharmacotherapy
Calcium is crucial in all phases of coagulation and plasma concentration of ionized
calcium should be kept between 1.15 and 1.29 mmol/l in bleeding patients (Lier
et al. 2008). In lactic acidosis (blood loss, vasoconstrictions, hypoxia), plasma lac-
tate and free ionized calcium levels are inversely related. It has been shown that
acidosis affects clot firmness and is not restored by sodium bicarbonate infusion
(Martini et al. 2006). Calcium is further depleted by the transfusion of citrate con-
taining allogeneic blood products (Vivien et al. 2005). Hence, acidosis, hypother-
mia, and hypocalcaemia must be avoided and treated at all times.
To reduce intraoperative blood loss, the Western Australian Blood Authority rec-
ommends the use of perioperative vasoconstrictors such as diluted epinephrine in
13 Patient Blood Management 229

combination with local anesthesia. Topical agents, like collagen or thrombin, are
additional means of reducing intraoperative blood loss (Achneck et al. 2010).
Other blood saving techniques include catecholamine administration and the
application of systemic antifibrinolytics, such as aminocaproic acid or tranexamic
acid (Gombotz 2011). Both compounds are synthetic lysine analogues that inhibit
fibrinolysis by blocking the lysine-binding site on plasminogen, thus preventing
fibrin from binding to plasminogen (Holcomb 2004; Zufferey et al. 2006).

13.3.2.3 Blood Products

Although fresh frozen plasma (FFP) is administered in massive bleeding due to
multifactor deficiency, for the reversal of vitamin K antagonist, and for treating
thrombotic thrombocytopenic purpura, the clinical effect of FFP transfusion remains
unproven (Stanworth et al. 2004; Spahn et al. 2007; Yang et al. 2012).
Various adverse effects are connected with the administration of FFP: allergic
reactions, TRALI, transfusion-associated circulatory overload (TACO), and trans-
mission of infectious pathogens. Furthermore, a threefold increase of nosocomial
infections has been reported (Dara et al. 2005; Toy et al. 2005; Buddeberg et al.
2008). Up to now, the administration of FFP has been reliant on trust in expert opin-
ion alone. Despite this, large quantities of FFP (>15 ml/kg body weight) are recom-
mended in cases of massive bleeding (Ho et al. 2005; Gajic et al. 2006; Spahn et al.
2007; Theusinger et al. 2009), given that a 1:1 ratio of plasma to RBCs is connected
with a decreased mortality in massively transfused trauma patients (Nunez and
Cotton 2009).
Furthermore it is suggested that freshly thawed plasma, in contrast to post thawed
storage, is endothelium-protective in shock (Pati et al. 2010). It should be noted that
1 ml/kg body weight of plasma, leads only to an increase of coagulation factors
of 1 %.
The indication of transfusing platelets should be restrictive because of the high
risk of bacterial contamination of platelet concentrates (1:2,000–1:8,000) (Norda
et al. 2006). So far only expert opinions are available. Nevertheless, in bleeding
patients platelets should be kept over 50 × 109/l, and over 100 × 109/l in patients with
traumatic brain injuries (Rossaint et al. 2006, 2010; Spahn et al. 2007). By admin-
istering one platelet concentrate containing 3 × 1011 platelets, platelet count is
increased by 20–40 × 109/l in a healthy adult patient.

13.3.2.4 Monitoring
Point of care (POC) monitoring devices, such as TEG® (Haemonetics® Corporation,
Braintree, MA, USA) or ROTEM® (TEM® International GmbH, Munich, Germany),
are increasingly used to monitor coagulation in vivo. Hemostatic tests are performed
on whole blood, evaluating platelet interaction with coagulation factors in all three
phases of coagulation: initiation, propagation, and lysis of the clot (Ganter and
Hofer 2008; Theusinger et al. 2010). Because the results are shown in real time,
clinicians can distinguish between surgical bleeding, hemostasis disorders, and
hyperfibrinolysis, and assess the extent of dilutional coagulopathy.
230 O.M. Theusinger et al.

The results of POC tests can guide the transfusion of blood products or the
administration of coagulation factors. The use of a POC, goal directed transfusion
algorithm improves outcomes in cases of massive hemorrhage (Spahn et al. 2008,
2012; Ganter and Spahn 2010; Gorlinger et al. 2011; Liumbruno et al. 2011; Young
et al. 2011; Theusinger et al. 2014).
Ideally, coagulation should be monitored using viscoelastic POC tests before and
after therapy, and 30 min after every administration of Factor XIII (Fibrogammin®).
Figure 13.2 illustrates just one possible means of handling massive bleeding in a
clinical setting and needs to be adjusted to local recommendations. The early use of
coagulation factors combined with POC testing leads to a reduction of RBC transfu-
sions, decreased incidence of thrombotic events, and better outcomes (Gorlinger
et al. 2011; Weber et al. 2012). Finally, the intraoperative collaboration between
anesthesiologists and surgeons can reduce intraoperative blood loss up to 50 %
(Filicori et al. 2010; Zwart et al. 2010).

13.3.3 Low Hemoglobin Transfusion Triggers: Pillar Three

Due to a correlation between physical symptoms and the amount of blood loss,
the American Society of Anesthesiologists (ASA) recommends using physiologi-
cal transfusions triggers to identify transfusion needs (Ferraris et al. 2011;
Carson et al. 2012a). Examples are tachycardia, hypotension, mixed venous oxy-
gen pressure of less than 32 mmHg, electrocardiogram (ECG) changes, oxygen
extraction greater than 50 %, or an increase in lactate (Madjdpour and Spahn
2005; Spahn and Madjdpour 2006; Ferraris et al. 2007) (Table 13.3). With hyper-
oxic ventilation in patients with critical hemoglobin values, tissue oxygenation is
not impaired (Meier et al. 2004; Weiskopf 2010). Thus a high fraction of inspired
oxygen (FiO2) is a possible bridge until blood products are available (Weiskopf
2010).
Low hemoglobin transfusion triggers should be applied. While the use of
restrictive transfusion triggers has not been shown to increase adverse outcomes,
a reduction in the RBC transfusion and infection rate can be found, leading to
decreased mortality and overall cost (Carless et al. 2010; Carson et al. 2012a). If
cardiovascular comorbidities are treated preoperatively, postoperative hemoglo-
bin values of 8 g/dl in orthopedic patients are well tolerated (Grover and
McManus 2006).
The individual minimal hematocrit depends on the patient and his/her comor-
bidities. In general surgical patients, hemoglobin levels of <7 g/dl are tolerated
(Carless et al. 2010), and <8 g/dl is accepted in high risk patients (Carson et al.
2011, 2012b). Elderly patients without cardiovascular disease tolerate hemoglobin
values of 9 g/dl (Spahn et al. 1996).
13 Patient Blood Management 231

Diagnostic Intervention
®
Preoperative history ROTEM after anesthesia induction
1. Drugs affecting coagulation - Transplant surgery
- Antiplatelet drugs - Cardiac and vascular surgery
- Heparin - Difficult cancer surgery
- Oral anticoagulation (Vit. K antagonists, - Liver insufficiency
Xa antagonists, IIa antagonists) - Intra-abdominal sepsis
2. Coagulation status? - Emergency room entry
3. HIT II?

Blood loss > 50% with diffuse bleeding

ROTEM® analysis Target values

- EXTEM, INTEM, FIBTEM, APTEM - Normothermia (Temp. > 35°C)
- Normocalcemia (Ca >1.15 mmol/l)
- HEPTEM in heart and vascular surgery
- No acidosis (pH > 7.2)
- Hematocrit > 0.21
- Hypotension (MAP 55–60 mmHg)

Crystalloid and/or colloid volume substitution

FIBTEM < 7 mm Fibrinogen 2–4 g iv (maximal 3×2g), after a total of 6 g give
FXIII

INTEM (CT and CFT prolonged) and HEPTEM normal Protamine sulfate 1:1 to heparin
OR crystalloid and colloid volume substitution
ACT pathological and heparinase ACT normal

EXTEM/INTEM:
Decrease of MCF after maximum was reached Tranexamic acid
APTEM: normal - 15 mg/kg BW as bolus iv
HYPERFIBRINOLYSIS - 1–2 mg/kg/h during surgery iv as perfusion

On-going diffuse bleeding

EXTEM/INTEM MCF < 40 mm

CT EXTEM/INTEM normal Fibrinogen up to 6 g, followed by Factor XIII 15 U/kg BW
MCF FIBTEM < 7 mm crystalloid and colloid volume substitution
Hematocrit > 0.21

MCF FIBTEM > 7 mm

Platelets < 50 G/L (< 100 G/L in cardiac surgery or in Platelet concentrates
patients suffering from traumatic brain injury)

Target of Factor XIII: > 60% (Factor XIII 15 U/kg BW)

Coagulation test incl. F XIII, F V, INR, PT, aPTT
Target of Factor V: > 20% (in particular in liver insufficiency
/trauma or intra-abdominal sepsis: 2–4 U FFP)
On-going diffuse bleeding

Quick’s value < 30% and 4 factor prothrombin complex concentrate 1000–2000 IU
Factor V > 20%
- Factor II, VII, IX and X
OR
EXTEM/INTEM: CT, CFT prolonged Depending on the patients’ body weight

In case of massive transfusion Target Hematocrit: 0.21–0.24

In massive diffuse bleeding continues and

Treated acidosis Recombinant Factor VIIa

Treated hypothermia
60 μg/kg Body weight iv
Hypocalcaemia excluded
Hematocrit: 0.21–0.24 A second dose of 60 μg/kg Body weight iv can be given again
DIC excluded
after 2–4 hours, if bleeding has not completely stopped.
Fibrinogen was substituted
Platelets > 50 G/L (> 100 G/L in cardiac surgery or in
patients suffering from traumatic brain injury)

Fig. 13.2 Second version of the transfusion algorithm of the University Hospital of Zürich 2012©,
Switzerland with permission from Theusinger et al. (2014)
232 O.M. Theusinger et al.

Table 13.3 Physiologic

transfusion triggers Physiologic transfusion triggers
Cardiopulmonary symptoms
Tachycardia
Hypotension
Dyspnea
Decrease in blood pressure of unknown origin
Ischemic ECG changes
Cardiac arrhythmia
ST elevation or deviation
Echocardiographic signs of myocardial dysfunction
Global indices of inadequate oxygenation
Increase in global oxygen extraction >50 %
Decreased oxygen uptake of >10 % of initial value
Decreased mixed venous oxygen saturation <50 %
Decreased central venous oxygen saturation <60 %
Decreased mixed venous oxygen partial pressure
<32 mmHg
Lactic acidosis
Lauscher et al. (2012)
Copy right does not exist up to now

13.4 Implementation of Patient Blood Management

In recent years, the doctrine for resuscitation of patients suffering from massive bleed-
ing has changed from a supportive treatment with crystalloids/colloids and RBC units,
to a standardized massive transfusion protocol (Young et al. 2011). In 2002, the
Province of Ontario, Canada, introduced the pioneering Ontario Nurse Transfusion
Coordinators Provincial Blood Conservation Program (ONTraC). A decrease of RBC
transfusion of 14–24 % was noticed 1 year after implementation (Freedman et al.
2005). To date, based on decreased mortality and morbidity, patient blood manage-
ment programs have shown themselves to be efficient in all medical fields, in vari-
ous countries (Moskowitz et al. 2010; Spahn 2010; Goodnough et al. 2011; Kotze
et al. 2012).
Western Australia’s patient blood management program is probably the best
known: it is very well organized and administered by the state government and all
major hospitals are included.
By carrying out RBC transfusion only when there is no other alternative and
thus reducing the use of blood products, health care costs are reduced. Due to
improved collection, testing and processing, the direct costs of blood products
have progressively increased (Kamper-Jorgensen et al. 2010; Abraham and Sun
2012). As stated in the introduction, the known and hidden costs have been esti-
mated to be USD 2,000 (Ferraris et al. 2012; Shander et al. 2010) per RBC unit.
USD 1.62 to USD 6.03 million per year and hospital are spent on transfusion
13 Patient Blood Management 233

related activities in surgical specialties only. Only 30 % of patients who have their
blood-typed and screened eventually receive peri- or postoperative transfusions.
These non-transfused patients contribute substantially to overall costs (Shander
et al. 2010). The introduction of a patient blood management program signifi-
cantly reduces the prevalence of anemia, transfusion rates, the length of hospital
stays, and re-admission rates, while also reducing costs (Kotze et al. 2012; Spahn
et al. 2012).
The patient blood management paradigm shift in transfusion medicine (Farrugia
2011) not only saves lives, but reduces health care costs (Spahn et al. 2012).
It should be therefore part of good clinical practice.

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 Part II
Per-operative Hemostasis
Perioperative Coagulation
in Cardiovascular Surgery 14
Fabrizio Gronchi and Marco Ranucci

14.1 Introduction

The evolution of scientific knowledge in cardiac surgery and cardiopulmonary

bypass (CPB) has enabled the reduction of perioperative complications, despite an
increase in patient-related risks and in the complexity of surgical procedures.
However, the management of hemostasis and coagulation remains a difficult issue,
and it is of note that the rates of allogeneic blood transfusion and surgical revision in
bleeding patients have not declined in recent years. It is widely recognized that allo-
geneic blood transfusion carries risks of increased morbidity and mortality (Koch
et al. 2006) and that there is a wide difference in transfusion thresholds and practice
among hospitals. Transfusion is a controversial issue in cardiac surgery, and there are
still gaps in knowledge with respect to indications, efficacy, and even safety.
It is currently recognized that a restrictive transfusion policy, guided by point-of-
care (POC) tests, significantly reduces the number of transfused packed red blood cell
(RBC) and fresh frozen plasma (FFP) units. Restrictive transfusion strategies do not
alter perioperative morbidity (Hajjar et al. 2010) or postoperative quality of life.
A number of risk factors help identify patients at high risk of receiving transfu-
sions, including:
• Chronic renal failure (CRF)
• Chronic heart failure (CHF)

F. Gronchi (*)
Department of Anesthesiology, Lausanne University Hospital (CHUV),
Lausanne CH-1011, Switzerland
e-mail: [email protected]
M. Ranucci
Department of Anesthesia and Intensive Care, IRCCS Policlinico San Donato,
20097 San Donato Milanese, Milan, Italy
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 243

DOI 10.1007/978-3-642-55004-1_14, © Springer-Verlag Berlin Heidelberg 2015
244 F. Gronchi and M. Ranucci

• Chronic obstructive pulmonary disease (COPD) in elderly patients

• Perioperative anticoagulation or antiaggregation
• Reduced RBC volume (preoperative anemia and/or small body surface)
• Complex surgery (emergency surgery, reoperation, aortic surgery, surgery other
than coronary artery bypass grafting (CABG), long-lasting CPB)
Different models for predicting the transfusion risk have been proposed and vali-
dated in cardiac surgery (Magovern et al. 1996; Litmathe et al. 2003; Karkouti et al.
2006; Alghamdi et al. 2006; Ranucci et al. 2009b). The guidelines in this chapter are
supported by the recommendations of the Society of Thoracic Surgeons (STS) and
the Society of Cardiovascular Anesthesiologists (SCA) clinical practice guidelines
on blood conservation (Society of Thoracic Surgeons Blood Conservation Guideline
Task Force et al. 2011). Additional information is provided by clinical practice,
expert opinions, and other guidelines and recommendations.

14.2 Preoperative Treatment with Anticoagulants

and/or Antiaggregant Agents

Due to the nature of their disease, cardiac surgery patients are usually treated with
anticoagulants and/or antiaggregant agents. The optimal timing for surgery on these
patients is still debated, and decisions should balance the risk of thrombosis and
postoperative bleeding.
A guideline to perioperative antithrombotic treatment management is summarized
in Table 14.1.

14.2.1 Unfractionated Heparin (UFH)

and Low-Molecular-Weight Heparins (LMWH)

In order to prevent excessive bleeding, LMWH should be stopped 12–24 h prior to

surgery, given the fact that LMWH are only partially reversible by protamine (Class
IIb, level of evidence C). Heparin can be reversed by protamine, making its use
simple, so that intravenous infusion of UFH (in patients with unstable angina or
acute coronary syndrome) is not usually stopped before surgery.

14.2.2 Oral Anticoagulants (OAC)

Patients treated with vitamin K antagonists (VKAs) are generally switched to

LMWH a few days before surgery. In case of emergency surgery, VKA may be
antagonized with a prothrombin complex concentrate (PCC) and vitamin K every
24 h. This treatment has largely proven its superiority over FFP (Class IIa, level of
evidence B). Patients with residual VKA effects, as well as patients with poor liver
function, have low levels of coagulation factors and a reduced capacity to generate
14 Perioperative Coagulation in Cardiovascular Surgery 245

Table 14.1 Common antithrombotics seen for cardiac surgery patients

Drug Class Half-life (h) Timing to surgery Reversibility
Heparin Thrombin and FXa 1–1.5 Up to skin incision Protamine
inhibitor
LMWH Thrombin and FXa 2.5–4 12–24 h Partial,
inhibitor protamine
a
Dabigatran Thrombin inhibitor 8–17 No
a
Apixaban FXa inhibitor 8–15 No
Rivaroxaban FXa inhibitor 9–13 24 h No
Bivalirudin FXa inhibitor 0.5 2 h before surgery No, but rapidly
(depending on renal metabolized and
function) removed by
hemofiltration
Warfarin Vitamin K inhibitor 40 5 days before Yes, prothrombin
surgery complex, FFP
Acenocoumarol Vitamin K inhibitor 8–11 4 days before Yes, prothrombin
surgery complex, FFP
Phenprocoumon Vitamin K inhibitor 160 7 days before Yes, prothrombin
surgery complex, FFP
Aspirin Cyclooxygenase Life of Usually not No
inhibitor platelet discontinued
Clopidogrel Thienopyridine ADP Life of 5–7 days before No
bisulfate receptor antagonist platelet surgery, Multiplate
AUC >40
Ticlopidine Thienopyridine ADP Life of 7 days before No
hydrochloride receptor antagonist platelet surgery
Prasugrel Thienopyridine ADP Life of 7 days before No
hydrochloride receptor antagonist platelet surgery
Ticagrelor Thienopyridine ADP 8–13 5 days before No
receptor reversible surgery
antagonist
Abciximab GP IIb/IIIa receptor 24 24 h before surgery Fibrinogen
antagonist (controversial)
Eptifibatide GP IIb/IIIa receptor 4–6 6–12 h before Fibrinogen
antagonist surgery (controversial)
Tirofiban GP IIb/IIIa receptor 4–6 6–12 h before Fibrinogen
antagonist surgery (controversial)
FXa activated factor X, ADP adenosine diphosphate, GP glycoprotein
a
No data available

thrombin. For these reasons they usually require lower doses of UFH to reach and
maintain adequate anticoagulation during CPB.
In recent years, VKAs have been partially replaced by novel oral anticoagulants
that probably will gain even wider popularity in years to come. The most com-
monly used are the direct thrombin inhibitor dabigatran and the direct factor Xa
inhibitors apixaban and rivaroxaban. Patients treated with these drugs cannot easily
be treated with PCC, and the timing of surgery should be based on their half-life
(Table 14.1).
246 F. Gronchi and M. Ranucci

14.2.3 Antiplatelet Therapy

14.2.3.1 Aspirin
Antiplatelet therapy has the most important role in the prevention of acute coronary
syndromes. Aspirin treatment may increase perioperative bleeding and transfusion
requirements; however, these side effects seem limited, and discontinuation of the
treatment is not recommended. In addition, withdrawing the treatment would unrea-
sonably increase the risk of ischemic events (Class IIa, level of evidence A).

14.2.3.2 P2Y12 Receptor Antagonists

The optimal delay between the last dose of clopidogrel and surgery has still to be
defined. The 2007 version of the STS/SCA guidelines (Society of Thoracic Surgeons
Blood Conservation Guideline Task Force et al. 2007) suggested at least 5–7 days
of discontinuation, but the most recent version (Society of Thoracic Surgeons Blood
Conservation Guideline Task Force et al. 2011) shortened this period to 3 days. A
position statement by the Canadian Cardiovascular Society (Fitchett et al. 2009)
suggests at least 5 days of discontinuation, and the European guidelines from the
European Society of Cardiology and the European Association for Cardio-Thoracic
Surgery (Task Force on Myocardial Revascularization of the European Society of,
C., S. the European Association for Cardio-Thoracic et al. 2010) also confirm 5 days
as the minimal discontinuation time for thienopyridine treatment for elective
patients undergoing coronary surgery.
Identifying patients resistant to antiplatelet therapy may prevent unnecessarily
postponing surgery; conversely, postponing patients who are strongly anti-aggregated
may limit the risk of severe postoperative bleeding. A recent study using impedance
aggregometry confirmed the interindividual response variability to clopidogrel bisul-
fate and also showed that its duration of action is not predictable (Ranucci et al.
2011). However, patients who experienced severe postoperative bleeding were iden-
tifiable using a preoperative platelet function test (Multiplate®). Therefore, it seems
reasonable to test platelet function to establish clear cutoffs for surgical timing (e.g.,
area under the curve (AUC) <30 on receptor P2Y12 measured on Multiplate®).
Prasugrel hydrochloride is a new-generation thienopyridine with a more pro-
nounced effect on platelet function and no, or a very limited number of, resistant
patients. It has been associated with a fourfold increase in the risk of bleeding after
CABG, compared to patients on clopidogrel (Wiviott et al. 2007). It is therefore
recommended to withdraw treatment 5–7 days prior to surgery, when feasible
(Class IIb, level of evidence C).
Ticagrelor is a P2Y12 receptor antagonist that does not belong to the thienopyri-
dine family. Its action is different from clopidogrel and prasugrel; it reversibly
inhibits platelet function and recovery can be expected 5 days after discontinuation
(Butler and Teng 2010).

14.2.3.3 Double Antiaggregant Therapy

Double antiaggregation by aspirin and P2Y12 inhibitors carries an increased risk of
bleeding in patients undergoing CABG (Hongo et al. 2002; Yende and Wunderink
2001; Berger et al. 2008; Pickard et al. 2008; Purkayastha et al. 2006).
14 Perioperative Coagulation in Cardiovascular Surgery 247

Continuing the treatment with aspirin and stopping clopidogrel prior to surgery
are currently the best compromise between hemorrhagic and thrombotic risks (Class
I, level of evidence B).

14.2.3.4 GP IIb/IIIa Inhibitors

The management of patients under GP IIb/IIIa inhibitors is more controversial;
short-acting drugs, such as eptifibatide or tirofiban, can be stopped 4–6 h before
surgery, whereas long-acting ones, such as abciximab, need a 24 h interval. In case
of emergency surgery, some authors recommend platelet transfusion (Lemmer et al.
2000) (Class IIb, level of evidence C).

14.3 Pathophysiology of Blood Clotting Disorders

Induced by CPB

The activation of the coagulation system induced by CPB is multifactorial and

involves all pathways. It can lead to microthrombi formation during CPB, excess
bleeding after CPB weaning, or a postoperative hypercoagulable state with an
increased risk of thrombotic complications.

14.3.1 Primary Hemostasis

During CPB, a significant increase in platelet activation markers, such as granule

membrane 140, P-selectin protein, PF4, and β-thrombomodulin, can be observed
(De Somer et al. 2002; Vallely et al. 2009; Diago et al. 1997). Platelet dysfunction
begins at the same time, with a subsequent decreased platelet response to thrombin.
The dysfunction is partially due to mechanical factors (CPB circuit, aspiration, and
pump interactions with platelets) and partially due to fibrinogen bound to the CPB
circuit. Fibrinogen links to the GP IIb/IIIa platelet receptor and induces the release
of procoagulant factors and platelet thrombin production.
Plasmin contributes to the platelet dysfunction by splitting the GP Ib receptor (de
Haan and van Oeveren 1998), partially activating the platelet and rendering it less
sensitive to agonists such as adenosine diphosphate (ADP) and arachidonic acid
(Slaughter et al. 2001; Velik-Salchner et al. 2009). Plasmin can also activate plate-
lets through protease-activated receptor 4 (PAR4), triggering aggregation and
degranulation with the release of procoagulant factors (Mao et al. 2009; Quinton
et al. 2004).

14.3.2 Secondary Hemostasis

Activation of the extrinsic pathway starts at the operative site, and in spite of the
administration of heparin (aiming an ACT >400 s), the initiation of CPB induces a
surge in thrombin and fibrin generation (Chandler and Velan 2003; Hunt et al. 1998)
even though the level of hemostatic proteins in the plasma is decreased by 30 % at
248 F. Gronchi and M. Ranucci

Fig. 14.1 Hemostatic Patient vascular system

activation mechanisms of
cardiopulmonary bypass. Endothelium
BK bradykinin, FXIIa
activated factor XII, TF tissue
factor, TPA tissue plasmino- BK TPA Fibrinolysis Plasmin
gen activator
Soluble fibrin
Platelets
TF Thrombin
Activation

BK FXIIa TF

Sheed
Contact Leukocyte
blood
activation activation
(open system)

Bypass circuit

that time. Hemodilution, blood loss, and volume replacement are responsible for
this decrease, whereas the role of consumption is variable and strongly dependent
on the duration of the CPB.
During cardiac operations both the extrinsic and the intrinsic coagulation path-
ways are activated, leading to thrombin generation (Fig. 14.1). However, thrombin
generation is largely due to the release of tissue factor (TF) (De Somer et al. 2002)
with the consequent activation of the extrinsic pathway. TF is expressed at the site
of surgical trauma but is also expressed by platelets due to an interaction with circu-
lating leucocytes (Chung et al. 2007). And, since inflammatory pathways, such as
the complement pathway, are intrinsically linked to the hemostatic system, the CPB
circuit’s surface can increase the release of TF by monocytes and neutrophils.
(Tabuchi et al. 2003; el Habbal et al. 1995).
After the onset of CPB, the intrinsic pathway (composed of factors XII and XI,
kininogen, and prekallikrein) is activated by interaction with the artificial surfaces
(Campbell et al. 2001). Factor XII is activated into factor XIIa, which converts
prekallikrein into kallikrein. Kallikrein then cleaves kininogen into kinin, which has
two effects: a potent hypotensive effect and a pathway amplifying effect, with a
positive feedback on bradykinin production and FXII activation. Factor XII also
cleaves inactive plasminogen into its active form plasmin, triggers the complement
pathway, and activates FXI into FXIa, initiating the intrinsic pathway.
Prekallikrein and kininogen levels decrease during CPB not only because of
hemodilution but also because of consumption and binding to the CPB circuit. On
the contrary, bradykinin levels are increased tenfold, through activation of the con-
tact system on the one hand and decreased pulmonary blood flow on the other; the
lung and the kidney are responsible for bradykinin metabolism (Campbell et al.
2001).
14 Perioperative Coagulation in Cardiovascular Surgery 249

14.3.3 Fibrinolysis

Increased levels of bradykinin enhance endothelial release of TPA. On average,

TPA levels increase tenfold during CPB (Chandler et al. 2000), which in turn
increase plasmin by a factor of 10–100. The result is an increase in fibrinolytic
activity by a factor of 10–20 (Chandler and Velan 2004). As a consequence, the
rates of fibrin generation and fibrinolysis (normally 1 %) are very similar, reflecting
predominantly systemic fibrinolysis, not limited to the site of surgery. This hyperfi-
brinolytic state consumes fibrinogen, decreasing levels available in the postopera-
tive phase. Conversely, during the 24 h after the operation, the patient may
experience a hypofibrinolytic state, due to a 15-fold increased level of plasmin acti-
vator inhibitor 1 (PAI-1) (Chandler and Velan 2004; Freyburger et al. 1993; Lu
et al. 1994). This level can further increase, carrying an associated risk of
thrombosis.

14.3.4 Anticoagulation, Antithrombin III, and Protein C

During CPB, 30 % of antithrombin III (AT III) is consumed because its natural
anticoagulant activity is markedly increased by UFH. Indeed, UFH increases the
catalytic activity of AT III by a factor of 1,000. Inactive thrombin-antithrombin III
complexes are formed and then eliminated, allowing for an effective anticoagula-
tion during CPB. If levels of AT III are too low, heparin resistance will be observed.
The clinical consequence of this will be the impossibility to reach an ACT >480 s
after UFH doses of 300–400 UI/kg. Hence, it is imperative to keep AT III levels
high enough to prevent excessive coagulation and inflammation activation, leading
to increased bleeding and transfusions (Ranucci et al. 2005a; Paparella et al. 2009).
AT III is a circulating plasma protein and can be administered through FFP; alterna-
tively, concentrated recombinant AT III is available and reduces volume load.
Although administration of recombinant AT III has proven to lower coagulation
and inflammation activation, no study has been able to demonstrate any impact on
postoperative bleeding and transfusion rates (Levy et al. 2002; Koster et al. 2003;
Avidan et al. 2005).
While thrombin production increases during CPB, protein C activity and endo-
thelial expression of its receptor decrease (Weiler 2010; Danese et al. 2010).
Hemodilution, negative protein C feedback on its own receptor, and negative
thrombomodulin feedback on the endothelium all participate in the increase of
thrombin formation.

14.3.5 Shed Blood

There also is marked activation of coagulation in shed blood, where large amounts
of TF generate thrombin, activating platelets and triggering fibrinolysis (de Haan
et al. 1993). Hence, the reinfusion of saved mediastinal blood can potentially
250 F. Gronchi and M. Ranucci

increase hemostasis activation and, as a consequence, the hemorrhagic risk. During

both CPB (Class IIb, level of evidence C) and postoperatively (Class IIb, level of
evidence B), the processing of mediastinal shed blood using a cell salvage device
may decrease lipid emboli, decrease the concentration of inflammatory cytokines,
and limit transfusions (De Somer et al. 2002).

14.4 Blood Conservation During CPB

It is currently recognized that measures that aim to reduce hemostasis activation

during CPB contribute to both the decrease of preoperative microvascular bleeding
and the requirement for blood transfusion (Sniecinski and Chandler 2011). Different
strategies may be used to limit the deleterious effects mentioned above.

14.4.1 Avoiding Excessive Hemodilution

The nadir hematocrit in CPB has been associated with postoperative morbidity
and mortality (Ranucci et al. 2005b; Karkouti et al. 2005; Fang et al. 1997; DeFoe
et al. 2001). Hemodilution during CPB is dependent on the priming volume, car-
dioplegia volume, and any additional fluid. Any strategy aimed at limiting infused
volumes will allow for a higher hematocrit during CPB and its postoperative
phase and, consequently, a lower transfusion rate. Many strategies are available in
order to diminish the priming volume, such as reducing the length and size of the
CPB circuits (Class I, level of evidence A), using vacuum-assisted venous drain-
age (Class IIb, level of evidence C), and applying retrograde autologous priming
(Class IIb, level of evidence B). Reducing priming volume from 1,400 to 800 ml
has been proven to significatively reduce transfusion rates. Another technique
available for minimizing hemodilution is modified ultrafiltration (MUF): after
CPB weaning, blood is ultrafiltrated through a hemofilter connected to the venous
and aortic cannulae (Class I, level of evidence A). MUF ensures not only the
removal of excess water, minimizing hemodilution, but also the removal of
inflammatory cytokines, resulting in a reduction of blood loss and transfusion
requirements.

14.4.2 Shed Blood Management

The recuperation of pericardial or pleural shed blood can potentially contribute to

saving blood units, since it returns blood and coagulation factors to the patient.
Nevertheless, hemostasis, inflammation, and fibrinolysis are very active in this
blood volume and if reinfused could worsen fibrinolysis and platelet dysfunction.
The treatment of salvaged shed blood using a cell salvage device, which includes
washing and centrifugation, reduces the activation of hemostasis and inflammation
and is associated with a decrease in blood loss and transfusion rates (Wang et al.
2009) (Class IIb, level of evidence B).
14 Perioperative Coagulation in Cardiovascular Surgery 251

14.4.3 Pumps and Circuits

Biocompatible circuits and oxygenators, by definition, decrease inflammatory

responses, limit hemostasis activation, and preserve platelet function. Closed circuits
are designed to reduce the foreign material contact surface and to minimize blood-
air contact by suppressing the cardiotomy reservoir. When used in combination with
closed systems, heparin-coated circuits allow for a reduction in the heparin dose,
with loading doses of less than 300 UI/kg still achieving an ACT of at least 300 s.
Two meta-analyses have confirmed the role of biocompatible circuits in reducing
allogeneic transfusion (Mangoush et al. 2007; Ranucci et al. 2009a). The type of
pump used in the CPB circuit may play a limited role in sparing blood. Roller
pumps are occlusive pumps that sequentially compress a segment of the CPB cir-
cuit, propelling blood through the tubing. Centrifugal pumps are nonocclusive,
generating blood flow by centrifugal force. This latter type of pump preserves plate-
let count and functions better than the former (Wheeldon et al. 1990) (Class IIb,
level of evidence B). Hence, it is thought that the use of centrifugal pumps can
reduce postoperative blood loss and the associated transfusion rate.

14.4.4 Anticoagulation

It is common to achieve anticoagulation for CPB by using a loading dose of 300–

400 UI/kg of heparin to obtain an ACT >400 s. Yet this strategy is based more on
tradition than on actual evidence. The response to an intravenous loading dose of
UFH is highly variable across patients (Young et al. 1978). Individual sensitivity to
heparin is influenced by nonspecific binding to plasma proteins and endothelial
cells and by AT III availability (Finley and Greenberg 2013). During CPB, measure-
ment of the plasma heparin level decay is problematic because its metabolism is
altered by hemodilution and hypothermia.
ACT monitoring during CPB is essential to accurately titrate the doses of heparin
and protamine. When compared with ACT-based anticoagulation management,
individualized heparin and protamine management during cardiac surgery with
CPB is associated with greater heparin doses, a lower protamine to heparin ratio,
and reduced platelet and plasma transfusions (Despotis et al. 1995). For individual-
ized management, heparin-ACT dose-response curves can be manually constructed
by measuring the ACT at baseline and after the administration of the loading dose
of heparin (Szalados 1994). The heparin concentration at the end of CPB and the
protamine dose needed can then be extrapolated from the curve. Today automated
devices are available that construct the patient-specific dose-response curves and
calculate the appropriate doses of heparin and protamine.
One prospective randomized study has demonstrated that the target ACT can be
achieved using a loading dose of 200 UI/kg and that patients having received smaller
amounts of heparin suffer less postoperative blood loss (Shuhaibar et al. 2004).
Few issues are more controversial than the adequate heparin dose during cardiac
surgery, with some authors supporting high-dose regimens and others suggesting
heparin dose reduction through the use of closed and biocompatible circuits.
252 F. Gronchi and M. Ranucci

14.4.5 Fibrinolysis

The hyperfibrinolytic state induced by CPB can be attenuated by the administration

of antifibrinolytic agents such as lysin inhibitors (tranexamic acid and aminocaproic
acid) or nonspecific serine protease inhibitors (aprotinin). Tranexamic acid is more
potent than aminocaproic acid, has a longer elimination half-life, and is the better
studied agent in cardiac surgery (Ozier and Bellamy 2010). The prophylactic admin-
istration of lysin inhibitors is associated with an overall reduction in blood loss, as
well as a reduction in the number of patients transfused (Class I, level of
evidence A).

14.4.6 Mini Circuits

Although all of the abovementioned strategies can be applied to a conventional

CPB circuit, using mini circuits can prove even more beneficial (Class I, level of
evidence A). These circuits are small closed loop CPB systems with or without
a flexible reservoir and driven by a centrifugal pump, minimizing hemolysis.
The priming volume is less than 1,000 ml, and the surfaces are biocompatible,
providing protection for blood components. Blood aspirated from the pericardial
area is treated separately in a cell salvage device. The total dose of heparin needed
is significantly reduced with these circuits. All these strategies, combined in a mini
extracorporeal circuit, result in a 60 % decrease in the transfusion rate (Ranucci
and Castelvecchio 2009).

14.5 Management of Perioperative Bleeding and Transfusion

The management of intraoperative bleeding encompasses the maintenance of

adequate oxygen delivery to tissues and the specific treatment of bleeding disorders.
Early intervention will prevent the occurrence of the fatal triad of hypothermia,
acidosis, and coagulopathy.

14.5.1 Anemia and Transfusion Triggers

The evaluation of intraoperative bleeding consists of a visual inspection of the

surgical field, the number of swabs, an estimation of aspirated blood, measurement
of hemoglobin (Hb) and hematocrit (Ht), and monitoring of body tolerance to ane-
mia. The latter is done by monitoring oxygen delivery, mixed venous oxygen satu-
ration, and lactic acidosis. Monitoring regional cerebral oxygen saturation helps
estimate brain tolerance to anemia. ST segment monitoring and evaluation of myo-
cardial wall motion by transesophageal echocardiography estimate the heart’s toler-
ance to anemia.
14 Perioperative Coagulation in Cardiovascular Surgery 253

Evidence supporting packed RBC transfusion is thin, and Hb and Ht thresholds

are arbitrary. Transfusion rates in cardiac surgery patients vary across different hos-
pitals, from 10 to 95 % (Stover et al. 1998; Snyder-Ramos et al. 2008). This wide
range of practice suggests that many transfusions and their related complications
could have been avoided.
Clinicians nevertheless face the challenge of identifying the ideal parameter on
which to base their decision to transfuse or not. Even if the prevention and treat-
ment of inadequate tissue oxygenation are generally accepted indications, it has
yet to be proven that blood transfusion actually increases oxygen delivery to the
microcirculation.
Indeed, in patients with Hb of 75–85 g/l, it has been demonstrated that the trans-
fusion of one to two blood units, when the fraction of inspired oxygen (FiO2) is 0.4,
has little effect on intramuscular oxygen partial pressure, whereas the latter is sig-
nificatively increased when the FiO2 is raised to 1.0 (Suttner et al. 2004).
Therefore, increasing FiO2 to 1.0 is an integral part of acute anemia
management.
Combining the use of transfusion thresholds with the monitoring and under-
standing of physiological parameters seems to be the best available tool to optimize
peripheral oxygenation (Spahn et al. 2004; Madjdpour et al. 2006).
If RBC transfusion is deliberately limited, the circulating volume should still
be maintained. Crystalloids and colloids will help maintain normovolemia, but
care must be taken not to worsen the hemodilution. Furthermore, the choice of the
solution can worsen coagulopathy, particularly in massive hemorrhage. Colloids
can be responsible for a decrease in factor VIII and von Willebrand activity, as
well as a decrease in platelet adhesion (Franz et al. 2001; Gallandat Huet et al.
2000).

14.5.2 Hypothermia and Acidosis

Hypothermia is relatively common in the intraoperative period and can significa-

tively contribute to bleeding (Arthurs et al. 2006). In vitro, viscoelastic tests show a
significant decrease in clot initiation and strength from temperatures below 35 °C.
At less than 16 °C, the coagulation cascade is completely inactivated. On the one
hand, hypothermia decreases coagulation factor activity, and on the other, it
decreases platelet activation and adhesion (Rivard et al. 2005).
The development of acidosis is the result of inadequate tissue perfusion and oxy-
genation, and with hypothermia it synergistically worsens coagulopathy. In vitro,
the effect on aggregometry of a pH <7.0 can be compared to that of hypothermia
<30 °C (Engstrom et al. 2006). Acidosis worsens coagulopathy by decreasing the
activity of pH-sensitive coagulation factors, such as FVIIa (activity is decreased by
90 % in an environment with pH <7.0) (Meng et al. 2003). The use of blood units
and blood-derived products can aggravate acidosis due to the fact that the pH of
stored products ranges from 6.0 to 7.0.
254 F. Gronchi and M. Ranucci

In summary, intraoperative bleeding in cardiac surgery is related to surgical

trauma but can also be caused by the development of a coagulopathy; in this case,
bleeding will be diffuse. The main mechanisms of the hemostasis dysfunction
are:
• Preoperative use of anticoagulants or antiaggregants
• CPB-induced thrombopenia and platelet dysfunction
• Hemodilution with a decrease of procoagulant factor levels
• Increased fibrinolysis
• Insufficient neutralization of heparin after CPB weaning
• Excess protamine
• Presence of physiological anticoagulants, inducing procoagulant factor
consumption
• Hypothermia and acidosis

14.5.3 Diagnosis and Treatment of Coagulopathy

Considering the complexity of the mechanisms of hemostasis and the multifacto-

rial pattern of postoperative coagulopathy in cardiac surgery, the therapeutic path-
way should be guided by the objective measurement of the various steps
contributing to coagulation. The targets are to rationalize bleeding management,
to tackle the underlying coagulopathy, to avoid the potentially deleterious effects
of transfusion, to improve patient outcome, and eventually to control transfusion-
related costs.
The first line of treatment consists of identifying patients at high risk of hemorrhage
and applying strategies to decrease coagulation activation (Class I, level of evidence A).
The use of POC transfusion algorithms in the perioperative phase has been shown
to better correlate with post-CPB bleeding than standard laboratory tests (Davidson
et al. 2008; Cammerer et al. 2003). Algorithms including viscoelastic and platelet func-
tion tests in particular target the coagulation deficit and its specific treatment more
precisely (Shore-Lesserson et al. 1999). This is currently the most efficient method of
reducing transfusion after cardiac surgery and improving patient outcomes (Weber
et al. 2012) (Class IIa, level of evidence C). A possible algorithm including the explora-
tion of the viscoelastic properties of the clot and platelet function is proposed in Fig. 14.2.
The use of viscoelastic tests (TEG® or ROTEM®) reveals the specific contribu-
tion of coagulation factors, fibrinogen, and platelets in clot formation, as well as the
influence of fibrinolysis or anticoagulation. It is important to keep in mind that
platelet dysfunction caused by antiaggregants such as aspirin or thienopyridines is
not revealed in viscoelastic coagulation tests (TEG® or ROTEM®) and will only be
highlighted by platelet function tests using specific agonists.
In Germany, K. Goerlinger’s team compared bleeding management guided by
standard laboratory tests to bleeding management guided by thromboelastometry
combined to multiple electrode impedance aggregometry (Weber et al. 2012). The
latter, POC-guided, management group received significantly less RBC, FFP, and
platelets. Interestingly, fibrinogen and PCC dosages were also inferior in the POC
group, even though the frequency of use was comparable. Finally, The POC-guided
14 Perioperative Coagulation in Cardiovascular Surgery 255

Bleeding patient ?
-Post CPB diffuse bleeding
-Post operative blood >250 ml/h or >50 ml/10 min

Maintain T° >36 °C, pH >7.3 Active rewarming, correct acidosis with NaHCO3, treat
Ca2+ >1.0 mmol/l, Hb >7 g/dl hypocalcemia with Ca2+, correct anemia with packed RBC

Check for residual heparin Heparinase-TEG or HEPTEM Protamine 30 IU/kg

PCC 30 UI/kg or
Check coagulation factors TEG or EX TEM/INTEM
FFP 15 ml/kg

Fibrinogen 25–50 mg/kg

Check clot firmness TEG FF or FIBTEM or FFP 15 ml/kg
or Platelets 0.1 UI/kg

Desmopressin 0.3 mcg/kg or

Check platelet function Multiplate or platelet mapping
platelets 0.1 UI/kg

Tranexamic acid
Check for hyperfibrinolysis TEG or APTEM
15 mg/kg

Surgical hemostasis or for life-threatening bleeding consider

All values in acceptable range?
factor XIII 1,250 UI or rFVII 90 µg/kg

Fig. 14.2 Hemostatic therapy algorithm. CPB cardiopulmonary bypass, RBC red blood cells,
TEG thromboelastography, TEG FF TEG-based functional fibrinogen assay, EXTEM tissue factor-
activated ROTEM assay, INTEM ellagic acid-activated ROTEM assay, HEPTEM heparinized
ROTEM assay, APTEM aprotinin-based ROTEM assay, PCC prothrombin complex concentrate,
FFP fresh frozen plasma

group received less rFVIIa. The conventional group, on the other hand, showed
more blood loss, a lower PaO2/FiO2 index, prolonged postoperative ventilation, an
increased rate of undesirable events, and a higher 6-month mortality rate. These
results confirm that a POC-guided approach is superior to an approach based on
standard laboratory tests. Whereas standard tests provide only quantitative information
on hemostasis, POCs rapidly provide qualitative information, allowing the clinician
to act faster and target a specific problem.
It should be noted that, even if controlling a bleeding defect is advisable, pick-
ing out the main culprit is difficult. This is due to the multitude of potential mech-
anisms causing the coagulopathy. Luckily, there is rarely a need to target a single
factor or specific clotting or fibrinolysis pathway. Indeed, acting on one part of the
clotting pathway is often sufficient to compensate for the disorder present else-
where in it.
Our pharmacological array allows us to promote hemostasis and fibrin for-
mation (and to slow down fibrinolysis) by interfering in the delicate balance
between coagulation activation and physiological anticoagulation (Mannucci
and Levi 2007). Nevertheless, the use of pharmacological agents carries the
potential risk of thrombotic complications. A transfusion algorithm is shown in
Fig. 14.2.
256 F. Gronchi and M. Ranucci

The use of fibrinogen, factor XIII, PCC, desmopressin, recombinant factor VII,
and antifibrinolytics is discussed in Chaps. 11 and 12.

14.5.4 Heparin and Protamine

Antagonization of heparin’s anticoagulant effects after CPB weaning is achieved

with protamine. Protamine is an alkaline arginine-rich (70 %) polypeptide extracted
from salmon sperm. It neutralizes heparin by binding to its acidic sulfate group,
preventing interaction with AT III. Controversy exists about which dose of prot-
amine should be administered after CPB. Dosing regimens range from 0.8 to 1.3 mg
of protamine for 100 IU of heparin. The calculation is often based on the initial or
total dose of heparin, without taking its elimination into account. This can lead to a
relative overdose of protamine with deleterious effects on coagulation and platelet
function, since protamine itself has anticoagulant as well as antiaggregant properties.
Protamine enhances endothelial release of t-PA and binds to thrombin, inhibiting
its capacity to convert fibrinogen into fibrin. Furthermore, protamine-heparin com-
plexes transiently decrease platelet count and function.
Ideally, the protamine dose should be based on the plasma heparin level (Despotis
et al. 1995; Jobes et al. 1995). After protamine administration, a residual heparin
effect can be caused by insufficient antagonization or heparin rebound – a reappear-
ance of anticoagulant activity after adequate neutralization. Residual heparin effects
can be responsible for pathological bleeding (Frick and Brogli 1966). Considering
its low sensitivity to low plasmatic heparin concentrations, ACT is an inadequate
measure for the detection of residual heparin effects. It is advisable to use specific
heparinase-based tests (ROTEM® HEPTEM or heparinase-TEG®).

14.5.5 Side Effects of Protamine

The undesired effects of protamine administration are mainly hemodynamic and

can be classified into three types.
The type I effect – the most frequent – is hypotension caused by mast cell release
of histamine and can be prevented by injecting protamine slowly (over 5 min).
Type II effects are classified as type IIa, anaphylaxis; type IIb, nonimmune-
dependent anaphylactoid reactions; and type IIc, delayed, non-cardiogenic pulmonary
edema probably linked to direct drug toxicity. Although type IIa reactions can occur
at any dosage and speed of infusion, careful titration is recommended with high-risk
patients (past exposure to protamine, insulin-dependent diabetes treated with Hagedorn
insulin, fish allergy, personal history of vasectomy) (Nybo and Madsen 2008).
A type III reaction consists of severe pulmonary vasoconstriction (probably
mediated by activation of complement by pulmonary macrophages) causing acute
right ventricular failure and systemic hypotension. This pulmonary hypertension
can be short lived or long enough to justify going back on the CPB circuit until the
hemodynamic parameters normalize. This phenomenon can be prevented by slow
administration of diluted protamine.
14 Perioperative Coagulation in Cardiovascular Surgery 257

In a case of protamine allergy, a 5 mg/kg dose of platelet factor 4 (PF4) and

5–7 mg/kg of heparinase have been proposed as alternatives for the reversal of a
dose of 300 UI/kg of heparin (Dehmer et al. 1995; Michelsen et al. 1996).
When no treatment is available, omitting heparin neutralization will cause heavy
bleeding (up to 5 l in 13 h (Campbell et al. 1984)) which can lead to a consumption
coagulopathy. In order to reduce the need for allogeneic blood transfusion, it is
recommended, in this specific case, to recycle blood collected from chest tubes in a
cell salvage device.

14.6 Heparin-Induced Thrombocytopenia (HIT)

in Cardiac Surgery

14.6.1 Pathophysiology of HIT

Unfractionated heparin remains the gold standard for anticoagulation in cardiac sur-
gery, with or without CPB, given its easy titration, safety margin, reversibility, and
low cost. However, its use carries the risk of developing heparin-induced thrombo-
cytopenia (HIT). Heparin binds to PF4 and 50 % of cardiac surgery patients develop
antibodies (Ab) to these heparin-PF4 complexes (anti-heparin-PF4 Ab). In 1–5 % of
these patients, the anti-heparin-PF4 Ab will activate platelets by binding its Fc frag-
ment to the platelet FcRII receptor (Warkentin et al. 2000).
The anti-heparin-PF4 Ab-mediated platelet activation and the resulting release
of proclotting factors increase the production of thrombin. The continuing expo-
sure, or reexposure, to heparin can lead to venous thrombosis (17–55 % of cases)
(Warkentin and Kelton 1996; Warkentin et al. 2000) or arterial thrombosis (3–10 %
of cases) (Warkentin and Kelton 1996). Although rare, it can also cause anaphylac-
toid reactions after intravenous injection, cutaneous necrosis at the site of injection,
adrenal hemorrhage, or disseminated intravascular coagulation (DIC).
In cardiac surgery, the most common complication of untreated or unrecognized
HIT is arterial thrombosis, which carries an associated mortality of 5–10 %.

14.6.2 Diagnosis of HIT

The diagnosis of HIT is based on a typical clinical presentation and the presence of
anti-PF4 Ab in patients treated with UFH or LMWH (although it is ten times less
frequent with the latter). HIT typically appears between the fifth and tenth day of
heparin treatment or within 24 h if anti-heparin-PF4 Ab are still circulating after
prior sensitization (<100 days). Less frequently, HIT can occur up to 3 weeks after
the cessation of heparin. In cardiac surgery, the pattern of HIT differs from the
thrombocytopenia generally seen after CPB: a patient who undergoes CPB gener-
ally experiences a platelet drop immediately on arrival in the intensive care unit;
subsequently, the platelet count starts recovering, reaching preoperative values
258 F. Gronchi and M. Ranucci

around 5–6 days after the operation (Pouplard et al. 2005). In this setting, HIT is
more often represented by a continuous drop in platelet count or a very late recovery
(Pouplard et al. 2005).
An easy tool for the clinical diagnosis of HIT is the 4Ts score (Table 14.2).
A low 4Ts score implies a very low probability of the patient actually having a HIT
(0–0.3 %) (Lo et al. 2006; Pouplard et al. 2007); however, some patients with a high
4Ts score (24–61 %) do not have HIT at all (Lo et al. 2006; Pouplard et al. 2007).
In cardiac surgery, the usefulness of the 4Ts score is limited because 2 of the 4 Ts
are always present after the procedure anyway (Thrombocytopenia and other
causes) and a third (Time) is unreliable.
HIT is associated with a daily thrombosis rate of 5 % (Lubenow et al. 2005). Thus,
considering the long laboratory turnaround times for HIT tests and the nondiagnostic
presence of isolated anti-PF4 Ab, a fast clinical diagnosis of HIT is imperative.

14.6.3 Treatment of HIT

After cardiac surgery, patients with strongly suspected or confirmed HIT, whether
or not complicated by thrombosis, should be treated with an alternative, nonheparin
anticoagulant such as danaparoid, lepirudin, argatroban, fondaparinux, or bivaliru-
din (Linkins et al. 2012). Any treatment with VKA must be interrupted until the
platelet count has substantially recovered (usually, to at least 150 × 109/l). VKA

Table 14.2 Estimating the pretest probability of HIT with the 4Ts score: low probability, 0–3
points; moderate probability, 4–5 points; and high probability, 6–8 points
Score = 2 Score = 1 Score = 0
Thrombocytopenia >50 % fall 30–50 % fall <30 % fall
or or or
>20 × 109/l 10–20 × 109/l <10 × 109/l
Timing of platelet Platelet fall days 5–10 Platelet fall > day 10 Platelet fall ≤ day
count fall or after start of heparin 4 without
thrombosis (day Platelet fall within Platelet fall within 1 day and exposure to
0 = first day of 1 day and exposure to exposure to heparin within heparin in past
most recent heparin within past past 31–100 days 100 days
heparin exposure) 5–30 days Platelet fall days 5–10 but not
clear (e.g., missing counts)
Thrombosis (or Confirmed new Recurrent venous thrombosis Thrombosis
other clinical thrombosis in patient receiving suspected
sequelae) therapeutic anticoagulants
Skin necrosis at Suspected thrombosis
injection site (awaiting confirmation)
Anaphylactoid reaction Erythematous skin lesions at
to IV heparin bolus heparin injection sites
Adrenal hemorrhage
OTher causes of No alternative Possible other cause is Probable other
Thrombocytopenia explanation for platelet evident cause is evident
fall is evident
14 Perioperative Coagulation in Cardiovascular Surgery 259

therapy can only be resumed with low maintenance doses (maximum 5 mg of war-
farin or 6 mg of phenprocoumon), and the nonheparin anticoagulant has to be con-
tinued until the platelet count has reached a stable plateau and the international
normalized ratio (INR) has reached the intended target range. There must be a mini-
mum overlap of 5 days between nonheparin anticoagulation and VKA therapy
before the nonheparin anticoagulant is withdrawn (Linkins et al. 2012).

14.6.4 Cardiac Surgery in Patients with HIT

Patients with a history, or a severe suspicion, of previous HIT should be tested for
anti-heparin-PF4 Ab. These usually disappear about 100 days after the last exposure
to heparin. If anti-heparin-PF4 Ab are no longer present, cardiac surgery can be per-
formed using standard UFH (Warkentin et al. 2008), but after receiving protamine,
no further doses of heparin should be administered, and the prophylaxis of throm-
botic events should be based on alternative anticoagulants. Conversely, if active anti-
bodies are still present, the operation should be postponed (if feasible) until they
disappear. An algorithm for the management of patients with HIT who need cardiac
surgery is presented in Fig. 14.3.
Different strategies have been proposed for patients with active antibodies whose
cardiac surgery cannot be postponed. A first possibility is to replace heparin with
another anticoagulant, such as argatroban (Edwards et al. 2003; Furukawa et al. 2001),
lepirudin (Koster et al. 2000a; Riess et al. 2007), or bivalirudin (Koster et al. 2000a,
2007; Dyke et al. 2007). However, caution should be applied in patients with impaired
renal function, especially when bivalirudin or, in particular, lepirudin is used.
In patients with acute HIT, there is no direct evidence supporting the use of one
alternative nonheparin anticoagulant over another. Although off-label, bivalirudin is

Acute episode of HIT

history of HIT

HIT-antibody positive HIT-antibody negative

Urgent surgery Elective surgery

Use alternative Wait until Use heparin

anticoagulation during CBPa HIT-antibody negative anticoagulation during CBP

Strictly avoid UFH or LMWH

pre and post surgery

Fig. 14.3 Heparin-induced thrombocytopenia (HIT) management algorithm. CBP cardiopulmonary

bypass, UFH unfractionated heparin, LMWH low-molecular-weight heparin. aSee text for details
260 F. Gronchi and M. Ranucci

Table 14.3 Alternative anticoagulation with bivalirudin for urgent cardiac surgery in patients
diagnosed with HIT
Drug Start Bolus Infusion Monitoring Additional doses Stop
Bivalirudin Before 1 mg/kg 2.5 mg/kg/min ACT >400 s During CPB: 10–15
(Koster cannulation IV and or 2.5 times 0.1–0.5 mg/kg IV min
et al. 2007) 50 mg of baseline After weaning: before
in CPB value 50 mg in CPB weaning
prime followed by
50 mg/h infusion
For details, see text

the only one that is supported by prospective multicenter cohort studies of patients
with HIT, who require urgent cardiac surgery, and indirectly by small randomized
heparin-controlled trials in patients without HIT (Dyke et al. 2007; Koster et al.
2007, 2009). This hirudin-derived peptide does not cross-react with anti-PF4 Ab.
Bivalirudin is a reversible thrombin inhibitor with a half-life of 25 min; it is elimi-
nated by plasmatic proteolysis and renal excretion (20 %) and can be ultrafiltrated.
Bivalirudin is administered with an initial bolus of 1 mg/kg IV, followed by an
infusion of 2.5 mg/kg/h (Koster et al. 2007) (Table 14.3). Targeting an ACT >300 s
(or 2.5 times the baseline), additional 0.1–0.5 mg/kg boluses can be given. The infu-
sion should be stopped 10–15 min before weaning. In the case of CPB, 50 mg has
to be added to the priming volume, and due to bivalirudin’s metabolic properties, its
use demands certain changes. First, surgery has to be normothermic. Second, since
stasis of blood can enhance the enzymatic breakdown of bivalirudin, the following
modifications of the CBP circuit are recommended:
• The use of a closed-circuit CPB when possible or replacing cardiotomy suction
by a citrate anticoagulated cell saver.
• Avoiding hemofiltration during CPB.
• Inserting shunt lines from arterial filter to the cardiotomy reservoir.
• Intermittent flushing of soft venous reservoirs.
• After weaning from CPB, add a bolus of 50 mg followed by a continued infusion
of 50 mg/h in the circuit.
• After weaning, once return on bypass is excluded, process the blood in the circuit
with a citrate anticoagulated cell saver for reinfusion.
In the case of CABG surgery, assessments of graft patency or leakage must be
performed with unheparinized normal saline. When grafting an internal mammary
artery, the vessel should be transected as late as possible before grafting.
Another strategy involves combining heparin with a short-acting potent anti-
platelet agent, such as a prostacyclin analog (e.g., epoprostenol, iloprost) (Antoniou
et al. 2002) or a glycoprotein (GP) IIb/IIIa inhibitor (e.g., tirofiban) (Koster et al.
2000b) to attenuate platelet activation (Table 14.4). Prostacyclin analogs inhibit
platelet activation by increasing adenylate cyclase activity and have very short half-
lives (6 min for epoprostenol and 15–30 min for iloprost). The most important side
effect reported is profound hypotension. Tirofiban has a half-life of about 2 h and is
eliminated by renal and biliary excretion.
Table 14.4 Anticoagulation with platelet inhibitors and heparin for urgent cardiac surgery in patient diagnosed with HIT
Drug Start Bolus Infusion Heparin Monitoring Additional doses Stop
Prostacyclin After induction Avoid 6–12 ng/kg/min 100–300 UI/kg when ACT Increase perfusion by 6 ng/kg/min 20 min after
(Antoniou et al. of anesthesia HIPA negative HIPA test until HIPA negative protamine
2002)
Tirofiban (Koster Before 10 mcg/kg 0.15 mcg/min 300 UI/kg after ACT None 1 h before end
et al. 2001) cannulation tirofiban bolus >480 s of CPB
14 Perioperative Coagulation in Cardiovascular Surgery

HIPA heparin-induced platelet aggregation

261
262 F. Gronchi and M. Ranucci

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Perioperative Hemostasis
in Hepatic Surgery 15
Klaus Görlinger, Eva Schaden, and Fuat H. Saner

15.1 Coagulopathy in Liver Cirrhosis

Blood coagulation is based on complex interactions between cells and plasmatic

coagulation factors, with elaborate feedback mechanisms including amplifying and
inhibiting loops. It is best described by the term “hemostasis,” highlighting the sen-
sible equilibrium between pro- and anticoagulants as well as fibrinolytic and antifi-
brinolytic factors.
Because most the coagulation factors are synthesized in the liver, their levels are
decreased in cases of chronic liver disease. This is particularly true for the vitamin
K-dependent coagulation factors II, VII, IX, and X, as well as for factor V; it is also
true for the vitamin K-dependent coagulation inhibitors protein C and protein S, as
well as for antithrombin (Schaden et al. 2013; Tripodi and Mannucci 2011). Notable
exceptions are von Willebrand factor (vWF) and coagulation factor VIII, which are
synthesized in the vascular endothelium and in compensation reach elevated levels
in patients with liver cirrhosis. On the other hand, the activity of the vWF-cleaving
enzyme ADAMTS13 (a metalloprotease exclusively produced in hepatic stellate
cells) is reduced in liver cirrhotic patients. Deficiency of ADAMTS13, particularly

K. Görlinger (*)
Department of Anesthesiology and Intensive Care Medicine,
University Hospital Essen, University Duisburg-Essen, Essen, Germany
e-mail: [email protected], [email protected]
E. Schaden
Department of Anesthesiology, General Intensive Care and Pain Control,
Medical University of Vienna, Vienna, Austria
F.H. Saner
Department of General, Visceral and Transplant Surgery,
University Hospital Essen, University Duisburg-Essen, Essen, Germany

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 267

DOI 10.1007/978-3-642-55004-1_15, © Springer-Verlag Berlin Heidelberg 2015
268 K. Görlinger et al.

in the presence of elevated levels of large vWF multimers, increases platelet micro-
thrombi formation and can therefore result in sinusoidal microcirculatory distur-
bances and subsequent progression of liver injury. This can eventually lead to
multiple organ failure (Lisman et al. 2006; Pereboom et al. 2009a; Uemura et al.
2011). A marked imbalance between decreased ADAMTS13 activity and increased
production of large vWF multimers has been shown to be closely related to func-
tional liver capacity, hepatic encephalopathy, hepatorenal syndrome, and intractable
ascites in advanced liver cirrhosis; it may also be useful in predicting long-term
survival of cirrhotic patients (Uemura et al. 2011; Takaya et al. 2012). Therefore,
some end-stage liver cirrhotic patients show conditions similar to thrombotic throm-
bocytopenic purpura (TTP). Besides sequestration of platelets in the spleen due to
portal hypertension and subsequent hypersplenism (Al-Busafi et al. 2012; Bhavsar
et al. 2012; Kedia et al. 2012), this mechanism may substantially contribute to
thrombocytopenia in liver cirrhotic patients. This thrombocytopenia seems to rebal-
ance the increased platelet adhesion and aggregation resulting from increased levels
of large vWF multimers in plasma and decreased ADAMTS13 activity. Therefore,
platelet transfusion should be restricted to bleeding complications since it may
result in further liver damage and exacerbated portal and portopulmonary hyperten-
sion (Elias et al. 2013). Notably, platelet dysfunction and acquired dysfibrinogen-
emia may also occur in liver cirrhosis (Caldwell and Sanyal 2009; Math et al. 2010;
Tripodi and Mannucci 2011). Furthermore, changes in pro- and antifibrinolytic
drivers have been reported. Here, plasminogen and alpha2-antiplasmin levels
decrease while tissue-plasminogen activator and plasminogen activator inhibitor-1
levels simultaneously increase (Schaden et al. 2013; Tripodi and Mannucci 2011).
Endotoxemia and subsequent tissue factor expression on monocytes are common in
patients with liver cirrhosis or following liver transplantation (Esch et al. 2010).
Therefore, infections can quickly result in alterations in hemostasis in cirrhotic
patients by inducing disseminated intravascular coagulation (DIC) (Smalberg and
Leebeek 2009; Chavez-Tapia et al. 2011b). Similar, but more pronounced changes
of pro- and anticoagulant factors are observed in acute liver injury/failure (Agarwal
et al. 2012), but data regarding fibrinolysis in acute liver dysfunction are inconclu-
sive (Agarwal et al. 2012; Lisman et al. 2012a, b). Recently published data showed
evidence of reduced fibrinolytic activity in acute liver failure, similar to that shown
in early phase sepsis (Adamzik et al. 2010; Brenner et al. 2012; Lisman et al. 2012a, b).
Taken together, blood coagulation in chronic liver dysfunction is rebalanced, even
though at an earlier stage it is prone to tipping toward thrombosis or hemorrhage,
depending on concomitant risk factors (Fig. 15.1) (Schaden et al. 2013; Tripodi and
Mannucci 2011). Recent studies have nevertheless shown that patients with liver
cirrhosis are at greater risk of thrombosis than bleeding, even if routine plasmatic
coagulation tests suggest hypocoagulability (Lisman et al. 2010; Ditisheim et al.
2012; Tripodi and Mannucci 2011; Tripodi et al. 2011). Therefore, prophylactic
correction of laboratory values by transfusion of blood products may have a delete-
rious effect on liver cirrhotic patients (Ditisheim et al. 2012; Schaden et al. 2013;
Tripodi and Mannucci 2011).
15 Perioperative Hemostasis in Hepatic Surgery 269

Fig. 15.1 Hemostatic Dysfibrinogen,

changes in liver cirrhotic platelet dysfunction,
patients. AT antithrombin, RES dysfunction LPS, TF,
α2-AP alpha 2-antiplasmin, vWF, FVIII,
tPA, PAI-1
LPS lipopolysaccharides, Platelets, vitamin K-dependent
PAI-1 plasminogen activator factors (II, VII, IX and X), V,
inhibitor-1, RES reticuloen- protein C and S, AT, Increased
dothelial system, tPA tissue plasminogen, α2–AP, up to 200 %
plasminogen activator, vWF ADAMTS13
von Willebrand factor
Decreased
to about 25–70 %
Low level balance →
High risk of bleeding and thrombosis!

15.2 Coagulation Tests in Liver Dysfunction

In order to understand the concept of balanced blood coagulation in liver dysfunc-

tion, knowledge of the scope and limits of coagulation tests performed in central
laboratories or at the point of care (POC) is essential.

15.2.1 Routine Coagulation Testing

The prothrombin time (PT) test, first described in 1935, was developed and imple-
mented to monitor anticoagulation with vitamin K antagonists (VKA) (Owren and
Aas 1951). Thromboplastins of different origin are added to recalcified citrated
plasma, and the time until coagulation starts is measured. This test only reflects the
activity of vitamin K-dependent procoagulant factors in plasma; it is neither capable
of measuring the activity of the vitamin K-dependent anticoagulants proteins C and
S, nor the complex interaction of cells and coagulation factors in whole blood
(Schaden et al. 2013; Tripodi and Mannucci 2011). Due to the use of different throm-
boplastins, results from different laboratories are not comparable. The INR was
established – and is indeed useful – to monitor anticoagulation in patients on VKA.
Later, the INR was used to detect and quantify coagulopathy in many other clinical
settings without ever having been validated for them, e.g., to predict bleeding in elec-
tive surgery, to guide hemostatic therapy in massive bleeding after trauma or surgery,
and also to define coagulopathy in liver disease. Meanwhile, it has been shown that
the correlation between INR and bleeding in patients scheduled for surgery is poor
(Koscielny et al. 2004). This has been demonstrated in patients with liver cirrhosis as
well (Stravitz et al. 2012; Tripodi and Mannucci 2011). In particular, no correlation
could be observed between PT and the bleeding time observed directly on the liver
surface during laparoscopic liver biopsy (Ewe 1981). However, the validity of the
INR as a prognostic parameter in liver dysfunction is not affected by this finding
(Stravitz et al. 2012).
270 K. Görlinger et al.

15.2.2 Thrombin Generation Assays

Thrombin generation (TG) assays measure the endogenous thrombin potential

(ETP) by adding phospholipids and thromboplastin to platelet-poor plasma: the
main parameters are the lag time, velocity, and area under the reaction curve. Using
this basic TG assay as a guide, TG seems to be reduced in patients with liver cir-
rhosis. However, the imbalance between pro- and anticoagulant activity – due to
the decrease in activity of proteins C and S in liver cirrhotic patients – cannot be
reflected by this basic TG assay performed in the absence of thrombomodulin. This
is because the thrombin-thrombomodulin complex is essential to the activation of
the protein C system (Tripodi and Mannucci 2011). Notably, results following ETP
tests in patients with acute and chronic liver disease were indistinguishable from
those in healthy volunteers and may even show higher TG in the presence of solu-
ble thrombomodulin (Lisman et al. 2012a, b; Tripodi and Mannucci 2011). A simi-
lar result can be achieved by the addition of Protac® (Pentapharm, Basel,
Switzerland), a snake venom that activates protein C in a manner similar to throm-
bomodulin (Agarwal et al. 2012; Gatt et al. 2010; Green et al. 2012; Tripodi et al.
2010). Furthermore, the results of TG assays are modified by the presence or
absence of platelets (Tripodi et al. 2006). Notably, platelet factor 4 modulates the
substrate specificity of the thrombin-thrombomodulin complex by selectively
enhancing protein C activation, while inhibiting thrombin-activatable fibrinolysis
inhibitor (TAFI) activation (Mosnier 2011). Altogether, modified TG assays can be
useful for the determination of coagulation function in patients with liver dysfunc-
tion, but they have the major drawback of not being available as a routine labora-
tory test.

15.2.3 Viscoelastic Tests (Thromboelastometry/

Thromboelastography)

Viscoelastic tests such as thromboelastometry (ROTEM®, Tem International

GmbH, Munich, Germany) and thromboelastography (TEG®, Haemonetics, Niles,
IL) are performed on whole blood, reflecting the interaction between blood cells
(platelets, leukocytes, and erythrocytes) and plasmatic coagulation factors (pro-
and anticoagulants). In addition to the dynamics of clot formation (CT, CFT, alpha
angle and r time, k time, alpha angle ), they provide essential information about
clot firmness (A5, A10, MCF and MA) and clot stability (ML, LI30, LI60). These
timely values for clot firmness (e.g., amplitude of clot firmness 5 or 10 min after
CT (A5, A10)) allow for fast, reliable prediction of thromboelastometric maximum
clot firmness (MCF) in patients with hypo-, normo-, and hypercoagulability; they
can therefore be used to guide hemostatic therapy in severe bleeding, including
patients undergoing liver transplantation (Görlinger et al. 2013). The short turn-
around times of thromboelastometric tests (15–25 min) are particularly important
for guiding therapy and preventing any inappropriate blood transfusions during
15 Perioperative Hemostasis in Hepatic Surgery 271

surgery and in intensive care units (Haas et al. 2012a, b). Furthermore, the diagnos-
tic performance of a panel of specific reagents and additives used in thromboelas-
tometry has been shown to be superior to mono-analysis using kaolin-based tests
(Larsen et al. 2011). On the one hand, algorithms based on the use of kaolin-acti-
vated tests alone, usually lead to platelet transfusion in cases of reduced clot firm-
ness (Larsen et al. 2011; Sakai et al. 2012). On the other hand, algorithms based on
a panel of ROTEM® reagents may avoid platelet transfusion when goal-directed
fibrinogen substitution is more appropriate (Figs. 15.2 and 15.3a–h) (Larsen et al.
2011; Görlinger et al. 2010, 2011a, b). This is of special importance in liver trans-
plantation since platelet transfusion is associated with a significant reduction in
1-year survival (74 % vs. 92 %; P < 0.001) in this clinical setting (Pereboom et al.
2009b). Notably, viscoelastic tests showed normo- (Stravitz et al. 2012) or even
hypercoagulability (Agarwal et al. 2012) in patients with acute liver failure, further
challenging the bleeding tendency concept in liver dysfunction. Here, hypercoagu-
lability seems to be better detected by whole blood thromboelastometry than by
TG tests using platelet-poor plasma (Fig. 15.3a) (Tripodi et al. 2009a). Furthermore,
tissue factor expression on monocytes, detected by thromboelastometry in septic
patients as well as in patients undergoing liver transplantation or extracorporeal
organ support, may play an important role in hypercoagulability and thrombosis in
liver cirrhotic patients (Fig. 15.3b) (Adamzik et al. 2010; Esch et al. 2010; Görlinger
et al. 2012a).

15.3 Bleeding Management in Patients with Liver

Dysfunction or Undergoing Liver Transplantation

Following the concept of balanced hemostasis in liver dysfunction, the adminis-

tration of blood products and coagulation factors in order to correct laboratory
values (e.g., prior to interventions) is inappropriate (Agarwal et al. 2012; Tripodi
and Mannucci 2011). Nevertheless, FFP and platelet transfusion are still used for
pre-procedural prophylaxis in cirrhosis patients (Shah et al. 2012; Violi et al.
2011), and in the UK, liver cirrhosis is one of the factors associated with a greater
use of prophylactic plasma transfusion (Hall et al. 2012). However, a high propor-
tion of current FFP transfusion is of unproven clinical benefit and has to be con-
sidered inappropriate (Stanworth et al. 2011a, b). In severe bleeding, FFP
transfusion is often recommended, but its risks and benefits should be assessed
critically (Kozek-Langenecker et al. 2011; Tripodi et al. 2012). High amounts of
FFP have to be applied for the correction of coagulopathy; this often results in
increased portal pressure and subsequently leads to increased bleeding and acute
lung injury (ALI) due to transfusion-associated circulatory overload (TACO).
Therefore, intravenous fluid restriction, rather than prophylactic administration of
large volumes of FFP, is recommended for patients with gastrointestinal bleeding
or undergoing major liver surgery (Kozek-Langenecker et al. 2013; Stellingwerff
et al. 2012). Moreover, transfusion-related acute lung injury (TRALI),
272 K. Görlinger et al.

CAVE:
Patients with chronic inflammatory
LTX diseases of the bile system (i.e.
PBC) or malignant tumors have a
high risk of thrombotic events or
vascular occlusion!

YES Thrombotic
Fulminant
events in patients NO
liver failure history
? ?
YES
NO
A10EX≤ 25 mm
YES Prophylactic administration
or CTEX> 80 s
of tranexamic acid
at beginning of (25 mg/kg bw)
surgery
NO

CLI60EX < 85% YES

during preanhepatic
or early anhepatic
phase
NO

CLI30EX < 50% YES Therapeutic administration

during late of tranexamic acid
anhepatic phase (25 mg/kg bw)

NO

CLI30EX< 50% YES Diffuse YES

after reperfusion clinical bleeding
?

NO NO

NO Aggravation of YES
fibrinolysis in close-
meshed controls
?
Check and optimise
No NO Diffuse YES basic conditions:
therapy clinical bleeding
! ? Tc> 35 °C pH > 7,2
Cai> 1 mmol/l Hb > 8 g/dl

A10EX ≤ 35 mm YES Administration of

and fibrinogen concentrate
A10FIB ≤ 8 mm (25-50-100 mg/kg bw)
NO

A10EX ≤ 35 mm YES Transfusion of

and platelet concentrates
A10FIB > 8 mm (1-2 U pooled or apharesis)

NO
Administration of Consider AT substitution,
CTEX > 80 s YES prothrombin complex if AT << Quick (PT in %)
(Check: PT !) concentrate (PCC) or in patients with high risk
(25(-40) IU/kg bw) of thrombotic events

NO Administration of protamine,
only if heparin effect
YES HEPTEM-Test: YES is undesirable
CTIN > 240 s CTHEP << CTIN
? NO
Transfusion of FFP
NO (6-12 U)
Ongoing
NO
diffuse bleeding
?
YES

A10EX ≤ 45 mm YES Administration of

and fibrinogen concentrate
A10FIB ≤ 15 mm (25-50 mg/kg bw)
NO

MULTIPLATE: Transfusion of
YES platelet concentrates
platelet dysfunction
? (1-2 U pooled or apharesis)
NO 10-15 min after each
pH > 7,2 specific intervention
and a reexamination of
Back to CTEX < 80 s
ROTEM NO
and
YES Consider ROTEM® - analysis
administration of
analysis A10FIB > 15 mm F XIII or rFVIIa should be done as a
(control) and control of sucess
A10EX > 45 mm
15 Perioperative Hemostasis in Hepatic Surgery 273

immunomodulation, increased nosocomial infection rates, and, last but not least,
therapy delay due to the thawing process all have to be considered when using
FFP (Pandit and Sarode 2012). Data from patients with liver cirrhosis are not
available yet (Levy et al. 2012; Sørensen et al. 2011). Results obtained in cardiac
surgery and liver transplantation, however, prove that when guided by POC coag-
ulation monitoring with thromboelastometry, the administration of specific coag-
ulation factor concentrates, like fibrinogen and 4-factor prothrombin complex
concentrates, corrects coagulopathy without increasing the thrombotic risk
(Fig. 15.2) (Görlinger et al. 2010; Görlinger et al. 2011a, 2012b; Kirchner et al.
2012; Weber et al. 2012). Furthermore, several other authors reported on the
advantages of coagulation management guided by thromboelastometry in liver
transplantation (Blasi et al. 2012; Minov et al. 2012; Noval-Padillo et al. 2010;
Roullet et al. 2010; Stancheva et al. 2011; Tripodi et al. 2009b; Trzebicki et al.
2010). Platelet transfusion can also be guided by POC monitoring (Figs. 15.2 and
15.3c–d) (Larsen et al. 2011; Görlinger et al. 2010, 2011a, b, 2012a, b). However,
platelet transfusion has been shown to be associated with a significant reduction
in 1-year survival (74 % vs. 92 %; P < 0.001) in liver transplantation, independent
of whether the platelet count was below or above 50/nL before platelet transfusion
(Pereboom et al. 2009b). Therefore, the indication to transfuse platelets should be
considered carefully. Cryoprecipitate, containing fibrinogen and factor XIII, but
also vWF and factor VIII, would further increase the already high levels of the
latter two, possibly contributing to a procoagulant switch with subsequent throm-
bosis (see below) (Dasher and Trotter 2012). Notably, the factor XIII Val34Leu
mutation, either alone or in combination with the PAI-1 4G/5G mutation, has been
shown to be a risk factor for an increased rate of liver fibrosis development in
patients with chronic hepatitis B or C (Dik et al. 2012).

15.4 Calculated First-Line Therapy with Fibrinogen

and Prothrombin Complex Concentrate Guided by
Thromboelastometry

Our algorithm for thromboelastometry-guided coagulation management during

liver transplantation, first published in 2006, clearly defines the indication, dosage,
and sequence of each hemostatic intervention in bleeding patients (Fig. 15.2)

Fig. 15.2 Point-of-care algorithm for thromboelastometry-guided coagulation management during

liver transplantation. A10 amplitude 10 min after CT, AT antithrombin, bw body weight, Cai ion-
ized calcium, CLI30 clot lysis index after 30 min, CLI60 clot lysis index after 60 min, CT clotting
time, EX EXTEM®, FXIII factor XIII concentrate, FFP fresh frozen plasma, FIB FIBTEM®, IN
INTEM®, Hb hemoglobin, HEP HEPTEM®, IU international units, LTX liver transplantation,
MCF maximum clot firmness, MULTIPLATE multiple electrode impedance aggregometry, PCC
4-factor prothrombin complex concentrate, PT prothrombin time, ROTEM® rotational thrombo-
elastometry, rFVIIa activated recombinant factor VII, Tc core temperature, U units
274 K. Görlinger et al.

a b
0’ 1 EXTEM 0’ 1 EXTEM
St. : 08h55 St. : 11h42

CT : 67s CT : 33s

MCF : 84mm MCF : 71mm

0’ 3 FIBTEM 0’ 3 FIBTEM
St. : 08h56 St. : 08h56

MCF : 47mm MCF : 31mm

Fig. 15.3 Interpretation of ROTEM® analyses in patients undergoing liver transplantation. (a)
Hypercoagulability in an infant with Budd-Chiari syndrome (hepatic vein thrombosis). Platelet
count 796/nL; plasma fibrinogen concentration >10 g/L; d-dimer 228 μg/dL; Quick 68 %; aPTT
33.8 s; AT 111 %. (b) Hypercoagulability due to infection and tissue factor expression on mono-
cytes. Quick 18 %; INR 3.5; aPTT 62.8; plasma fibrinogen concentration 6.56 g/L. The mismatch
between an increased INR (PT) in routine plasmatic coagulation tests and a reduced CT in whole
blood viscoelastic tests (ROTEM®) is typical for tissue factor expression on circulation cells (mono-
cytes or malignant cells). (c) Fibrinogen deficiency. Administration of fibrinogen concentrate (cryo-
precipitate) is indicated according to the POC algorithm in Fig. 15.2 in case of bleeding and A10EX
≤35 mm and A10FIB ≤8 mm (corresponding to MCFEX ≤45 mm and MCFFIB ≤10 mm). Fibrinogen
dosage (mg) = targeted increase in A10FIB (mm) × 6.25 mg/kg fibrinogen × kg bw. (d)
Thrombocytopenia compensated by a high plasma fibrinogen level. Platelet count 22/nL; plasma
fibrinogen concentration 4.2 g/L. Transfusion of platelet concentrates is indicated according to the
POC algorithm in Fig. 15.2 in case of bleeding and A10EX ≤35 mm and A10FIB >8 mm (correspond-
ing to MCFEX ≤45 mm and MCFFIB >10 mm). (e) Fulminant fibrinolysis in the anhepatic phase of
liver transplantation. Clot firmness in EXTEM® is reduced to zero within 15 min; flat line in
FIBTEM®. Recommended therapy according to the POC algorithm in Fig. 15.2: 25 mg/kg
tranexamic acid and 50 mg/kg fibrinogen concentrate (cryoprecipitate if fibrinogen concentrate is
not available). (f) Self-limiting fibrinolysis after reperfusion in a liver transplantation with a good
graft function. In the absence of bleeding, there is no need for therapeutic intervention. (g) Liberation
of heparinoids from the liver graft after reperfusion. Marked prolongation of CT and CFT in
INTEM® and almost normal CT in HEPTEM® (reference range for CT in INTEM® and HEPTEM®.
100–240 s). The effect of heparinoids usually is short acting and does not require any therapy in the
absence of bleeding. In principle, administration of FFP or PCC is not indicated here. (h) Deficiency
of vitamin K-dependent coagulation factors (II, VII, IX, X). Administration of PCC (or FFP if PCC
is not available) is indicated according to the POC algorithm in Fig. 15.2 in case of bleeding and
normalization of clot firmness (A10 or MCF) in EXTEM® and FIBTEM®, and CTEX >80 s (refer-
ence range for CT in EXTEM®. 40–80 s). Dosage of PCC = 25 (−40) IU/kg bw; dosage of FFP = 15
(−30) mL/kg bw. alp alpha angle, AT antithrombin, bw body weight, CFT clot formation time, CT
clotting time, EX EXTEM®, FFP fresh frozen plasma, FIB FIBTEM®, HEP HEPTEM®, IN
INTEM®, MCF maximum clot firmness, PCC 4-factor prothrombin complex concentrate, Quick
activity as % of normal based on PT, PT prothrombin time, aPTT activated partial thromboplastin
time, Run run time of the test, St. start time of the test
15 Perioperative Hemostasis in Hepatic Surgery 275

c d
0’ 1 EXTEM 0’ 1 EXTEM
St. : 18h27 St. : 09h02

CT : 73s CT : 57s

MCF : 41mm MCF : 46mm

0’ 3 FIBTEM 0’ 3 FIBTEM
St. : 18h29 St. : 09h04

MCF : 4mm MCF : 19mm

e f
0’ 1 EXTEM 0’ 1 EXTEM
St. : 17h06 St. : 08h27
Run : 65.1’
CT : 325s CT : 32s
CFT : 103s
MCF : 9mm MCF : 51mm
alp : 72°
0’ 3 FIBTEM 0’ 1 EXTEM
St. : 17h08 St. : 10h24
Run : 108.2
CT : 47s
CFT : 226s
MCF : 44mm
alp : 63°
g h
0’ 2 INTEM 0’ 1 EXTEM
St. : 15h04 St. : 23h38

CT : 621s CT : 119s

MCF : 24mm MCF : 54mm

0’ 4 HEPTEM 0’ 3 FIBTEM
St. : 16h26 St. : 23h40

CT : 260s

MCF : 42mm MCF : 13mm

Fig. 15.3 (continued)

276 K. Görlinger et al.

(Görlinger 2006; Görlinger et al. 2011b). This algorithm has been shown to reduce
transfusion requirements in patients undergoing liver transplantation, without
increasing the incidence of thrombotic/thromboembolic events (Görlinger et al.
2010, 2012b; Kirchner et al. 2012). Use of ROTEM®/TEG® for perioperative coagu-
lation monitoring and targeted therapy of coagulopathy in patients undergoing vis-
ceral and transplant surgery is highly recommended in the European Society of
Anesthesiology’s guidelines for the management of severe perioperative bleeding
(Kozek-Langenecker et al. 2013). However, all therapeutic interventions which
reduce the need for blood transfusion and help avoid thrombotic/thromboembolic
events should be investigated further since the strongest predictor of survival in
patients undergoing liver transplantation is the number of blood transfusions (Esmat
Gamil et al. 2012).

15.4.1 Antifibrinolytic Drugs (Tranexamic Acid)

Apart specific cases of prophylactic intervention (see thereafter), ROTEM®-guided

haemostatic therapy has been administered in cases of diffuse bleeding. Tranexamic
acid has been given prophylactically in a dose of 25 mg/kg bw in cases where
thromboelastometry detected severe coagulopathy (CT in EXTEM® >80 s and/or
A10 in EXTEM® <25 mm) at the beginning of surgery. A therapeutic dose of 25 mg/
kg bw tranexamic was administered in case of thromboelastometric detection of
hyperfibrinolysis (CLI30 <50 % or CLI60 <85 %) in presence of clinical diffuse
bleeding (Figs. 15.2 and 15.3e). In case of self-limiting fibrinolysis after reperfusion
without clinically relevant bleeding, no therapeutic intervention has been performed
in about 30 % of patients presenting fibrinolysis (Fig. 15.3f).

15.4.2 Fibrinogen Concentrate or Cryoprecipitate

According to our ROTEM®-guided algorithm, fibrinogen concentrate

(Haemocomplettan® P, CSL Behring GmbH, Marburg, Germany; marketed in the
US under the name RiaSTAP®) has been given as a first-line therapy in case of clini-
cally relevant diffuse bleeding and a decreased A10 value in both EXTEM® (A10
≤35 mm) and FIBTEM® (A10 ≤8 mm) (Figs. 15.2 and 15.3c). Usually, 25 mg/kg
bw fibrinogen concentrate was administered in order to increase A10 in FIBTEM®
by 4 mm or 50 mg/kg bw to increase A10 in FIBTEM® by 8 mm (Görlinger et al.
2012b; Lier et al. 2013). If bleeding continued, further fibrinogen concentrate was
administered until reaching a targeted A10 >15 mm in FIBTEM® and an A10
>45 mm in EXTEM®. Fibrinogen concentrate has been approved in Germany since
1985 for hereditary hypo-, dys-, and afibrinogenemia, as well as for any case of
acquired hypofibrinogenemia when cryoprecipitate is not in use. However, cryopre-
cipitate can be used instead of fibrinogen concentrate in countries where fibrinogen
concentrate is not available or approved for this indication (Kozek-Langenecker
et al. 2013).
15 Perioperative Hemostasis in Hepatic Surgery 277

15.4.3 Platelet Concentrate

Platelet transfusion was administered in cases of clinically relevant diffuse bleeding

and a low platelet count not compensated by higher fibrinogen levels (EXTEM®
A10 ≤35 mm and FIBTEM® A10 >8 mm) (Figs. 15.2 and 15.3d). Notably, platelet
transfusion during liver transplantation was associated with an increased incidence
of acute lung injury and a decreased 1-year survival rate (Pereboom et al. 2009b).
Therefore, the potential benefits of platelet transfusion have to be balanced against
their risks.

15.4.4 Prothrombin Complex Concentrate (PCC)

According to our ROTEM®-guided algorithm, four-factor PCCs (Beriplex® P/N,

CSL Behring GmbH, Marburg, Germany, or Octaplex®, Octapharma AG, Lachen,
Switzerland) were administered at a dose of 20–25 IU/kg bw in cases of clinically
relevant diffuse bleeding, with adequate clot firmness in EXTEM® and FIBTEM®
(A10 >35 mm and 10 mm, respectively) but with prolonged CT in the EXTEM®
(>80 s). In case of ongoing diffuse bleeding, further PCC administration (up to 40 IU/
kg bw) was considered if the CT in the EXTEM® assay did not reach values below
80 s (Figs. 15.2 and 15.3h) (Görlinger et al. 2012b). Antithrombin concentrate was
not routinely substituted for PCC. The four-factor PCCs used in Europe (such as
Beriplex® and Octaplex®) contain balanced amounts of all vitamin K-dependent
coagulation factors (II, VII, IX, and X), as well as the vitamin K-dependent antico-
agulants proteins C and S (Holland et al. 2009; Sørensen et al. 2011; Kalina et al.
2008). Since 1996 in Germany, these four-factor PCCs have been approved for the
prophylaxis and therapy of bleeding in patients with a hereditary or acquired defi-
ciency of vitamin K-dependent coagulation factors. The safety profile of these four-
factor PCCs has been considered good (Sørensen et al. 2011; Hanke et al. 2013).

15.4.5 Fresh Frozen Plasma (FFP)

A transfusion of FFP as a sole treatment was administered in cases of clinically

diffuse bleeding and hyperfibrinolysis associated to a deficiency of fibrinogen,
platelets, and vitamin K-dependent coagulation factors while an effect of hepari-
noids liberated from the liver graft could be excluded (Figs. 15.2 and 15.3g). In these
cases, we assumed that a coagulation factor was missing and not included in the
coagulation factor concentrates we used in the perioperative setting, e.g., factor V,
VIII, or IX. Accordingly, 6–12 units of FFP were transfused as a hemostatic inter-
vention. It is of note that large FFP transfusion are linked with transfusion-associated
circulatory overload, acute lung injury, multiple organ failure, hepatic artery throm-
bosis, nosocomial infections, and sepsis (Dara et al. 2005; Hatano et al. 1997; Khan
et al. 2007; Sarani et al. 2008; Watson et al. 2009). The potential benefits of FFP
transfusion therefore have to be balanced against their risks.
278 K. Görlinger et al.

15.4.6 Recombinant Activated Factor VII (rFVIIa)

It is of note that rFVIIa (NovoSeven®, Novo Nordisk A/S, Bagsværd, Denmark) is not
labeled for use in liver dysfunction and liver transplantation, and studies have failed to
demonstrate a significant benefit in bleeding of the upper gastrointestinal tract or in
liver transplantation (Chavez-Tapia et al. 2011a; Dasher and Trotter 2012; Pandit and
Sarode 2012; Simpson et al. 2012). Keeping a potential increased risk of thrombosis in
mind, the off-label use of rVIIa in patients with severe bleeding that is unresponsive to
other hemostatic interventions can be considered (Kozek-Langenecker et al. 2013).
According to our ROTEM®-guided algorithm, the administration of rFVIIa can be con-
sidered as a rescue therapy in case of ongoing diffuse bleeding despite optimization of
hemostasis, surgical hemostasis, and ROTEM®-guided hemostatic therapy (Fig. 15.2).
However, this has not been necessary in any cases since the implementation of our
ROTEM®-guided algorithm (Görlinger et al. 2010).

15.5 Venous Thromboembolism in Liver Dysfunction

In line with the observations described above, patients with liver dysfunction are not
“auto-anticoagulated” (Pincus et al. 2012; Schaden et al. 2013; Tripodi et al. 2011),
but according to the findings of more global coagulation tests (thromboelastometry
and thrombin generation assays), they tend rather to hypercoagulability with the
inherent risk of thrombosis (Agarwal et al. 2012). Besides deep vein thrombosis,
portal vein thrombosis and pulmonary embolism thrombosis can also affect the arte-
rial system (hepatic artery thrombosis, myocardial infarction, or stroke). Even the
progression of liver fibrosis in chronic liver disease might be a consequence of pro-
coagulant imbalance (Tripodi et al. 2011). Hence, venous thromboembolism (VTE)
prophylaxis is required during the hospitalization of patients with liver dysfunction
(Koliscak and Maynor 2012). Despite this, 75 % of these patients do not receive
VTE prophylaxis (Dabbagh et al. 2010; Aldawood et al. 2011).

15.6 Venous Thromboprophylaxis in Patients with Liver

Dysfunction

VTE prophylaxis can be performed by pharmacological and/or mechanical means

(compression stockings, intermittent pneumatic compression). The American
College of Chest Physicians guidelines are updated every 4 years and present and
grade the available evidence regarding thrombosis and thromboprophylaxis (Guyatt
et al. 2012). Interestingly, these comprehensive guidelines do not offer any recom-
mendations for VTE prophylaxis in patients with liver disease. This might be due to
the lack of evidence, as in most studies dealing with thromboprophylaxis, patients
with liver dysfunction are excluded. A recent study investigating the prevention of
portal vein thrombosis in patients with chronic liver disease proved the efficacy and
safety of enoxaparin application (4,000 U subcutaneously once daily) in cirrhotic
patients (Villa et al. 2012). Prophylactic use of low-molecular-weight heparins
15 Perioperative Hemostasis in Hepatic Surgery 279

(LMWH) in patients with cirrhosis appears to be safe (Bechmann et al. 2011).

A decreased anti-Xa value in cirrhotic patients and a negative correlation with liver
function challenge the unconditional use of anti-Xa assays in LMWH monitoring in
cirrhotic patients; it also reveals a potential limitation of anti-Xa analysis in these
patients. A low level of AT, due to reduced hepatic synthesis, is the most likely
cause of this phenomenon (Bechmann et al. 2011).
Early anticoagulation treatment, in both cirrhotic and non-cirrhotic patients with
portal vein thrombosis and acute variceal bleeding, resulted in a satisfactory rate of
recanalization with minimal procedure-associated morbidity (Hall et al. 2011;
Maruyama et al. 2012). Since argatroban is mainly metabolized in the liver, it should
be used with caution in patients with liver dysfunction (Garcia et al. 2012) and/or
hyperbilirubinemia (Doepker et al. 2012). Despite some absolute contraindications
(e.g., peripheral vascular disease), mechanical deep vein thrombosis (DVT) prophy-
laxis can be used in most patients and is of particular benefit to patients with a sus-
pected bleeding risk. Nevertheless, mechanical DVT prophylaxis is used only in a
minority of patients in intensive care units (Schaden et al. 2012).

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Perioperative Hemostasis in
Pediatric Surgery 16
Thorsten Haas

16.1 Pediatric Hemostasis

The development of hemostasis during childhood is a complex physiological pro-

cess which aims to build a stable clot in situations of vascular injury, but which is
also responsible for clot dissolution to maintain blood flow (Andrew et al. 1987,
1988, 1992). Although the most significant changes in this maturation process can
be observed during the first 6 months of life, the hemostatic system continues to
mature thereafter (Andrew et al. 1992; Miller et al. 1997). These changes include
lower quantities of most of the coagulation factors (except for factor VIII and von
Willebrand factor, vWF), decreased platelet activity, and a fetal dysfunctional
fibrinogen (Guzzetta and Miller 2011). However, as the anticoagulant system (such
as plasmin generation and fibrinolytic activity) is also diminished at birth, the over-
all hemostasis potential in neonates and young infants can be evaluated as good,
with no increased risk of thrombosis or hemorrhage in the face of minor challenges
(Kuhle et al. 2003). However, this maturation process is certainly not rigidly cou-
pled to a child’s age group, but rather it is highly individual. It is therefore essential
that careful anamnesis, physical examination, and laboratory work-up should be
adapted to actual age and underlying medical condition.

16.2 Perioperative Coagulation Testing in Children

16.2.1 Preoperative Screening of Hemostasis

At present, guidelines and recommendations for perioperative coagulation manage-

ment do not support routine coagulation screening tests in otherwise healthy patients

T. Haas, MD
Department of Anesthesia, Zurich University Children’s Hospital,
Steinwiesstrasse 75, Zurich CH-8032, Switzerland
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 285

DOI 10.1007/978-3-642-55004-1_16, © Springer-Verlag Berlin Heidelberg 2015
286 T. Haas

if their bleeding history shows negative results (Dzik 2004; Koscielny et al. 2004;
Chee et al. 2008; Kozek-Langenecker 2010; Samkova et al. 2012). This approach is
based on the fact that the prediction of perioperative bleeding could not be reliably
determined by routine coagulation screening tests, while the combination of a clini-
cal examination, together with a detailed (family) history, showed superior results
in ensuring the detection of impaired hemostasis. For example, von Willebrand syn-
drome type I is the most common type of a clinically relevant congenital bleeding
disorder, with an incidence of 1 in 500; because it cannot be detected by a prolonged
activated partial thromboplastin time (aPTT), it will most likely come to light via a
detailed bleeding history. Templates of standardized questionnaires can be down-
loaded from the Austrian Society of Anesthesiology (ÖGARI) (http://www.oegari.
at/web_files/dateiarchiv/116/Recommendation%20questions%20bleeding%20
symptoms%202009.pdf), the Canadian Pediatric Bleeding Questionnaire (http://
www.ahcdc.ca/inheritedbleeds.html), and the International Society on Thrombosis
and Haemostasis bleeding assessment tool (http://www.isth.org/default/assets/file/
bleeding_type1_vwd.pdf).
If this preoperative approach reveals evidence of impaired hemostasis, or a child
suffers from a congenital or known acquired coagulation disorder, an interdisciplin-
ary work-up with a hematologist or another dedicated physician specialized in pedi-
atric bleeding disorders is indicated.

16.2.2 Intraoperative Coagulation Testing

16.2.2.1 Standard Plasmatic Coagulation Testing

Intraoperative coagulation testing is a cornerstone of the identification of an underlying
coagulation disorder, but is also an essential tool for guiding appropriate coagulation
management. Unfortunately, routine plasmatic coagulation tests are of limited help
for timely management of perioperative bleeding; this is due to long turnaround times,
insufficient differential diagnosis of complex acquired intraoperative coagulopathy,
and insensitivity to fibrinogen function, hyperfibrinolysis, and platelet dysfunction
(Kozek-Langenecker 2010). Other important limitations are that the measurement of
fibrinogen levels using the photometric Clauss assay can be considerably altered after
massive fluid resuscitation, and that colloids may erroneously induce increased levels
of fibrinogen (Fenger-Eriksen et al. 2010; Kozek-Langenecker 2010).

16.2.2.2 Thromboelastometry
Although data on the use of rotational thromboelastometry for intraoperative coagula-
tion management in children were scarce (Haas et al. 2008, 2012c; Hayashi et al.
2011; Romlin et al. 2011), a recently published meta-analysis showed significant
reduction in requirements of allogeneic blood products if thrombelastography/throm-
boelastometry was used to guide transfusion strategy (Afshari et al. 2011). In addition,
the use of thromboelastometry for pediatric care is recommended by the European
guidelines for perioperative bleeding management (Kozek-Langenecker et al. 2013).
Thus it seems reasonable to also use this advanced coagulation test for coagulation
management in children once it has been implemented as routine for adults.
16 Perioperative Hemostasis in Pediatric Surgery 287

While keeping in mind the functional maturity of the coagulation system, age-
dependent reference ranges for the ROTEM® (Oswald et al. 2010) or TEG® (Miller
et al. 1997) should be taken into account. The most striking finding from the evalu-
ation of these reference ranges is that children aged 0–3 months exhibited acceler-
ated coagulation and strong clot firmness, despite showing prolonged standard
plasma coagulation test results. Similarly to adults, fibrinogen concentrations, plate-
let count, and FXIII in children also contribute to clot firmness as measured using
ROTEM® assays. Furthermore, it was demonstrated that children aged 4–24 months
showed the lowest 2.5 % percentiles for clot strength, indicating low reserve when
exposed to hemodilution and blood loss. However, as a rule of thumb, from the 6th
month of life, adult reference ranges from ROTEM® can safely be used to guide
intraoperative coagulation management.

16.2.2.3 Pre-analytical Considerations

Depending on local resources, the following coagulation tests could reasonably be
used for baseline measurements, for regular check-ups, and in situations of increased
bleeding tendency or severe bleeding:
• ROTEM® INTEM, EXTEM, FIBTEM, and APTEM
• Plasmatic coagulation testing (including FXIII, if possible)
• Blood count (platelet count, hemoglobin level, hematocrit)
• Blood gas analysis
This full panel of coagulation tests can be performed with a total withdrawal of
only 3.6 ml blood.
Thought must be given to the possibility of pre-analytical errors that can have
considerable impact on the interpretation of laboratory results. These can include
important but avoidable errors, such as an artificial activation of the blood sample
by forced aspiration through the small diameters of pediatric cannulas, temperature
effects, and an alteration of the correct whole blood/citrate ratio. Although labora-
tory tests should be repeatedly analyzed during any surgical procedure with massive
or expected bleeding, only the minimum volume necessary should be withdrawn in
order to prevent artificial anemia.

16.3 Perioperative Coagulation Management

16.3.1 Preoperative Considerations

Several publications have investigated coagulopathies in the clinical setting of car-

diac surgery. However, if a cardiac bypass were used, additional disturbance to the
coagulation system, such as platelet dysfunction, excessive fibrinolysis, or con-
sumption of coagulation factors might aggravate dilution following administration
of the priming volume (Friesen et al. 2006). Thus, coagulation testing and manage-
ment should be adapted to the type of surgery.
There are some important prerequisites for adequate hemostasis that need
to be carefully checked and treated throughout the entire perioperative phase.
Anesthetized children are particularly prone to becoming hypothermic which, like
288 T. Haas

acidosis, inevitably leads to impairment of the coagulation process and may worsen
bleeding (Dirkmann et al. 2008). Thus, forced-air warming should be rigorously
performed, and temperature, as well as pH values, continuously measured during
pediatric surgery.
Meta-analyses of major pediatric surgery (Sethna et al. 2005; Tzortzopoulou et
al. 2008; Schouten et al. 2009; Goobie et al. 2011) and scoliosis surgery in children
(Tzortzopoulou et al. 2008) have nicely demonstrated that the prophylactic admin-
istration of antifibrinolytic agents (e.g. tranexamic acid or TXA) may decrease
blood loss and reduce allogeneic blood transfusion significantly. Therefore, the
prophylactic use of TXA can generally be recommended for major pediatric sur-
gery with estimated high blood loss or need for transfusion. Optimum doses are
still debated; reported dosing ranges from 10 to 100 mg/kg bolus, while high doses
might provoke seizures. Recent studies favored an initial bolus followed by con-
tinuous infusion due to TXA’s relatively short half-live of about 120 min. Based on
recently published data it seems reasonable to use an initial dose of 10–15 mg/kg
infused over 15 min, followed by continuous infusion of up to 5 mg/kg/h through-
out the entire surgical phase and upon transfer to the postoperative ward (Goobie
et al. 2013).
Alternative means to minimize blood transfusion in major pediatric surgery were
recently reviewed (Lavoie 2011). Results showed that acute normovolemic hemo-
dilution (mostly in adolescents) showed modest benefits. Other strategies such as
preoperative autologous donations (partly in combination with administration of
erythropoietin), intraoperative cell salvage (may be feasible if child’s body weight
is >10 kg), or deliberate hypotension (in the absence of a hypovolemic state), or
a combination of them, might be helpful in reducing allogeneic blood transfu-
sion. However, approaches must largely depend on individual expertise and local
facilities.

16.3.2 Intraoperative Fluid Management

Prevention and treatment of hypovolemia during major pediatric surgery is essential

and may be carried out by appropriate fluid management using crystalloids or col-
loids. Besides the ‘traditional’ usage of albumin for pediatric fluid resuscitation,
modern synthetic colloids, e.g. gelatin solutions or hydroxyethyl starches, can be
safely used even in neonates and small children (Standl et al. 2008; Sumpelmann et
al. 2012). As with adults, the use of any synthetic or natural colloids may lead to
volume-dependent changes in the hemostatic profile and eventually to dilutional
coagulopathy and occurrences of generalized microvascular oozing (Osthaus et al.
2009; Haas et al. 2012b). One can only speculate as to whether early vasopressor
therapy might have a beneficial impact on perioperative bleeding by reducing the
amount of fluids administered during major surgery. However, to date, no conclu-
sive statement can be made about which type of fluid should be used to stabilize
hemodynamics in children, but caution should be exercised in clinical scenarios
were colloids are administered to children with an increased risk of bleeding.
16 Perioperative Hemostasis in Pediatric Surgery 289

16.3.3 Intraoperative Laboratory Findings and Therapy

It is important to note that the reported triggers of standard plasmatic coagulation

tests for assessment of coagulopathy or initiation of bleeding therapy are based on
empirical rather than evidence based data. In addition, the results of standard labo-
ratory tests and ROTEM® data cannot be used interchangeably for the detection of
hemostatic disorders. As an example, the results of standard laboratory tests (pro-
thrombin time, PT, or aPTT) alter frequently during early stages of surgery, thus
indicating transfusion of fresh frozen plasma (FFP) or prothrombin complex con-
centrates (PCC), while abnormal ROTEM® clotting time is a late phenomenon that
may be observed after severe disturbances of hemostasis (Haas et al. 2012c). Thus,
transfusion requirements will be completely different according to the underlying
laboratory methods and transfusion triggers. The European guidelines for periop-
erative bleeding recommend the use of thromboelastometry in this setting (Kozek-
Langenecker et al. 2013) (Table 16.1).

16.3.3.1 Impaired Clot Firmness

16.3.3.1.1 Fibrinogen Deficiency: Diagnostic and Therapy
Functional fibrinogen/fibrin activity can be quickly and reliably assessed using the
ROTEM® FIBTEM assay. If the maximum clot firmness (MCF) at 10 min (A10)
showed values <7 mm (which is approximate to a Clauss assay of ≤150 mg/dl) in a
scenario of significant bleeding, fibrinogen should be administered (Fries et al.
2010; Kozek-Langenecker et al. 2013). It should be noticed that besides of fibrino-
gen deficiency, a low FIBTEM MCF may be also caused by inadequate amounts of
FXIII necessary to stabilize the clot.

Table 16.1 Intraoperative laboratory findings and therapy

Hemostatic
disorder ROTEM® Standard laboratory test Therapy
Fibrinogen FIBTEM A10 Clauss assay 150– Fibrinogen concentrate:
deficiency <7 mm 200 mg/dl (Cave: 30–50 mg/kg
overestimation in Cryoprecipitate: 5 ml/kg (or
presence of colloids) 15–30 kg bodyweight = 5
Units; >30 kg = 10 Units)
FFP: 20 (−30) ml/kg
FXIII FIBTEM MCF FXIII activity <60 % FXIII concentrate: 20 IU/kg
deficiency remains low despite FFP: 20 (−30) ml/kg
adequate substitution
with fibrinogen
Low platelet EXTEM MCF Platelet count <50,000– 10 (−20) ml/kg of apheresis
count <40 mm with normal 100,000/µl platelet concentrate (to a
FIBTEM MCF maximum of 1 Unit)
Inadequate EXTEM or INTEM Needs to be determined FFP: 20 (−30) ml/kg
thrombin CT prolonged PCC: about 20 IU/kg (Cave:
generation thromboembolic risk)
290 T. Haas

Fig. 16.1 ROTEM® trace of mm

fibrinogen deficiency.
FIBTEM MCF weak (6 mm) 60
40
20

20
40
60

10 20 30 40 50 min

Using the conventional Clauss assay, current recommendations (for adult

patients) emphasize a trigger level of 150–200 mg/dl for initiating fibrinogen sub-
stitution therapy. However, if colloids were administered, fibrinogen levels ana-
lyzed using the Clauss assay may be erroneously high (Fenger-Eriksen et al.
2010).
Treatment of acquired fibrinogen deficiency consists of the administration of
purified fibrinogen concentrate, transfusion of cryoprecipitate, or FFP (Fig. 16.1).

16.3.3.1.2 Fibrinogen Deficiency: Rationale

Fibrinogen plays several key roles in the maintenance of hemostasis (Levy et al.
2012; Sorensen et al. 2012). Fibrinogen acts by bridging activated platelets and is
the key substrate by which thrombin forms a mechanically stable clot. Accumulating
data suggest that acquired fibrinogen deficiency seems to be the leading determinant
in dilutional coagulopathy in adults and children (Fries 2006; Levy 2006; Kozek-
Langenecker 2007; Fenger-Eriksen et al. 2009; Innerhofer and Kienast 2010; Haas
et al. 2012b). Clinical trials and observations indicated a beneficial role for intraop-
erative substitution with human fibrinogen concentrate to treat fibrinogen deficiency
(Danes et al. 2008; Fenger-Eriksen et al. 2008; Haas et al. 2008; Weinkove and
Rangarajan 2008; Fenger-Eriksen et al. 2009a; Rahe-Meyer et al. 2009) with a very
good safety profile (Dickneite et al. 2009; Manco-Johnson et al. 2009).
FFP and cryoprecipitate may also serve as alternative sources of fibrinogen,
although this is not supported by evidence from good-quality randomized trials
(Stanworth et al. 2004). Cryoprecipitate contains higher concentrations of fibrino-
gen than FFP, but was withdrawn from several European countries because of the
risk of immunologic reactions and potential transmission of infectious agents.
Recommended dosages for FFP of 10–15 ml/kg may not be adequate to achieve a
clinically meaningful improvement in hemostatic potential, but the considerable
necessary volume load often limits higher doses.

16.3.3.1.3 FXIII Deficiency: Diagnostic and Therapy

For clinical purposes, weak factor activity of FXIII can be either accurately ana-
lyzed in a laboratory (FXIII <60 % and severe bleeding indicative for therapy), or
can be estimated in a clinical case, when clot firmness in the ROTEM® FIBTEM
16 Perioperative Hemostasis in Pediatric Surgery 291

assay remains relatively low despite adequate substitution with fibrinogen. Although
it was shown that the FXIII-dependent increase in clot firmness can be displayed
using the ROTEM®/TEG® (Nielsen et al. 2004; Theusinger et al. 2010), to date no
commercially available point-of-care test for measuring FXIII activity is available.
Recommended means of substitution for FXIII include administration of a purified
factor concentrate, or FFP.

16.3.3.1.4 FXIII Deficiency: Rationale

Factor XIII is a significant ingredient in achieving clot stability by cross-linking
fibrin monomers, and preventing clot lysis by covalent binding of α2-plasmin inhib-
itor to fibrin molecules. Although congenital FXIII deficiency is a very rare bleed-
ing disorder, there is growing evidence that acquired FXIII deficiency can also be
frequently observed in perioperative settings in the pediatric age group (Korte 2006;
Haas et al. 2012a). More recent data point towards the importance of FXIII in clot
stabilization during major surgery and consequent blood loss (Gerlach et al. 2002;
Korte et al. 2009; Korte 2010). However, improvement of clot firmness and the
concomitant decreased bleeding tendency following substitution of FXIII in pediat-
ric surgery is currently based on clinical observation, not on evidence based data.

16.3.3.1.5 Low Platelet Count: Diagnostic and Therapy

Platelet transfusion should be considered if platelet counts fall to levels between
50,000–100,000/µl during major surgery with the presence of severe bleeding. To
distinguish a platelet-based weakening of clots from a deficiency in fibrinogen and/
or FXIII, results of EXTEM MCF and FIBTEM MCF were gathered and analyzed.
An MCF <40 mm in the EXTEM test, in combination with a normal FIBTEM MCF,
will be indicative of a low platelet count. Transfusion of 10–20 ml/kg of apheresis
platelet concentrate (to a maximum of 1 Unit) should raise the platelet count by
50,000/µl (Fig. 16.2).

mm mm

60 60
40 40
20 20

20 20
40 40
60 60

10 20 30 40 10 20 30

Fig. 16.2 ROTEM® trace of low platelet count. INTEM MCF decreased (40 mm); FIBTEM MCF
normal (10 mm)
292 T. Haas

16.3.3.1.6 Low Platelet Count: Rationale

Recommendations for a safe lower platelet count threshold vary significantly in cur-
rent literature. However, a significant decrease in platelet count seems to be a rather
late phenomenon. In a retrospective analysis of 150 children who had undergone
craniofacial surgery only 2 showed a platelet count ≤50,000/µl (Stricker et al. 2011).
Note that the transfusion of platelet concentrate carries the highest risk of side-effects
of all allogeneic blood products and should therefore be performed with caution.

16.3.3.2 Inadequate Thrombin Generation

16.3.3.2.1 Diagnostic and Therapy
Inadequate thrombin generation due to a deficiency of coagulation factors can be
quite accurately estimated by prolonged clotting time (CT) in both the EXTEM and
the INTEM assay, although no clear cut-off value was defined by now. Additionally,
results from the ROTEM® HEPTEM assay may more usefully distinguish the
impact of heparin, compared to the results of an INTEM test, if heparin was used
during the procedure. It should be noticed that arbitrarily defined threshold for
aPTT or PT prolonged >1.5–1.8 times are still used in the literature although no
evidence based data exists to justify these values in this setting. Transfusion of FFP
at a dose of about 20 ml/kg was routinely used if any signs of impaired hemostasis
were observed, however, evidence based data to support its general use are weak.
Administration of PCC (about 20 IU/kg) might offer an alternative approach,
although no high quality data from pediatric trials are available (Fig. 16.3).

16.3.3.2.2 Rationale
Adequate thrombin generation is inevitably needed to induce the building of a sta-
ble clot. Notably, a perioperative decrease in thrombin generation, to levels that are
unlikely to initiate clot building, is typically found late on in severe bleeding, even
in neonates with lower vitamin K dependent coagulation factor levels. Unfortunately,
neither aPTT nor PT correlates with clinically relevant coagulopathies or bleeding
conditions (Johansson et al. 2010). Little evidence supports the use of standard
coagulation tests for the guidance of perioperative coagulation therapy (Spahn et al.
2013). As viscoelastic tests are not used everywhere, empirical thresholds still exist
to serve as rough estimates of disturbed hemostasis. In contrast, the prolonged coag-
ulation times of thromboelastometry, in conjunction with increased bleeding ten-
dency, might be interpreted as a relevant deficiency in coagulation factors and can

Fig. 16.3 ROTEM® trace of

inadequate thrombin building
16 Perioperative Hemostasis in Pediatric Surgery 293

be treated with either an administration of PCC or a transfusion of FFP (Schochl et

al. 2009, 2010). The accepted indication for administering PCC is reversal of the
effects of vitamin K antagonists, but also for prophylaxis and treatment of factors of
the prothrombin complex. Although numerous publications have shown the effec-
tive use of PCC in the latter indication, no evidence for its safe use in children exists
to date. However, in severe bleeding episodes, where FFP is unavailable as a source
of coagulation factors, or where there is a risk of hypervolemia due to large amounts
of FFP, using PCC might offer a useful approach.

16.3.3.3 Hyperfibrinolysis
Besides the recommendation to use antifibrinolytic agents as prophylactic treat-
ment, there is no evidence based data published that hyperfibrinolysis is a common
problem during major surgery in children. However, due to the fact that hyperfibri-
nolysis is significantly associated with higher morbidity and mortality (Schochl et
al. 2009), and in light of current recommendations for adults, it seems adequate to
treat signs of hyperfibrinolysis (ROTEM® maximum lysis >15 % and maintenance
of MCF using the APTEM test) in children with 10–20 mg/kg tranexamic acid, if
relevant bleeding occurs (Fig. 16.4).

16.3.3.4 Bleeding Without Abnormal ROTEM® Results

Anesthesiologists can be challenged by intraoperative diffuse bleeding which nei-
ther the results from standard laboratory tests nor ROTEM® can explain. The usual
reasons are the presence of congenital or acquired von Willebrand disease, or plate-
let disorders. In both cases, a timely, reliable diagnosis can be hard to achieve. First,
the patient’s bleeding anamnesis should be checked, as should any possible hypo-
thermic, acidotic, or hypocalcemic condition, and then surgical bleeding should be
ruled out. Thereafter, a clear work-up procedure, preferably involving a hematolo-
gist or a physician specialized in pediatric hemostasis, should be put in place. For
severe cases, an empirical administration of tranexamic acid (bolus of up to 20 mg/
kg over 15 min) is reasonable. Depending on the effectiveness of the antifibrinolytic
therapy, a supplementary desmopressin infusion of 0.3 µg/kg over 15–30 min can be
administered if a mild von Willebrand syndrome or impaired platelet function is
suspected. It is important to keep in mind that the highest levels FVIII and von

mm

60
40
20

20
40
60
Fig. 16.4 ROTEM® trace of
hyperfibrinolysis. Moderate
lysis. Severe lysis 10 20 30 40 50 min
294 T. Haas

Willebrand factor (vWF) released from their storage sites within endothelial cells
occur 30–60 min after desmopressin administration. If bleeding persists, adminis-
tration of either vWF/FVIII concentrate (50 IU vWF:c/kg) or a platelet transfusion
(20 ml/kg in children <15 kg; 1 apheresis unit platelets for children >15 kg) may be
initiated, depending on the assumed underlying coagulation disorder.

16.3.3.5 Rescue Therapy

Final rescue therapy encompasses transfusion of at least FFP 20 ml/kg and/or
administration of recombinant activated factor VII 90 µg/kg (rFVIIa). Final rescue
therapy should only be considered after sufficient and timely treatment with stan-
dard therapy (as previously mentioned) has failed.
The licensed indications for rFVIIa are treatment of patients with hemophilia A
or B with inhibitors, and patients with congenital FVII deficiency. In Europe, addi-
tional approval was granted for treatment of Glanzmann’s thrombasthenia. Off-
label treatment using rFVIIa to stop severe bleeding in children has been published
concerning neurosurgical procedures (Heisel et al. 2004; Uhrig et al. 2007) and
cardiac surgery (Ekert et al. 2006), but there is insufficient data to prove it is effec-
tive in off-label indications. It has been hypothesized that administration of rFVIIa
for treatment of severe bleeding may only be efficacious if critical amounts of
fibrinogen and platelets have been established or if extremely high doses of rFVIIa
were administered (Spahn et al. 2013). Care should be taken to avoid excessive
treatment with rFVIIa and PCC, as both substances may increase thromboembolic
risk considerably. For this reason, rFVIIa is no longer recommended outside its
licensed indications (Simpson et al. 2012).
This chapter reviewed acquired changes to hemostasis that may occur during
major pediatric surgery. It also gave clinically useful trigger levels for ROTEM® as
well as thresholds for standard laboratory tests for initiating structured and timely
coagulation therapy. Further studies are urgently needed to elucidate optimal and
safe thresholds for transfusion/coagulation management. As a general rule, treat-
ment of laboratory findings without clinically relevant bleeding should be avoided,
or considered very carefully, only if there is a high risk of bleeding.

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Perioperative Hemostasis in Obstetrics
17
Albrice Levrat, Christian Kern, and Cyril Huissoud

17.1 Introduction

Coagulation in pregnant women undergoes profound changes that lead to a

hypercoagulable state, thus raising the risk of thrombosis (Cerneca et al. 1997;
Holmes and Wallace 2005; Uchikova and Ledjev 2005). This increased coagulabil-
ity is the body’s means of reaching its primary objective—reducing bleeding during
delivery. Postpartum hemorrhage (PPH) represents a major birth complication, with
an overall incidence that has been shown to be close to 5 % (Dupont et al. 2009).
Severe forms of PPH occur in nearly 1 % of births (Dupont et al. 2011), and they
remain the primary cause of maternal mortality during pregnancy (Bouvier-Colle
et al. 2004). PPH is often purely obstetric in origin, but whatever the precise etiology,
severe PPH is frequently aggravated by coagulation disorders, which can worsen
bleeding and even be life threatening. In rare cases, coagulopathies themselves may
constitute the principal cause of PPH, often resulting in fatal hemorrhages.
In France and in many countries, there is a strong consensus around the use of
guidelines. These advocate early detection of PPH and speedy obstetrical manage-
ment as the crucial factors for a good prognosis. Conversely, there is no national or
international consensus on the diagnosis and treatment of obstetric coagulopathies.
This situation means that there is a great diversity of practice. The 2009–2011

A. Levrat
Department of Critical Care, Annecy Regional Hospital, Annecy, France
C. Kern
Department of Anesthesia, University Hospital Vaud CHUV, Lausanne, Switzerland
C. Huissoud (*)
Department of Obstetrics and Gynecology, Croix Rousse University Hospital,
Hospices Civils de Lyon, Lyon, France
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 299

DOI 10.1007/978-3-642-55004-1_17, © Springer-Verlag Berlin Heidelberg 2015
300 A. Levrat et al.

guidelines of the United Kingdom’s Royal College of Obstetricians and

Gynaecologists underlined the importance of coagulopathy management and rec-
ommended the involvement of a hematologist (RCOG 2011). In the absence of
appropriate studies in obstetrics and due to the specificities of pregnant women,
including pregnancy-associated changes in coagulation, treatment is primarily
based on data from elective surgery or the management of polytrauma victims.
In cases of acute hemorrhage, any secondary coagulopathy will be governed by
a lower fibrinogen level—the central factor in coagulation—at the interface of the
intrinsic and extrinsic coagulation pathways with the fibrinolysis pathways. In
recent decades, the role of fibrinogen in clinical practice has probably been under-
estimated. Clinical and experimental data are virtually unanimous in suggesting that
the target fibrinogen levels used for indicating the transfusion of procoagulant blood
derivatives (fibrinogen, fresh frozen plasma, cryoprecipitates, etc.) are usually too
low (Rossaint et al. 2010). The data which lead to these conclusions were drawn
almost exclusively from non-obstetrical hemorrhages: they were therefore not
directly transferable to pregnant women, and no expert guidelines currently exist to
propose a transfusion algorithm which takes into account the changes in coagula-
tion associated with pregnancy.

17.2 Specificities of Hemorrhage Linked

to Placental Expulsion

17.2.1 Hemorrhages During Placental Expulsion

PPH is defined as blood loss >500 mL within 24 h of vaginal delivery (Subtil et al.
2004). Apart from certain exceptional cases, the occurrence of bleeding is unpre-
dictable. There are multiple hemorrhage mechanisms (e.g., wounds to the birth
canal, post-cesarean hemoperitoneum), and not all of them correspond to placental
expulsion pathologies. Primary uterine atony is the most frequent cause of PPH,
while uterine inertia may be secondary and can complicate any type of PPH.
PPH can be aggravated by uncontrollable uterine bleeding, caused by two
main mechanisms: tissue hypoxia associated with acute anemia or reduced circu-
lation or the occurrence of a coagulopathy leading to abnormal bleeding of the
placental bed.

17.2.1.1 Normal Placental Expulsion

Placental expulsion—the third and final stage of labor—can be defined as the set of
mechanisms leading to the placenta and membranes coming out of the birth canal.
Placental expulsion systematically involves a certain amount of blood loss, which
can vary from a few tens of mL to several liters. Hemorrhage will usually occur in
the first 2 h following birth.
Natural placental expulsion is induced by spontaneous uterine contractions. If this
has not taken place 30 to 60 min of birth, there is an increased risk of hemorrhage
(Tessier and Pierre 2004), and it is recommended that the expulsion should be
17 Perioperative Hemostasis in Obstetrics 301

actively assisted via manual removal of the placenta from the uterus. Placental expul-
sion is systematically followed by a uterine examination, mainly in order to check
that the uterine cavity is empty.
Four phases can be distinguished in a normal placental expulsion:
• Phase one: uterine contraction immediately after the fetus is pushed out. Because
the uterus is less distended, it undergoes a simple phenomenon of passive elastic
retraction. This phase is usually followed by a few minutes of rest during which
the contractions are less intense.
• Phase two: characterized by renewed, more intense uterine contractions. These
contractions will lead to a reduction of the placental insertion site and will put a
strain on the chorionic villi in the compact layer of the basal plate. This creates a
gap between the compact outer layer and the spongy intermediate layer of the
decidua, and the lesion of these uteroplacental blood vessels leads to the forma-
tion of a hematoma. The hematoma widens the gap and completes the detach-
ment of the placenta.
• Phase three: processus of hemostasis. This crucial phase is carried out by:
• The formation of clots in the affected uteroplacental blood vessels. Hemostasis
is set off by an abundant liberation of tissue factor as the gap between the layers
grows. It is reinforced by the modifications to coagulation which develop during
pregnancy.
• Uterine contractions that will seal off the open blood vessels embedded in the
uterine wall.
• Phase four: the migration of the freed placenta down the birth canal and its expulsion
from the vagina.
Relaxation of the uterus, or an intrauterine retention of placental tissue, may
lead to the development of a hemorrhage. It is imperative to carry out a uterine
examination and to keep the patient under strict observation.
In case of a cesarean section, placental expulsion is actively managed or it is manu-
ally extracted; uterine examination is systematic. Cesarean birth is associated with an
increased risk of hemorrhage: intrinsically (sectioning of veins during hysterotomy,
hemoperitoneum, and hematoma), due to its causes (e.g., placenta previa, HELLP
syndrome), and due to more frequent uterine atony.

17.2.1.2 Principal Causes of PPH

The causes of PPH are numerous, and in the majority of cases, they are of obstetri-
cal origin. It is rare for primary coagulation disorders to be the principal etiology
of PPH.
Uterine atony is the leading cause of PPH and several conditions will readily
increase its likelihood (e.g., long working hours, uterine distention, and uterine
fibroids). Secondary atony may also occur after cases of severe PPH. In such cases,
it maintains bleeding and can lead to a worsening of PPH. A retained placenta
(e.g., membranes, cotyledon of full placenta retention) can also lead to hemorrhage.
Surgical causes of PPH are frequent: hemorrhagic hysterotomy, wounds to the birth
canal (e.g., vaginal tearing, uterine rupture), etc. Uterine inversions are a classic,
although now rare, cause of PPH.
302 A. Levrat et al.

An abnormal position of the placenta can be a source of massive PPH. This is

notably the case with placenta previa and placenta accreta for which antenatal iden-
tification is vital so as to prepare birth and delivery in the best possible conditions.

17.2.2 Coagulopathies in PPH

Hemostasis of the uterine placental bed plays an important role in reducing the risks
of hemorrhage. The hemostatic system enters into action as soon as the placenta
detaches itself, allowing the formation of clots in the blood vessels. The modifications
in coagulation activity linked to pregnancy are designed to increase the effectiveness
of hemostasis.

17.2.3 Modifications to Coagulation During Pregnancy

Fibrinogen is the blood factor which undergoes the greatest variations in concentra-
tion during pregnancy, but coagulation modifications are by no means limited to
fibrinogen. Fibrin formation depends directly on the capacity to generate thrombin.
Understanding all these modifications is therefore fundamental to understanding its
impact on the blood clot.

17.2.3.1 Evolution of Fibrinogen Levels

The level of fibrinogen increases progressively throughout pregnancy. Personal data
collected by this chapter’s authors on 4,022 women in their third trimester showed
that the 5th and 95th percentiles were 3.5 g/L (95 % CI [3.4–3.5]) and 6.4 g/L (95 %
CI [6.3–6.5]), respectively. This increase in the level of fibrinogen is accompanied by
an increase in the firmness of the clot as measured by thromboelastometry. Clot for-
mation is firmer towards the end of pregnancy, which certainly helps to improve
hemostasis of the placental bed at birth. The increase in fibrinogen levels during preg-
nancy can fulfill two objectives: first to improve the firmness and hemostatic effec-
tiveness of clotting and second to constitute rapidly available reserves in case of PPH.

17.2.3.2 Changes in the Different Pathways of Hemostasis

• Primary hemostasis is subject to major upheavals. Levels of von Willebrand fac-
tor (vWF) increase considerably during pregnancy (Clark et al. 1998; Wickstrom
et al. 2004). The contribution of platelets to hemostasis is warranted despite the
reduction in platelet count that often occurs in the third trimester: firstly because
the reduction is small and the count rarely goes below 100,000/mm3 and sec-
ondly because there may be increased platelet adhesion linked to over-activation.
Data related to the increased activation of platelets during normal pregnancies are
the subject of some controversy, however (Nicolini et al. 1994; Star et al. 1997).
• The coagulation stage is subject to many changes. Concentrations of almost all the
coagulation factors either increase or remain stable. The only factor which shows
a significant reduction throughout pregnancy is factor XI (Hellgren and Blomback
17 Perioperative Hemostasis in Obstetrics 303

1981), which plays an important role in the generation of thrombin. The reduction
of this factor occurs in order to counterbalance increases in the other factors
(Holmes and Wallace 2005). Tissue factor plays a key role in triggering coagula-
tion in vivo. The absence of an increase in soluble tissue factor (Bellart et al.
1998b), the reduction in monocyte tissue factor (Holmes et al. 2002), and the
increase in tissue factor pathway inhibitor (TFPI) (Sandset et al. 1989) may con-
tribute to limiting the risks of activating coagulation during pregnancy.
• The factors inhibiting coagulation pathways are also affected by pregnancy.
The level of antithrombin remains stable (Hellgren and Blomback 1981; Stirling
et al. 1984) or increases slightly (Dargaud et al. 2010). The level of protein C
hardly changes or also increases slightly, perhaps due to the influence of increased
levels of thrombomodulin; concentrations of its inhibitor do increase (Hellgren
2003). The levels of the free form of protein S and the total level of protein S both
diminish (Clark et al. 1998; Kjellberg et al. 1999). Holmes and Wallace sug-
gested that these modifications were aimed at a reducing coagulation inhibition
(Holmes and Wallace 2005).
• The fibrinolytic system is also subject to changes. Overall fibrinolytic activity is
reduced despite increases in plasminogen and its activators, tissue plasminogen
activator (tPA) and urokinase (Nakashima et al. 1996). This is because of parallel
increases of plasminogen activator inhibitor 1 (PAI-1) and especially of plas-
minogen activator inhibitor 2 (PAI-2) secreted by the placenta. The level of PAI-
2, which is very low outside of pregnancy, rises considerably and may lead to
strong inhibition of the conversion of plasminogen to plasmin (Nakashima et al.
1996; Bellart et al. 1997). However, the concentration of thrombin-activatable
fibrinolysis inhibitor (TAFI) is not affected by pregnancy (Chetaille et al. 2000),
and the level of α2-antiplasmin remains stable or increases slightly (Hellgren and
Blomback 1981).
Pregnancy has little effect on standard plasmatic tests such as prothrombin time
(PT, or Quick’s time) or activated coagulation time (ACT), and they are poor at
detecting hypercoagulable states (Holmes and Wallace 2005; Huissoud et al. 2009).
During pregnancy, there is an increase in activation markers for coagulation,
such as the thrombin-antithrombin complex (TAT) and fragments Fi and F2 released
by the degradation of prothrombin (Clark et al. 1998; Holmes and Wallace 2005;
Uchikova and Ledjev 2005). Dargaud et al. (2010) suggested that the increase in F1
and F2 is linked to the significant increase of FVII. Likewise, during pregnancy,
there is an increase in the levels of fibrinopeptide A (which is a product of the con-
version of fibrinogen to fibrin) and of d-dimers (Bellart et al. 1998a, b; Uchikova
and Ledjev 2005; Dargaud et al. 2010). The best way to evaluate coagulability is to
calculate the capacity to generate thrombin or the endogenous thrombin potential
(ETP). Recent work by Dargaud et al. demonstrated that ETP levels increased from
the first to the third trimester (Dargaud et al. 2010). These results support data from
thromboelastometry which show an increase in the α angle and a reduction in clot
formation time (CFT) as gestation progresses. All these results reflect an increase in
the “capacity to coagulate” which occurs from the first through to the third trimester
(Huissoud et al. 2009; Dargaud et al. 2010).
304 A. Levrat et al.

The third trimester of pregnancy is thus characterized by:

• Increased reserves of coagulation factors and of fibrinogen in particular
• Increased capacity for coagulation which reduces clotting time
• A clot whose firmness is maximized by strong fibrinogen concentrations
All these changes work together to promote better conditions for hemostasis at birth.
Above all, successful management of PPH from its earliest phase requires treat-
ment of the bleeding and thus its direct causes. The appropriate obstetric measures
should be taken promptly at each phase in order to stop hemorrhage rapidly. Obstetric
treatment follows several essential steps: verification that the uterus is empty and that
the birth canal is undamaged and a rapid initiation of uterotonic treatment using oxy-
tocin and prostaglandins. If bleeding persists, a specific uterine balloon tamponade
should be used. If this is not available or fails, then a uterine artery embolization pro-
cedure, or a surgical intervention, will become essential. Surgery is primarily based on
techniques involving vascular ligatures or uterine compression. It is possible to com-
bine both of these methods by using a total uterine ligation note: the total uterine liga-
tion is the name of the technique that simultaneously combines multiple arterial
ligations and compression of the uterus; this has the notable advantage of causing the
least damage to the uterine cavity (Huissoud et al. 2012). Should all these stabilization
techniques fail, then a hemostatic hysterectomy may become necessary.
In most cases, disruptions of hemostasis at the beginning of PPH are either non-
existent or moderate. These disruptions often develop progressively and generally
follow the same chronological sequence. Once coagulation problems have mani-
fested themselves, they can prolong PPH or even worsen bleeding through such
different mechanisms as:
• A worsening of the hemorrhage at its initial site
• A secondary hemorrhage following an initial successful hemostasis of the placental
site (e.g., an overlooked wound in the birth canal)
• Reactions such as tissue hypoxia that can promote uterine atony
• A worsening of the coagulopathy itself via a self-perpetuating process linked to
disseminated intravascular coagulopathies or the consumption of coagulation
factors through bleeding
• The hemodilution frequently induced by fluid administration of non-blood trans-
fusion products
• A worsening of maternal hemodynamics
Inversely, there are rare instances where primary hemostatic problems are the
cause of PPH, such as:
• An obstetric pathology (e.g., placental abruption, an amniotic fluid embolism,
intrauterine fetal demise, HELLP syndrome, acute fatty liver of pregnancy, and
even more rarely intrahepatic cholestasis of pregnancy)
• A quantitative or functional congenital hemostatic disorder, some of which are
actually improved by pregnancy
• A treatment with anticoagulant or antiplatelet drugs
Regardless of the circumstances, the existence of a coagulopathy, whether
primary or secondary, constitutes an aggravating factor for the mother’s functional
prognosis and even her prognosis for survival. The onset of a coagulopathy is
undoubtedly a critical point in the development and management of PPH.
17 Perioperative Hemostasis in Obstetrics 305

17.3 Hemostatic Management of PPH

PPH is a true race against time. Gaining hemostatic control of macroscopic bleeding
remains an absolute priority, whether this must be done using surgery or via embo-
lization using interventional radiology.
At the same time, resuscitation management must be aggressive: the early use of
hemostatic products associated with constant monitoring of coagulation efficacy is
mandatory. As with any serious situation, the existence of written protocols is essen-
tial. Adequate management of these patients will require nonstop collaboration
between specialist obstetricians, anesthetists, and radiologists.

17.3.1 General Management

• Monitoring. Early cardiac monitoring of vital signs is essential. Changes in arte-

rial blood pressure, heart rate, and capillary refill are useful for the diagnosis of
hypovolemia, but are not correlated to its intensity; their predictive impact is
often too late, especially if blood loss is superior to 30 %. Therefore, an ensuing
diagnosis of hypotension is a serious sign. Before clinical evidence of poor toler-
ance, it is essential to quantify a patient’s blood loss using a specialized gradu-
ated collection bag and, furthermore, to ensure continuous monitoring of her
hemoglobin level using a micromethod. The time factor is a fundamental part of
the prognosis; early use of today’s widespread alert scores (such as Modified
Obstetric Early Warning Scoring, MOEWS) by maternity ward personnel in the
period following birth aids the early detection of any modifications to patient’s
vital signs.
• Therapeutic measures linked to transfusion.
• The first treatment of hypovolemia must be symptomatic and initially based on
the use of crystalloid volume expanders, while awaiting blood-based products.
Hydroxyethyl starches have their own side effects on hemostasis and on fibrino-
gen in particular; thus, it is important to limit their use. Maintaining sufficient
perfusion and tissue oxygenation is essential in order to avoid progression
towards organ dysfunction; lactic acid levels have been shown useful in monitor-
ing the adequacy of resuscitation in traumatology; rising lactic acid levels are
closely correlated to the risk of onset of a coagulopathy.
Fighting acidosis is essential: this should be done by optimizing blood volume,
if necessary by using alkaline solutions when blood pH values drop below 7.20, so
as to best preserve coagulation factor functionalities.
• Monitoring hypercalcemia, by measuring free (unbound) ionized calcium,
should be carried out as soon as a transfusion procedure administering calcium
intravenously is started (1 g for every 4–6 units of packed red blood cells, pRBC);
maintaining normal levels of calcium is indispensable for optimizing patients’
coagulation.
• Finally, continuous monitoring of body temperature must be ensured along with
other vital signs. There is a variety of means of fighting hypothermia such as
thermal blankets and above all by warming blood products before administration.
306 A. Levrat et al.

In all cases, the objective must be to keep body temperature above 34 °C so as to

maintain sufficient platelet aggregation and coagulation factor activity.

17.3.2 Transfusion Strategy

Stopping obstetrical hemorrhage remains difficult; it requires the development of

clear procedures within hospital maternity units. These procedures must ensure
that blood products and coagulation factors are rapidly available as any transfusion
strategy must begin early.
Correction of anemia is paramount in order to avoid developments towards organ
dysfunction when hemorrhaging is severe.
The target level of hemoglobin should therefore be above 8 g/L. This level not
only enables a better transport of oxygen but also improves the hemostatic process.
The rheological role of red blood cells themselves favors platelet adhesion at the site
of the endothelial injury, and via their surface receptors, these red blood cells also
participate in setting off the initiation phase of coagulation.
Finally, anemia’s deleterious role in the onset of myocardial ischemia in severe
forms of PPH has been demonstrated (34); its role can be even more damaging in
the presence of strong doses of prostaglandins.
Should the clinical situation demand it (extremely high blood loss), then a perfu-
sion of fresh frozen plasma (FFP) can be initiated before the results of the hemo-
static tests are available; in cases with lower bleeding kinetics, perfusion of FFP
should be carried out using guidance from the results from standard coagulation
tests or thromboelastometry.
Thus, in situations involving massive transfusion, the strategy proposed here rests
essentially on data obtained from non-obstetric studies. These have shown that mor-
bidity and mortality are significantly reduced by initiating transfusion early, with a
fixed rate of FFP to pRBC; however, these arguments are based mainly on biased
retrospective studies. Perfusion of significant quantities of plasma increases the risks
inherent to transfusion itself. The ideal FFP/pRBC ratio remains unknown, but results
currently available in the literature, notably Murad et al.’s meta-analysis, show
that transfusions of FFP, in ratios about one-third, are associated with a significant
reduction in mortality (35).
FFP ratios are increased when the objective is to correct the coagulopathy by
increasing the intake of coagulation factors, notably fibrinogen: each unit of FFP
contains around 400 mg of fibrinogen. Using plasma also enables an increase in
blood volume when oncotic pressure is high, thus reducing hemodilution. However,
the use of high ratios of FFP in a massive transfusion protocol should be reserved
for patients showing massive bleeding, which only represents a minority of situations.
Using such high ratios on patients presenting only minor hemorrhage could, in fact,
lead to an increase in morbidity- and mortality-related complications.
Prothrombin complex concentrates (PCC) can be a good alternative in situations
involving obstetric hemorrhage for a number of reasons: they provide easily pre-
pared and administered coagulation factors with immediate availability and few
17 Perioperative Hemostasis in Obstetrics 307

side effects. PCC therefore seem to be a potential solution for the management of
such hemorrhages despite the fact that there are currently no specific guidelines.
Several retrospective studies have emphasized the value of PCC during periopera-
tive bleeding, especially in combination with the administration of fibrinogen. The
advantages of a strategy combining the targeted transfusion of coagulation factors
with thromboelastographic monitoring seem to be an interesting alternative to the
conventional transfusion strategies which are still often quite empirical. However,
the thromboembolic risks linked to using PCC have yet to be properly evaluated:
vigilance is recommended when using these products during PPH.
As with severe trauma, platelet levels should be maintained at over 100,000/mm3
during active bleeding: Simon et al.’s retrospective analysis identified a lower
threshold to be a risk factor independent of PPH. Thus, the more the platelet level
decreases, the greater the number of pRBC that should be administered.
The administration of fibrinogen is recommended if the perfusion of FFP is
unable to maintain fibrinogen levels above 2 g/L. Indeed, in the study by Charbit
et al., fibrinogen concentration was the only independent parameter to be associated
with PPH developing a severe course (a fibrinogen level of less than 2 g/L gave a
100 % positive predictive value of serious bleeding).
In addition to fibrinogen’s role in clot formation, it has the other advantages of
only requiring a low infusion volume and very little preparation time. Thus, fibrino-
gen use allows a reduction of transfusion volume requirements during massive bleed-
ing. These studies also underlined the importance of regularly measuring fibrinogen
levels during PPH, while keeping in mind that normal fibrinogen levels during late
pregnancy are around 4 g/L.
United Kingdom recommendations emphasize that a level of at least 1.5 g/L is
needed to improve hemostasis.
Thromboelastometry allows for close monitoring of fibrinogen levels in plasma:
in patients suffering PPH, this level is highly correlated to the amplitude of the fibrin
clot measured after 5 min, using rotational thromboelastometry (ROTEM®). When
using an algorithm with appropriate transfusion thresholds, ROTEM® can thus help
save on transfusion requirements, as in cardiac surgery. A FIBTEM® or TEG ampli-
tude measured below 12 mm (about 2 g/L fibrinogen) is a sign that justifies early
administration of fibrinogen. Finally, monitoring fibrinogen levels using ROTEM’s
FIBTEM® test highlights the potential effects that fluids can have on coagulopathy:
in vitro clot firmness decreases significantly after hemodilution using colloids rather
than crystalloids.
Several case studies, case series, and registry studies have been published on the
use of recombinant activated factor VII (rFVIIa). Results suggest that rFVIIa provides
a reduction in transfusion requirements and facilitates surgical hemostasis in 60–80 %
of obstetric cases. The dose is variable: 90–120 μg/kg. rFVIIa can be used after the
failure of other medical and surgical treatments but also prior to hysterectomy. In order
to optimize rFVIIa’s efficacy, the patient’s blood should have a pH >7.20, a tempera-
ture >34 °C, a fibrinogen level >1 g/L, and platelets above 50,000/mm3.
Ferrer et al.’s meta-analysis showed that tranexamic acid reduces obstetric bleed-
ing. Since then, a randomized multicenter study evaluating high doses of tranexamic
308 A. Levrat et al.

acid for use in PPH (4 g in the first hour, then 1 g/h for 6 h) versus placebo showed
significant reductions in blood loss and transfusion requirements in the group
receiving tranexamic acid. Side effects (nausea, vomiting, or problems of vision)
are more common however, and appear to be linked to the high doses; an interna-
tional randomized trial (WOMAN Trial) is underway using lower doses. There has
been a great deal of recent interest in antifibrinolytics in the context of traumatic
hemorrhage: they are inexpensive products, reduce blood product use, and do not
appear to increase the risk of thromboembolism. In short, the significant efficacy of
antifibrinolytic agents demonstrates the importance of fibrinolysis in the pathophys-
iology of PPH.
In practice, the evaluation of hyperfibrinolysis using conventional biological
tests (d-dimers, fibrin degradation products, and euglobulin lysis time) is not easily
applicable in emergency situations. On the other hand, thromboelastometry permits
a rapid diagnosis of acute hyperfibrinolysis, such as coagulopathies associated with
catastrophic amniotic fluid embolism.
Overall, optimal management of PPH necessitates:
• The existence of protocols adapted to the institution’s organization of critical
obstetric care and transfusion services, in order to optimize timely coordination
• Bearing in mind the limits of standard hemostasis tests in this type of situation
and acknowledging the increasing preference for using thromboelastometric
techniques to guide the transfusion process
• Several weeks of monitoring for patients who have suffered a severe hemor-
rhagic event (this appears indispensable; indeed, in a series of 317 patients with
severe PPH, 22 % of them, in fact, had a constitutional defect of hemostasis:
hypofibrinogenemia, drops in von Willebrand factor or factor XI)

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Perioperative Hemostasis in Trauma
18
Catherine Heim and Karim Brohi

18.1 Introduction

Injury is a major public health problem: it is the leading cause of death in the first
four decades of life (Krug et al. 2000; Eastridge et al. 2006). Exsanguination
accounts for up to 50 % of trauma deaths in the first 24 h and for up to 80 % in the
operating theater (Association of Anaesthetists of Great et al. 2010). Despite signifi-
cant advances in trauma care, exsanguination remains the leading cause of prevent-
able death (Sauaia et al. 1995; Demetriades et al. 2004; Kauvar and Wade 2005;
Gruen et al. 2006; Kauvar et al. 2006; Cothren et al. 2007). Caring for a severely
injured and bleeding patient is to face a challenge of timely and effective hemor-
rhage control and rapid restoration of physiology.
Coagulopathy is common after trauma and directly related to poor outcome (Brohi
et al. 2003; MacLeod et al. 2003; Maegele et al. 2007). Over the last years, transfusion
strategies for patients with severe trauma-related bleeding have undergone important
changes due to a better understanding of epidemiology, the mechanisms and conse-
quences of bleeding and coagulopathy (Spinella and Holcomb 2009). Impaired hemo-
stasis following trauma was thought to be essentially due to a loss or inhibition of
coagulation proteases, similar as in surgical haemorrhage. In 2003, two large observa-
tional studies found that 1 in 4 trauma patients presents impaired coagulation on hos-
pital arrival, independent of exogenous factors (Brohi et al. 2003; MacLeod et al.
2003). This identification of early coagulopathy has progressed to the recognition of
an endogenous component of trauma-related hemostatic impairment, and the term
“acute traumatic coagulopathy” (ATC) has been adopted (Brohi et al. 2003). ATC is

C. Heim (*)
Department of Anaesthesia, Centre Hospitalier Universitaire Vaudois CHUV,
Lausanne, Switzerland
e-mail: [email protected]
K. Brohi
Trauma Service, Department of Surgery,
Royal London Hospital, London, UK

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 311

DOI 10.1007/978-3-642-55004-1_18, © Springer-Verlag Berlin Heidelberg 2015
312 C. Heim and K. Brohi

characterized by systemic anticoagulation and fibrinolysis. It is secondarily exacer-

bated by dilution, inhibition, and consumption of clotting factors. The combination of
tissue injury and shock is a key factor in the development of ATC.
Coagulopathy on hospital arrival is associated with increased bleeding, higher
morbidity, and death (Brohi et al. 2003; MacLeod et al. 2003; Frith et al. 2010).
Early identification is therefore crucial to rapid, goal-directed interventions and thus
improved outcome (Borgman et al. 2007; Hess et al. 2008). Laboratory-guided
transfusion strategies have been shown to result in delayed correction of ATC and
suboptimal use of blood products (Hess and Hiippala 2005; Gonzalez et al. 2007).
Rapid control of bleeding and early administration of hemostatic blood compo-
nents, restoration of volume status, and limiting amounts of clear fluids have all
been shown to improve outcomes (Hess et al. 2006; Borgman et al. 2007; Holcomb
et al. 2007; Gunter et al. 2008; Maegele et al. 2008; Cotton et al. 2009; Jansen et al.
2009; Duchesne et al. 2010). This strategy has been termed “hemostatic resuscita-
tion” or “damage control resuscitation.” The concept of ATC has revolutionized the
comprehension of trauma-related bleeding and therefore influenced clinical man-
agement. However, the exact underlying pathophysiological mechanisms are not
yet fully understood, and there is no generally accepted algorithm for hemostatic
resuscitation and blood product use. The innate physiological responses to trauma,
and optimal therapeutic strategies for hemostatic resuscitation and organ protection,
are subject to extensive ongoing research (Brohi et al. 2008; Frith et al. 2010).

18.2 Acute Traumatic Coagulopathy, a Component

of Trauma-Induced Coagulopathy

One in four trauma patients presents signs of established coagulopathy on hospital

admission, independently of fluid administration or hypothermia (Brohi et al. 2003;
MacLeod et al. 2003; Maegele et al. 2007). ATC occurs within minutes of the trau-
matic event (Brohi et al. 2003, 2007a, b; Floccard et al. 2012). The presence of ATC
is associated with mortality close to 50 %, higher transfusion requirements, and
significantly increased morbidity in terms of acute lung injury, infections, and mul-
tiple organ failure (Brohi et al. 2003; MacLeod et al. 2003; Maegele et al. 2007).
Lengths of hospital stay are consequently increased too. However, 10 years after its
description, the functional characterization of the causes and effects of ATC is still
not fully understood. Current knowledge suggests an innate physiological response
to tissue injury and cellular hypoperfusion, which together lead to a systematic acti-
vation of anticoagulation and fibrinolysis (Brohi et al. 2008). The simultaneous
presence of severe tissue trauma and shock seem to be necessary for the develop-
ment of ATC; the worst coagulopathy is seen in patients with a high injury severity
score (ISS) and very low base excess (Frith et al. 2010). Endothelial activation and
protein C seem to be key actors in the concept of ATC. Several studies suggest that
tissue injury and hypoperfusion lead to increased expression of thrombomodulin,
resulting in increased activation of protein C (aPC). aPC impairs clotting factors V
and VIII and reduces thrombin generation. Furthermore, aPC has an inhibitory
18 Perioperative Hemostasis in Trauma 313

+ + +
VIIa IXa Xa
Platelet Thrombin Fibrin FDPs
VIII V +
− −
Plasmin
+
−
PAI- tPA
−1
aPC

Thrombin-TM
PC TM TM TM TM Endothelium

Fig. 18.1 The ATC pathway (From Brohi et al. (2007a) with permission)

effect on plasminogen activator inhibitor 1 (PAI-1). The resulting combination of

high levels of tissue plasminogen activator (tPA) and low levels of PAI-1 leads to a
hyperfibrinolytic state with unregulated tPA activity and fibrinolysis (Hrafnkelsdottir
et al. 2001; Brohi et al. 2007a, b, 2008; Frith et al. 2010; Cohen et al. 2012)
(Fig. 18.1).
Hyperfibrinolysis (HF) is a significant component of ATC, presenting as an
excessive, inappropriate process leading to accelerated clot breakdown and enhanced
bleeding (Brohi et al. 2008). The purpose of enhanced fibrinolysis after trauma
might be the body’s attempt to limit clotting to the site of vascular injury (Hess et al.
2008). HF after trauma has been reported in up to 34 % of cases; it correlates posi-
tively with transfusion requirements; and it has a mortality rate of close to 80 %
(Kashuk et al. 2010a, b; Schochl et al. 2010, 2011; Tauber et al. 2011). A large
randomized control trial (RCT) on trauma supports the role of fibrinolysis in trauma-
related coagulopathy, as administration of tranexamic acid (TXA) was associated
with a significant reduction of mortality (CRASH-2 trail Collaborators et al. 2010).
Factors contributing to HF include high ISS, shock, and hypothermia. Some authors
suggest that crystalloids promote HF (Cotton et al. 2012).
Platelet counts are generally preserved early after trauma, but there seems to
exist some degree of traumarelated dysfunction (Brown et al. 2011; Wohlauer et al.
2012). Known factors impairing platelet function, such as hypothermia, acidosis,
consumption and dilution of coagulation factors, and HF, are frequent after trauma.
Activation of platelets and generation of fibrin are mutually dependent processes.
Injury to the endothelium will activate platelets leading to the transformation of
glycoprotein IIb/IIIa into high-affinity receptors for fibrinogen, promoting a solid
plug (Varga-Szabo et al. 2008). Further, the platelet membrane acts as an amplifier
of the hemostatic process and facilitates activation and binding of coagulation fac-
tors (Furie and Furie 2008). Overall, it seems likely that platelets are a bigger con-
tributor to clot strength than fibrin (Chakroun et al. 2006). Correlation between
314 C. Heim and K. Brohi

Fig. 18.2 Recognized

Trauma Shock
mechanisms leading to
trauma-induced coagulopathy
(TIC) (From Davenport and ATC
Khan (2011) with Haemorrhage
permission) Fibrinolysis Inflammation Hypothermia Acidaemia
Genetics Loss, dilution

Trauma-induced
coagulopathy

platelet count and clot integrity, as analyzed by viscoelastic tests, has been demon-
strated. However, studies examining functional characterization of platelets after
trauma are sparse, and the pathophysiological role of platelets in this condition has
yet to be defined (Rugeri et al. 2007; Plotkin et al. 2008).
Trauma-related impairment of hemostasis has been described with multiple terms,
the most frequently used being acute traumatic coagulopathy (ATC), acute coagu-
lopathy of trauma shock (ACoTS), endogenous acute coagulopathy (EAC), and
trauma-induced coagulopathy (TIC). In this chapter, we use ATC as the term describ-
ing the endogenous component of trauma-related coagulopathy, while TIC describes
the concomitant factors worsening coagulopathy further (Frith et al. 2010). While
ATC occurs immediately after the injury, other mediators of TIC develop over time
and in conjunction with measures against shock and resuscitation. TIC is multifacto-
rial and involves all the components of the hemostatic system, notably dysfunctional
platelets and activation of the endothelium (Fig. 18.2).
Six key initiators of TIC have been identified (Hess et al. 2008):
• Tissue trauma
• Shock
• Hemodilution
• Hypothermia
• Acidemia
• Inflammation

18.2.1 Tissue Trauma

Tissue damage activates coagulation via the exposure of subendothelial collagen

and increased expression of tissue factor (TF). This leads to binding of von
Willebrand factor (vWF), platelets, and activated factor VII (Mann 1999), as well as
concomitant generation of large amounts of thrombin and fibrin (Roberts et al.
2006). Further, endothelial injury will also promote HF via a direct release of tPA
and induce clot breakdown (Hrafnkelsdottir et al. 2001). All trauma patients have
tissue injury to some extent. However, according to the type and mechanism of
injury, the tissue damage load, expressed as an ISS, can be variable – crush or blast
18 Perioperative Hemostasis in Trauma 315

injuries destroy more cells than an isolated penetrating injury. As mentioned above,
tissue injury is a prerequisite, but in isolation is not sufficient to have a full picture
of ATC (Frith et al. 2010).

18.2.2 Shock

Shock – next to tissue injury – seems to be the other key driver of ATC. Several
studies have shown a linear relationship between the extent of systemic hypoperfu-
sion, measured by base deficit (BD), and the degree of coagulopathy (Brohi et al.
2007a, b; Niles et al. 2008; Frith et al. 2010; Jansen et al. 2011). Systemic hypoper-
fusion seems to activate protein C via increased generation of the thrombin-
thrombomodulin complex. aPC exerts an anticoagulant effect by irreversibly
deactivating factors Va and VIIIa (Brohi et al. 2007a, b). Further, in shock, fibrino-
lysis is exacerbated through the combined effects of endothelial tPA release and the
shock-mediated inhibition of PAI-1(Brohi et al. 2008). Cellular hypoperfusion and
activation of inflammation are closely related. Hemorrhagic shock and resuscitation
lead to alterations in microcirculation via the release of a multitude of inflammatory
mediators, cytokines, and oxidants. The activation of inflammation and the induc-
tion of apoptotic cell death as a consequence of hypoxic cellular damage and
ischemia-reperfusion phenomena are the presumed causes of secondary organ
injury leading to organ failure and death (Duchesne et al. 2010). At the coagulation
level, cellular hypoxia, thrombin, and various cytokines will together promote endo-
thelial cell activation (ECA) (Faller 1999). ECA will induce a downregulation of
thrombomodulin (TM) and enhance fibrinolysis via increased levels of PAI-1.
Destruction of the endothelial glycocalyx limits activation of antithrombin and
upregulates platelet-activating factor and the expression of TF (Johansson et al.
2011) (Fig. 18.3).

18.2.3 Hemodilution

During fluid resuscitation, the dilution of coagulation factors can be a major con-
tributor to clinical coagulopathy (Armand and Hess 2003; Maegele et al. 2007).
High volumes (>2,000 ml) of crystalloids or colloids during prehospital resuscita-
tion are associated with a worse coagulation profile, an increased need for blood
transfusion, and a higher incidence of organ failure (Wafaisade et al. 2010;
Hubetamann et al. 2011; Hussmann et al. 2011). Further, administration of blood-
products such as packed red blood cells (PRBC), fresh frozen plasma (FFP), and
platelets (PLT) may cause significant dilution due to the anticoagulant properties of
their storage solutions. Coagulopathy is directly proportional to the volume of clear
fluid infused, independent of their type (Haas et al. 2008a, b; Bolliger et al. 2009).
Even in the absence of exogenous resuscitation, endogenous hemodilution occurs as
a physiological response to hypovolemia. The shift of hypocoagulable fluid from
the cellular and interstitial space into plasma will lead to minor dilution of
316 C. Heim and K. Brohi

Fig. 18.3 Tissue trauma and ∗

systemic hypoperfusion a
appear to be the main drivers 2
of ATC. (a) Median 1.9
prothrombin ratios of patients 1.8

Prothrombin ratio
grouped according to injury ∗ ∗
1.7
severity score (ISS) and base ∗
1.6
deficit (BD). (b) Mortality of
patients grouped according to
1.5 ∗ ∗
1.4 ∗
ISS and BD (From Frith et al. ∗
(2010) with permission) 1.3
1.2 >12
1.1 6.1−12
1 0.6−6
<16 ≤0
16−24 Base deficit
25−35
ISS >35 (mmol L−1)
∗
b
∗
70
60 ∗ ∗
Mortality (%)

50
∗ ∗
40
∗ ∗
30
∗ ∗
20 ∗ ∗
∗
>12
10 ∗ 6.1−12
0 0.6−6
<16 ≤0
16−24 Base deficit
25−35
ISS >35 (mmol L−1)

coagulation factors but in insufficient quantities to explain established coagulopathy

(Rizoli et al. 2011; Rourke et al. 2012). Fibrinogen is the first clotting factor to be
reduced but initially remains above substitution thresholds (Martini 2011; Rizoli
et al. 2011; Rourke et al. 2012).

18.2.4 Hypothermia

Trauma patients are prone to hypothermia. This is due to either environmental fac-
tors or administration of cold resuscitation fluids combined with the reduced heat
production of maximally vasoconstricted musculature. Hypothermia has important,
reversible effects on the functionality of coagulation factors, platelet protease activ-
ity, and fibrinolysis (Wolberg et al. 2004; Thorsen et al. 2011). The activity of TF or
FVIIa complex decreases in a linear fashion with reduced body temperature.
Hypothermia reduces platelet adhesion to vWF on endothelial surfaces, limiting the
signal transduction from initial adhesion to activation. Whereas platelet function
18 Perioperative Hemostasis in Trauma 317

starts to be impaired at temperatures below 35 °C, important functional decreases in

protease activity occur only with severe hypothermia (Kermode et al. 1999; Martini
2009). Above 33 °C; however, isolated hypothermia probably has a minimal clinical
impact on hemostasis, and some authors see hypothermia rather as a marker of the
severity of shock and the resulting endogenous coagulopathy (Gruen et al. 2012).

18.2.5 Acidemia

Acidemia in trauma is most often due to hypoperfusion and may be enhanced by

administration of large volumes of ionic chloride as found in normal saline (Hess et al.
2008). In animal models, inducing acidemia by infusing hydrochloric acid led to pro-
longed clotting times, reduced clot strength, and increased degradation of fibrinogen
(Martini and Holcomb 2007). Low pH levels lead to structural changes of platelets
(Djaldetti et al. 1979) and impairment of procoagulant protease functions (Meng et al.
2003). This reduces the activity of coagulation factor complexes, leading to impaired
thrombin generation. Further, acidemia increases degradation of fibrinogen, promot-
ing fibrinolysis (Martini and Holcomb 2007). At pH levels below 7.2, coagulation
factor activity is reduced by 50 % and plasma protease activity is seriously impaired
(Meng et al. 2003; Lier et al. 2008). Correction of acidemia alone, using buffer solu-
tions such as sodium bicarbonate, for instance, has not been proven efficient for nor-
malization of coagulopathy (Martini et al. 2006; Darlington et al. 2011).

18.2.6 Inflammation

Coagulation and inflammation are closely linked (Esmon 2005). The combination
of tissue injury and shock is an important inducer of a systemic inflammatory
response syndrome. Inflammation initiates clotting, decreases the activity of physi-
ological anticoagulatory mechanisms, and impairs the fibrinolytic system (Gruen
et al. 2012). The innate immune system is activated early after traumatic injury
through the release of intracellular debris, exposure of the subendothelium, endo-
thelial activation, and the hypoxic environment of the microcirculation. Further,
resuscitation fluids have been shown to have immunomodulating properties.
Crystalloids and colloids cause neutrophil activation in patients in hemorrhagic
shock (Rhee et al. 1998, 2000), and crystalloids lead to degradation of glycocalyx,
contributing to further activation of inflammation (Van der Linden and Ickx 2006).
Immunomodulatory treatment strategies, limiting the activation of the inflammatory
response, might constitute promising novel approaches in the future.

18.3 Diagnosis of Trauma-Induced Coagulopathy

There is no consensus about the definition and characterization of ATC. Diagnosis

of ATC has so far been based on traditional plasma-based laboratory test results,
such as abnormal aPTT, prothrombin time (PT), and international normalized ratio
318 C. Heim and K. Brohi

(INR) (Brohi et al. 2003). Laboratory-based clotting tests have logistic issues, limit-
ing their utility in acute trauma care, and there is an emerging consensus that such
tests are inappropriate for monitoring coagulopathy and guiding therapy in trauma
hemorrhage (Segal et al. 2005; Yuan et al. 2007; Toulon et al. 2009; Kashuk et al.
2010a, b). The absence of rapid diagnostic tools has been shown to lead to delayed
correction of ATC and suboptimal use of blood products (Hess and Hiippala 2005;
Gonzalez et al. 2007; Davenport et al. 2011). There is renewed interest in viscoelas-
tic hemostatic assays (VHA), such as thromboelastography (TEG®) and rotational
thromboelastometry (ROTEM®). Several studies support the superiority of VHA in
terms of guiding adequate blood product provision in comparison with traditional
plasma-based coagulation tests (Afshari et al. 2011), and the use of TEG/ROTEM
in massively bleeding trauma patients is recommended in current guidelines
(Rossaint et al. 2010). Davenport et al. (2011) identified the typical thromboelasto-
graphic profile of ATC as slow clot formation and persistently reduced clot strength
of around 40 %. This prospective study (the largest to date) on the diagnostic modal-
ities of ATC identified a clot amplitude at 5 min (CA5) ≤35 mm as diagnostic
marker of ATC; it had a greater sensitivity than PT in predicting the need for mas-
sive transfusion. Furthermore, all ROTEM parameters showed a negative predictive
value of close to 100 % for massive transfusion, indicating that a normal ROTEM
trace can be used for timely termination of massive hemorrhage protocols (Davenport
et al. 2011). Based on current knowledge, it would seem reasonable to implement
VHA-based algorithms allowing for a goal-directed resuscitation strategy, although
evidence from clinical trials is still lacking (Dzik et al. 2011).

18.4 Management of Trauma-Induced Coagulopathy:

Damage Control Resuscitation

A massively bleeding patient is a multidisciplinary challenge at every time point through

the chain of resuscitation. Prompt recognition of established or pending hemorrhagic
shock is crucial in order to minimize the time to hemostatic intervention and supportive
care. Effective teamwork and communication are an essential part of this process.
Faced with trauma hemorrhage, the most important goal is to gain rapid control
of the source of bleeding. In the 1990s, “damage control surgery” (DCS) was shown
to improve survival for exsanguinating trauma patients (Duchesne et al. 2010). DCS
advocates a focused effort to only correct life-threatening conditions during the
initial intervention, while deferring definitive repair of less severe injuries to a later
stage (Rotondo et al. 1993; Jaunoo and Harji 2009). In order to support the rapid
restoration of patient homeostasis, it became clear that the focus had to go beyond
the types and timings of operative interventions and that the nonsurgical part of
resuscitation strategy had to follow a similar and supportive concept. Hemostatic
resuscitation (HR), aimed at a carefully weighted and goal-directed restitution of
lost volume and blood components, is crucial for improved outcome (Cotton et al.
2011; Curry et al. 2012). HR completes DCS to build a more comprehensive and
multidisciplinary concept of “damage control resuscitation” (DCR). DCR aims to
18 Perioperative Hemostasis in Trauma 319

rapidly restore physiological conditions, facilitate clotting, improve hypoperfusion,

and restore endothelial integrity. HR relies principally on four pillars:
• Early hemorrhage control (damage control surgery)
• Permissive hypotension
• Limited fluids
• Rapid reversal of coagulopathy
Administration of large volumes of fluid before achieving control of a hemor-
rhage will, independently of the type of fluid, contribute to worsening coagulopathy
(Bolliger et al. 2009). Bleeding will be enhanced through increased perfusion pres-
sure, reversal of autoprotective vasoconstrictory reflexes, dislocation of spontane-
ous clotting, and dilution of coagulation factors (Stern et al. 1993, 1995). The
recognition of these negative effects has led to the doctrine that for trauma patients
in need of DCS, “only fluids that either clots or carry oxygen should be given”
(Dutton 2012).
The concept of permissive hypotension advocates deliberate maintenance of
blood pressure at subnormal values until surgical control of hemorrhage has been
achieved. Systolic blood pressure is thus limited to the minimum necessary to main-
tain the perfusion of vital organs; in animal studies, this lead to reduced blood loss
and improved survival (Bickell et al. 1994; Shoemaker et al. 1996; Burris et al.
1999; Jansen et al. 2009; Li et al. 2011). This concept is adequate only for a limited
time, and systolic blood pressure values need to be adapted to higher values in case
of concomitant traumatic brain injury (Li et al. 2011). Although RCTs showing
improved survival and fewer complications using permissive hypotension are
sparse, the concept of low-volume resuscitation has gained wide acceptance (Bickell
et al. 1994; Shoemaker et al. 1996; Burris et al. 1999; Li et al. 2011; Morrison et al.
2011). The threshold for minimal systolic blood pressure remains controversial.
Concerns about aggravating hypoperfusion through insufficient however perfusion
pressure and enhancing post-injury coagulopathy with further activation of the
innate immune response have not been conclusively addressed yet.
Early therapy with blood components is part of the core strategy for trauma-
induced coagulopathy. Retrospective studies suggest that improved survival involves
a transfusion strategy with a high ratio of FFP to PRBC (Godier et al. 2012). A
high-dose approach has also been recommended for platelet transfusion and fibrino-
gen concentrates (Inaba et al. 2010; Rourke et al. 2012). However, RCTs providing
evidence are still awaited. Preventing hypothermia, correcting acidosis by restoring
adequate tissue perfusion, and avoiding dilution of coagulation factors are still valid
doctrines and compose the core of strategy for avoiding worsening TIC.

18.5 Components of Hemostatic Resuscitation

18.5.1 Packed Red Blood Cells

Tissue oxygenation remains the principle goal of resuscitation. Due to the relationship
between tissue oxygenation, impaired hemostasis, and mortality, the most important
320 C. Heim and K. Brohi

blood component for the prevention and treatment of ATC are packed red blood cells
(Hess et al. 2008; Dzik et al. 2011). Erythrocytes contribute to hemostasis by promot-
ing marginalization of platelets and allowing their interaction with the endothelium
(Valeri et al. 2007). An inverse correlation has been demonstrated between the hema-
tocrit and bleeding time in vitro (Eugster and Reinhart 2005). Furthermore, erythro-
cytes support thrombin generation through the exposure of procoagulant phospholipids
(Peyrou et al. 1999) and activate platelets via liberation of adenosine diphosphate
(ADP) (Joist et al. 1998). Clearly defined targets for hemoglobin or hematocrit during
active hemorrhage are lacking, but the most recent European guidelines recommend a
hemoglobin target of 7–9 g/l (Spahn 2013).

18.5.2 Fresh Frozen Plasma

Transfusion of FFP in massively bleeding trauma patients is an essential part of

most guidelines, even though the clinical efficacy of FFP is unproven (Stanworth
et al. 2004). Nevertheless, most experts agree that FFP is beneficial in cases of
important bleeding and concomitant coagulopathy. Several retrospective analyses
suggest that early administration of FFP in a 1:1 ratio with PRBC might be benefi-
cial (Borgman et al. 2007; Cotton et al. 2008; Gunter et al. 2008; Maegele et al.
2008; Spinella et al. 2008; Zink et al. 2009). This conclusion, however, might be
subject to “survivor bias”: FFP is often administered at a delayed time point; thus
some patients did not survive because they received plasma, but rather they received
plasma because they survived long enough (Snyder et al. 2009).
The optimal ratio of FFP to PRBC remains unclear. Despite the low quality of
evidence, actual data seem to tend to a more liberal use of FFP, indicating that a
higher FFP to PRBC ratio is associated with improved survival (Holcomb et al. 2008;
Snyder et al. 2009; Murad et al. 2010; Johansson et al. 2012). The first RCT on this
topic, the PROPPR trial (http://cetir-tmc.org/research/proppr), is ongoing and will
hopefully bring more insights. Currently, the European guidelines recommend FFP
administration with an initial dose of 10–15 mg/kg followed by goal-directed man-
agement (Spahn 2013).

18.5.3 Platelet Concentrates

Even in severely injured patients, PLT counts on admission are rarely below critical
levels (Murthi et al. 2008; Stansbury et al. 2013). The fall in PLT count seen later in
the resuscitation time course is probably due to dilution. Low PLT count at admis-
sion, however, is strongly related to mortality and a need for PRBC (Brown et al.
2011; Stansbury et al. 2013). High PLT to PRBC transfusion ratios have reportedly
increased survival in massively transfused patients (Inaba et al. 2010; Holcomb
et al. 2011; Johansson et al. 2012). However, evidence is even scarcer than for FFP
ratios. Current recommendations indicate maintaining a PLT count above 100,000/
μl with an initial dose of 4–8 platelet concentrates (Spahn 2013). However, there is
18 Perioperative Hemostasis in Trauma 321

currently no clear evidence to support the use of up-front administration of PLT

concentrates. In trauma patients previously treated with antiplatelet drugs, PLT
transfusion does not reverse their action and no benefit has been demonstrated
(Flower and Smith 2011).

18.5.4 Antifibrinolytic Drugs

Fibrinolytic processes are an essential part of ATC and HF has a mortality rate of
close to 80 % (Brohi et al. 2008; Kashuk et al. 2010a, b; Schochl et al. 2011; Tauber
et al. 2011). Antifibrinolytic agents reduce blood loss in patients (with both normal
and exaggerated fibrinolytic response to surgery) by inhibiting plasminogen activa-
tion and therefore activation of fibrinolysis (Henry et al. 2011). The recent placebo-
controlled randomized CRASH-2 trial including over 20,000 trauma patients has
shown a significant reduction in all-cause mortality of approximately 10 % for
trauma patients receiving TXA versus placebo and to an approximately 30 % reduc-
tion in transfusion requirements. Benefit was maximal when administration was
early – within 3 h of injury (CRASH-2 trail Collaborators et al. 2010). This might
be due to high levels of free tPA detected early after a traumatic event, resulting in
enhanced plasmin generation and therefore increased fibrin degradation products
(Brohi et al. 2007a, b, 2008; Rugeri et al. 2007; Levrat et al. 2008). However, admin-
istration later than 3 h after injury was associated with worsened outcome (CRASH-2
trail Collaborators et al. 2010). The risk for thromboembolic complications appeared
to be relatively low. The use of antifibrinolytic drugs, such as TXA, is therefore
recommended in patients suffering from, or at risk of, hemorrhagic shock
(Association of Anaesthetists of Great et al. 2010).

18.5.5 Fibrinogen

Fibrinogen is an endogenous acute phase protein and an essential substrate for clot
formation. Activated by thrombin, fibrinogen forms insoluble fibrin strands and
functions as a ligand for platelet aggregation. After major trauma, fibrinogen is one
of the first coagulant proteins to reach critically low concentrations, and hypofibrino-
genemia has been associated with poor outcome (Harrigan et al. 1989; Hiippala et al.
1995; Rourke et al. 2012). Administration of crystalloids and colloids leads to dilu-
tion, functional deficiency, and abnormal fibrinogen polymerization. Furthermore,
hypothermia increases the breakdown of fibrinogen as its production is impaired in
acidemia. The use of fibrinogen concentrate results in reduced perioperative bleeding
and transfusion requirements (Rahe-Meyer et al. 2009), improves clot strength in
dilutional coagulopathy (Haas et al. 2008a, b), and shows that higher fibrinogen to
PRBC ratios have been associated with improved survival (Stinger et al. 2008).
Recent data indicate that coagulopathy induced by synthetic colloids may be reversed
by fibrinogen administration (Fenger-Eriksen et al. 2009). Despite the lack of high
quality RCT data supporting the benefit of fibrinogen supplementation, European
322 C. Heim and K. Brohi

guidelines recommend supplementary fibrinogen in trauma hemorrhage in cases of

significant bleeding when VHA show signs of functional fibrinogen deficit and/or a
plasma fibrinogen level of <1.5–2 g/l (Spahn 2013).

18.5.6 Calcium

Hypocalcemia after trauma occurs during resuscitation with citrate-containing blood

products, most importantly with FFP and PLT. Further, hypocalcemia can be attrib-
uted to the binding of calcium to lactate or through colloid-induced hemodilution
(Vivien et al. 2005). Calcium has an important role in clotting, acting as a bridge
between vitamin-K-dependent coagulation factors, phospholipids, and the endothe-
lium. It protects fibrinogen from proteolysis, therefore contributing to the stabiliza-
tion of fibrin polymerization. Low cytosolic calcium also impairs PLT activity (Lier
et al. 2008). Despite the lack of solid evidence, recommendations suggest maintain-
ing levels of ionized calcium above 1.1 mmol/l (Lier et al. 2008; Spahn 2013).

18.5.7 Prothrombin Complex Concentrate

Coagulation factor concentrates allow a more rapid reversal of established coagu-

lopathy than that achieved with plasma alone. Several studies have demonstrated the
successful use of prothrombin complex concentrate (PCC) in trauma-induced coag-
ulopathy, leading to reduction in use of blood products and improved survival
(Honickel et al. 2011; McSwain and Barbeau 2011; Patanwala et al. 2011). However,
PCC does not provide any volume expanding, raising the question of whether it can
be used concomitantly with FFP for restoring volume. To date, there have been no
prospective RCT demonstrating a definite clinical benefit of PCC over FPP.
Therefore, the use of PCC in traumatic hemorrhage is currently off-label, and the
risk of thrombotic complications needs to be considered (Sorensen et al. 2011).

18.5.8 Factor XIII

Factor XIII (FXIII) is fundamental to clot firmness because it binds to platelets via
their GP IIb/IIIa receptor. Furthermore, FXIII increases clot resistance against fibri-
nolysis by cross-linking to fibrin. In combination with functional platelets, it appears
to have inhibitory effects on plasmin-mediated HF (Dirkmann et al. 2012). Trauma
and major hemorrhage are known causes of acquired FXIII deficiency (Egbring
et al. 1996). Its substitution has been shown to improve clot firmness and might
therefore contribute to reduced bleeding (Nielsen et al. 2004). It has also been
shown to have some compensatory effects in settings with low fibrinogen levels
(Theusinger et al. 2010). A clinical combination suggesting the need for substitu-
tion of FXIII might be weak clot strength despite adequate fibrinogen levels. A clear
role for FXIII administration to bleeding trauma patients, however, has yet to be
defined.
18 Perioperative Hemostasis in Trauma 323

18.5.9 Recombinant Activated Factor VII

Supraphysiological doses of recombinant activated factor VII (rFVIIa) induce a throm-

bin burst via the transformation of fibrinogen to fibrin and direct binding to platelets.
In several case reports, administration in trauma-related bleeding has been shown to
reduce PRBC requirements and improve hemostasis (Martinowitz et al. 2001; Dutton
et al. 2004). A large multicenter RCT assessing the efficacy and safety of rFVIIa in
bleeding trauma patients was unable to show any survival benefit but found an increased
incidence of arterial thromboembolic events (Boffard et al. 2005; Hauser et al. 2010).
Although it is currently not an approved indication, the European guidelines for
management of bleeding after trauma recommends considering rFVIIa as a “last-
resort” drug in persistent major bleeding in blunt trauma (Rossaint et al. 2010).
Prerequisites are control of surgical bleeding, restoration of adequate hematocrit,
PLT and fibrinogen levels, as well as correction of acidosis, hypothermia, and
hypocalcemia.

18.6 Resuscitation Strategies: Formula Driven Versus Goal

Directed/Laboratory Driven

Clinical pathways in healthcare tend to improve the quality of the delivered care
(Rotter et al. 2010). Timely provision of blood products to a massively bleeding
patient is a challenge for any institution. The concept of hemostatic resuscitation
calls for the immediate readiness of components so as to enable their delivery in an
empirically agreed ratio on site. The implementation of massive transfusion proto-
cols (MTP) has been shown to facilitate this process (Cotton et al. 2009; Young
et al. 2011). Based on a mathematical model suggesting that a 1:1:1 ratio of PRBC
to FFP to PLT will come close to the composition of whole blood, formula-driven
resuscitation strategies have been advocated as the structural base for MTP (Hess
et al. 2008). Retrospective studies suggesting that early transfusion of FFP at a
fixed, high ratio will improve survival rates support the formula-driven approach
(Borgman et al. 2007; Cotton et al. 2008; Gunter et al. 2008; Maegele et al. 2008;
Spinella et al. 2008; Zink et al. 2009). However, in a study correcting for survivor
bias, no similar reduction in mortality was seen (Snyder et al. 2009). Regarding the
incidence of morbidity, there seems to be a controversy in the literature as to whether
formula-driven care increases or decreases the risk of multiple organ failure and
other complications in the trauma population (Maegele et al. 2008; Cotton et al.
2009). Furthermore, empirical administration of blood products can lead to over-
transfusion and has been shown to result in delayed correction of ATC and subopti-
mal use of blood products (Hess and Hiippala 2005; Gonzalez et al. 2007). Lastly,
identification of patients in need of this formula-based approach may be difficult as
there is no evidence-based strategy allowing for adequate triggers of a MTP. To date,
the vast majority of studies on formula-driven resuscitation focus essentially on
finding the optimal ratio of empirical blood-product use. However, whether the
concept of formula-driven resuscitation improves coagulation parameters and
patient outcomes has not been reliably addressed yet.
324 C. Heim and K. Brohi

In the absence of clear evidence, a 2011 conference on massive transfusion

gave a consensus opinion that neither laboratory testing-based transfusion strate-
gies nor predetermined blood component ratios would provide the optimal hemo-
static support for bleeding trauma patients (Dzik et al. 2011). Emphasis is put on
the importance of individually tailored therapy over rigid, predetermined protocols
for hemostatic resuscitation strategies. In conclusion, a three-strategy manage-
ment approach composed of “up-front hemostatic support, a foundation ratio of
blood components, and a goal-directed adjustment of transfusion therapy” has
been recommended (Box 18.1). Better and faster laboratory testing, rather than
formula-driven transfusion practices, may be the preferred strategy (Callum et al.
2009). Point-of care testing, such as viscoelastic tests, seems to be a promising
option for real-time transfusion decision making (Davenport et al. 2011; Curry
et al. 2012).

Box 18.1
Three-strategy approach to transfusion in trauma patients at risk/with verified
massive hemorrhage (Adapted from Dzik et al. (2011))
1. Early administration of tranexamic acid (1 g over 10 min followed by an
infusion of 1 g over 8 h)
2. If critical bleeding, immediate administration of blood components (RBC
and FFP) in a fixed ratio
3. Adjustments of the fixed ratio of transfusion support based on clinical
course and results of goal-directed blood therapy

Conclusion
Coagulopathy after traumatic injury is incompletely understood and has a poor
prognosis. Early identification and proactive management is crucial for optimal
patient outcome. The concept of hemostatic resuscitation has become a pivotal
part of major trauma management. However, solid evidence for optimal transfu-
sion strategies is lacking. In the massively bleeding patient, a readily available
up-front hemostatic support with a predefined foundation ratio of blood compo-
nents seems adequate as first-line approach. This standardized initial step will
ideally be followed by an individualized goal-directed therapy, guided by the
clinical course and point-of-care testing.
Whichever strategy is chosen – the formula-driven or the individually tailored
approach – the 4 pillars of damage control resuscitation remain the major deter-
minants in achieving the best possible outcome:
• Early hemorrhage control
• Permissive hypotension
• Limited fluids
• Rapid reversal of coagulopathy
18 Perioperative Hemostasis in Trauma 325

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Perioperative Hemostasis
in Neurosurgery 19
Julien Picard, Pierre Bouzat, Gilles Francony,
Jean-François Payen, and Patrick Schoettker

19.1 Particularities of Neurosurgical Patients

Neurosurgeons, intensive care specialists, and anesthesiologists who deal with

neurosurgical management know the crucial factors surrounding coagulation and
hemostasis disorders. However, it is striking to note that most neurosurgery text-
books hardly mention coagulation management. With regard to the particularities
of neurosurgical patients, we will describe the pathophysiological backgrounds of
the specific mechanisms that lead to hemostatic perturbations, the implications
of neurological pathologies and surgical procedures on hemostasis, and the effects
of specific drugs on coagulation.

19.1.1 Specific Mechanisms Leading to Hemostatic Disorders

19.1.1.1 Activation of Coagulation Processes

Various mechanisms launch and accelerate the coagulation process and platelet
activation: endothelial injury, ischemia, and secondary inflammatory reactions all
trigger the release of brain thromboplastins, thrombin, iron, and the degradation
products of lysed red blood cells that will result in hemostatic perturbations.

19.1.1.2 Release of Thromboplastins

Hemostasis is a complex process; tissue factor, or thromboplastin, has a central role
in the initiation of coagulation. Thromboplastins are widely expressed on the

J. Picard (*) • P. Bouzat • G. Francony • J.-F. Payen

Pôle d’Anesthésie-Réanimation, Hôpital Michallon, Grenoble, F-38043, France
e-mail: [email protected]
P. Schoettker
Service d’Anesthésie, Centre Hospitalier Universitaire Vaudois CHUV,
Lausanne CH-1011, Switzerland

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 331

DOI 10.1007/978-3-642-55004-1_19, © Springer-Verlag Berlin Heidelberg 2015
332 J. Picard et al.

surface of normal brain tissue cells, and their thromboplastin content increases after
brain trauma (Pathak et al. 2005; Goh et al. 2005). Thromboplastins can be expressed
on the surface of injured blood vessels in brain lesions. This expression can also
result from inflammatory or tumoral processes. Increased expression of tissue factor
has been reported in astrocytic tumors and is correlated to their degree of malig-
nancy (Guan et al. 2002).
Injured brains and certain tumors in particular have a direct effect on fibrinolysis
(Goh et al. 1997). Tissue plasminogen activator (tPA) is an initiator of fibrinolysis,
and increased levels of tPA are reported in brain tumors. Hyperfibrinolysis is also
seen in trauma-related bleeding. This cascade of mechanisms can result in an exag-
gerated response called disseminated intravascular coagulation (DIC).
Hyperfibrinolysis can sometimes result from factor XIII deficiency, as this factor
will catalyze fibrin cross-linking into stable polymers (Gerlach et al. 2002). Cases
of postoperative bleeding have been reported in such situations (Vrettou et al. 2010),
and some authors recommend screening factor XIII levels before neurosurgery
(Gerlach et al. 2002).

19.1.1.3 Role of Thrombin and Iron

Recent advances in knowledge of the mechanisms underlying intracranial,
hemorrhage-induced brain injuries have focused attention on the role of the thrombin
and iron released by red blood cell lysis. In vitro, high concentrations of thrombin
will cause neuronal and astrocyte death. The infusion of large doses of thrombin into
brain tissue causes inflammatory reactions, with microglia activation, cell infiltration
and proliferation, brain edema, and finally neuronal death (Xi et al. 2006). This early
brain edema is partially due to an increased permeability of the blood-brain barrier
(Lee et al. 1997). Interestingly, these effects seem to be attenuated by the infusion of
nonclotting heparinized blood (Xi et al. 1998). However, thrombin can also have
neuroprotective effects. As an essential component of the coagulation cascade,
thrombin’s first role is to stop bleeding (Mayer et al. 2005). Many studies have shown
a beneficial effect on the brain of low concentrations of thrombin, with reduction of
injury size in models of cerebral ischemia or hemorrhage (Xi et al. 2003).
Various studies suggest that brain edema after intracranial hemorrhage is attrib-
utable to red blood cell lysis (Wu et al. 2006). The importance of the edema appears
to be related to an increased blood-brain barrier permeability resulting from the
toxic effects of the degradation products of lysed red blood cells (Xi et al. 2001).
Red blood cell lysis can result in iron release, and intracerebral iron infusion is
shown to be a direct cause of brain edema or of the promotion of thrombin-induced
brain edema (Huang et al. 2002).

19.1.2 Effects of Brain Injury and Neurosurgical

Pathologies on Hemostasis

Brain injuries and brain tumors, as well as other neurosurgical procedures in general,
can have an impact on overall coagulation, leading to thrombotic or hemorrhagic
disorders (Seifman et al. 2011). This can be explained by an imbalance between
19 Perioperative Hemostasis in Neurosurgery 333

procoagulant and anticoagulant systems, both locally and systemically, and by the
expression of several substances in physiological or pathological cerebral tissues.
These substances include tissue plasminogen activator and tissue factor, the latter
known as the main initiator of coagulation processes in the cell-based model of coag-
ulation activation (Gerlach et al. 2009). Hemorrhagic coagulopathy from cerebral or
systemic causes raises a significant risk of secondary central nervous system injury
by the hemorrhagic progression of lesions. Thrombotic events, however, will only
affect global outcome.

19.1.2.1 Thrombosis
Hypercoagulability can be detected during neurosurgical procedures as soon as the
intraoperative period (Abrahams et al. 2002). Deep venous thrombosis and pulmo-
nary emboli are frequent complications in the neurosurgical setting. Risk factors
include intracranial surgery, age, active malignancy, and hemi/para-paresia or para-
plegia. Surgery for brain tumors and vertebro-medullary trauma is considered to be at
a high risk of thromboembolic complications. Symptomatic deep venous thrombosis
can affect up to 32 % of patients undergoing brain tumor neurosurgery (Agnelli
1999). The incidence of symptomatic and asymptomatic deep venous thrombosis
ranges from 4 to 34 % for all causes of intracranial surgery (Hamilton et al. 2011) and
from 1.5 to 18 % for subarachnoid hemorrhage (Vespa et al. 2011). The risk of throm-
bosis is heterogenous during spinal surgery: vertebro-medullary traumas show a high
incidence of symptomatic deep venous thrombosis (12–23 %) and asymptomatic
deep venous thrombosis (81 % diagnosed by phlebography), whereas the risks for
other surgical procedures are mild (osteosynthesis and extended laminectomy, 0.3–
2.7 %) or low (herniated disc or less than two levels of laminectomy, <1 %) (Audibert
et al. 2005). We have seen that thromboplastin release increases in traumatic brain
injury (TBI) and tumoral lesions, but procoagulant mediators are also promoted in
such situations. Significantly higher concentrations of plasma tissue factor pathway
inhibitor have been reported in patients with brain tumors (Gerlach et al. 2003).

19.1.2.2 Bleeding
Coagulopathy resulting from brain injury has been extensively studied. It includes
multiple mechanisms: release of cerebral tissue factor and activation/amplification
of coagulation, disseminated intravascular coagulation, hyperfibrinolysis, platelet
dysfunction, brain and global hypoperfusion, and activation of protein C.
These mechanisms are well documented in trauma settings (Laroche et al. 2012).
They can occur in isolation or in association with acute traumatic coagulopathy,
acidosis, and hypothermia. Coagulopathy due to TBI is statistically associated with
the severity of injury, progression of hemorrhagic lesions, and increased morbidity
and mortality. Mortality rises from 8 to 32 % in cases of hemorrhagic progression
lesions (Allard et al. 2009). It is, however, difficult to establish a strong unilateral
causal relationship between coagulopathy and the severity of brain injury: hemor-
rhagic progression of lesions seems to be partly predetermined by the primary injury
whatever the state of coagulation (Kurland et al. 2012), and the severity of the pri-
mary injury determines the severity of coagulopathy. This is probably a phenome-
non of autoamplification: the more severe the primary injury, the more severe the
334 J. Picard et al.

consecutive brain hypoperfusion and the worser the coagulopathy, affecting the evo-
lution of lesions and outcome. This could explain why it may not be possible to
completely reverse outcome even while normalizing coagulation. However, acquired
iatrogenic coagulopathy is a risk factor for bad outcomes. The incidence of TBI-
related coagulopathy ranges from 10 to 97 % depending on severity and definition.
Its mean incidence is 33 % (Harhangi et al. 2008). The time course of TBI coagu-
lopathy has been studied. It occurs in the first 5 days, mostly in the first 24 h (mean
23 ± 2 h post admission). Early onset (<12 h) has been associated with greater sever-
ity and poorer outcome (Lustenberger et al. 2010). It is important to note that thera-
peutic hypothermia does not seem to cause hemorrhagic progression of brain
contusions (Resnick et al. 1994). What is observed in brain trauma is also relevant
in neurosurgery, and some of the mechanisms described in TBI coagulopathy have
been documented in the perioperative period (Goh et al. 1997).

19.1.3 Effects and Management of Specific Drugs

Both congenital and acquired coagulation disorders can be involved in inducing or

worsening brain injury, particularly intracerebral hemorrhage (ICH). Coagulation
disorders induced by medical therapies are of particular interest because of the wide
use of such drugs and procedures for other diseases.

19.1.3.1 Effects and Management of Antiepileptic Drugs

The use of antiepileptic drugs has been related to hemostatic disorders, mainly
platelet dysfunction. Thrombocytopenia is the most frequently reported hemostatic
side effect (Priziola et al. 2010). This has been reported with valproic acid (Lackmann
2004), carbamazepine (Finsterer et al. 2001; Taher et al. 2012), phenytoin (Holtzer
and Reisner-Keller 1997), levetiracetam (Sahaya et al. 2010), and lamotrigine (Okur
et al. 2012). In addition, gabapentin and valproic acid have been associated with
hypofibrinogenemia, acquired von Willebrand syndrome, and lowered factor XIII
(Gerstner et al. 2006; Pan et al. 2007). Despite these observations, the pathophysi-
ological mechanisms of these disturbances and their association with increased
bleeding or blood product administration remain unclear. The literature reveals
many cases of thrombocytopenia in patients on valproic acid antiepileptic therapy.
Topf et al. (2011) used calibrated automated thrombography to study the effects of
valproate antiepileptic therapy on thrombin generation; however, they found no
major differences between their 90 patient samples and controls not using the drug.
Manohar et al. (2011) evaluated 84 children who had undergone epilepsy surgery
and examined the effects of antiepileptic treatments on perioperative coagulation
parameters, blood loss, and the amount of blood products transfused. They con-
cluded that antiepileptic drugs did not appear to be associated with perioperative
coagulation disorders or blood transfusion requirements.
Antiepileptic drugs have numerous positive effects which, despite their effects
on hemostasis, must be taken into account in patients undergoing potentially hemor-
rhagic surgery.
19 Perioperative Hemostasis in Neurosurgery 335

19.1.3.2 Effects of Hydroxyethyl Starch on Coagulation

Hydroxyethyl starches (HES) are widely used to restore intravascular volume.
This can be particularly important in neurosurgical procedures to maintain cere-
bral or medullary perfusion pressure. Recent developments have focused on the
effects of HES on hemostasis, questioning its clinical use. The impairment of
hemostasis is dependent on the physicochemical characteristics of HES solutions,
such as molecular weight, pattern of hydroxyethyl substitution at carbon positions
C2 and C6 (C2/C6 ratio), and molar substitution (Kozek-Langenecker 2005).
HES use has been related to acquired von Willebrand syndrome and decreased
coagulation factor VIII activity. The use of HES has been associated with increased
risk of bleeding, alteration of fibrin function, and a decrease in platelet count in
patients with cerebrovascular diseases (Treib et al. 1996a, b); however, many of
these studies were conducted with old-generation HES (Treib et al. 1997). No
clear association with increased transfusion requirements has been reported with
the latest generation of 6 % hydroxyethyl starch 130/0.4, but studies are of poor-
quality and further high-quality trials are needed (Gattas et al. 2012). No major
changes in coagulation variables were found in patients with severe brain injury
despite large HES 130/0.4 doses administered (Neff et al. 2003). Nevertheless,
clinicians must be aware of these effects on hemostasis, particularly when HES is
used repeatedly over several days, and maximal doses must absolutely be
respected.

19.1.3.3 Effects of Hypertonic Saline and Mannitol on Hemostasis

Both hypertonic saline and mannitol are used in neurosurgery to decrease intracranial
pressure (osmotherapy). They can also be used to quickly restore intravascular
volume in hemorrhagic situations. Nevertheless, they do interfere with blood coag-
ulation (Brummel-Ziedins et al. 2006), altering plasma clotting time and platelet
aggregation (Reed et al. 1991). Hypertonic saline has also been shown to induce
hyperfibrinolysis in vitro (Tan et al. 2002). These effects on coagulation are particu-
larly obvious in thromboelastometric tests, which show altered fibrin clot firmness
(Luostarinen et al. 2011). As these drugs cause significant side effects, such as
hypernatremia, they must be considered as rescue drugs and their use limited to
specific situations.

19.1.3.4 Effects of Desmopressin on Coagulation

Desmopressin is a synthetic analogue of the natural hormone vasopressin, charac-
terized by its strong and prolonged antidiuretic effects but decreased pressor activ-
ity. Its use is common in the treatment of neurosurgically induced diabetes insipidus.
Desmopressin is also a classic treatment for von Willebrand disease, mild hemo-
philia A, or platelet dysfunctions (Mannucci et al. 1977), and it can be proposed to
reduce blood loss in surgical hemorrhage. Desmopressin will increase the plasmatic
concentration of coagulation factor VIII, von Willebrand factor, and t-PA; it will
also promote platelet adhesion. These effects are dose-dependent (Aberg et al.
1979), and the optimal hemostatic effect seems to be obtained with a dosage of
0.3 μg/kg administered intravenously (Lethagen 1994).
336 J. Picard et al.

19.1.3.5 Effects and Management of Antiplatelet

Agents in Neurosurgery
Patients undergoing neurosurgery often suffer from significant cardiovascular
comorbidities. Antiplatelet (AP) therapies are thus commonly encountered.
Theoretically, this treatment is usually interrupted before neurosurgical interven-
tions because of the potential for perioperative bleeding. Data is more consistent
with aspirin than with thienopyridines, which seem to have worse effects on bleed-
ing. Risk of spontaneous ICH is very low in patients receiving aspirin (0.2 events
per 1,000 patient years) (Gorelick and Weisman 2005). However, aspirin use before
the onset of ICH has been shown to be associated with an increase in size of the
hematoma and higher mortality (Saloheimo et al. 2006). This was confirmed in a
meta-analysis comparing AP therapy to no-AP therapy at the time of intracranial
hemorrhage (Thompson et al. 2010). It is interesting to note that AP therapy was
associated with increased mortality, but not with poor functional outcome. Similarly,
mortality after traumatic brain injury is higher in patients receiving AP medication,
particularly if they present hemorrhagic contusions (Beynon et al. 2012).
However, this interruption itself can have dramatic consequences, as patients will
be at a high risk of perioperative thromboembolism. Depending on the AP medica-
tion itself (aspirin, clopidogrel, or glycoprotein IIb/IIIa inhibitors), on its indication
(coronary stent implantation vs. carotid artery stenosis), and the type of surgery
(intracranial vs. spinal surgery, planned vs. emergency surgery), risks will be differ-
ent and AP therapy disruption will have to be balanced against the risk of thrombo-
embolic events. Glycoprotein IIb/IIIa inhibitors like abciximab, eptifibatide, and
tirofiban have an intense and sustained effect on platelet function and therefore
dramatically more pronounced effects on bleeding than aspirin.
Because AP medications do not decrease platelet count but rather alter their
function, standard biological tests do not offer a proper assessment: a normal plate-
let count is no guarantee of satisfactory perioperative primary hemostasis. Whole-
blood in vitro systems like the platelet function analyzer (PFA-100®) can be useful
to investigate platelet function, helping clinicians to decide whether or not to inter-
rupt AP therapy before planned surgery (Kottke-Marchant et al. 1999). Similarly,
whole-blood POC platelet function (Multiplate®) can detect possible unknown AP
medications in emergency situations or in comatose patients (Weber et al. 2008).
There are no guidelines or recommendations for the management of platelet
function substitution in such situations. Decisional algorithms integrating clinical
data, and both laboratory and POC information, can be proposed to help manage AP
therapy in these patients (Figs. 19.1 and 19.2).

19.1.3.6 Vitamin K Antagonists

Vitamin K antagonists (VKA) are involved in 10–20 % of spontaneous ICH, repre-
senting an annual incidence of 2.2 % of treated patients (Quinones-Hinojosa et al.
2003). Furthermore, the onset of ICH in these patients is complicated by a higher
frequency of hematoma enlargement (56 % vs. 26 % in patients without oral antico-
agulation) and a higher mortality (62 % vs. 17 %) (Cucchiara et al. 2008). Ongoing
19 Perioperative Hemostasis in Neurosurgery 337

Planned surgery

Aspirin Clopidogrel
GP IIb/IIIa-antagonists

Spinal surgery Intracranial surgery Spinal surgery Intracranial surgery

STOP medication ?
STOP medication ?

Special hemostasis Special hemostasis

laboratory investigations laboratory investigations

Platelet dysfunction ? Platelet dysfunction ?

Yes No No Yes

Surgery
Delay surgery Delay surgery

Point-of-care whole-blood Intraoperative Consider platelet

platelet function analysis bleeding ? transfusion

Fig. 19.1 Management of antiplatelet agents in planned neurosurgery (Gerlach et al. 2009;
Beynon et al. 2012; Okano et al. 2014)

warfarin treatment also dramatically increases mortality in patients suffering trau-

matic brain injury (40 % vs. 21 %) (Lavoie et al. 2004). VKA should therefore be
withheld from patients before a planned neurosurgical intervention. Usually, inter-
rupting VKA treatment 4 days prior to surgery will normalize the international nor-
malized ratio (INR). Depending on the therapeutic indication and the thrombotic
risk and potential consequences, anticoagulation can be maintained using
338 J. Picard et al.

Emergency surgery

Aspirin Clopidogrel
GP IIb/IIIa-antagonists

Spinal surgery Intracranial surgery Spinal surgery Intracranial surgery

Consider platelet
transfusion

Point-of-care whole-blood
platelet function analysis

Platelet dysfunction ?

Yes No

Consider platelet
Surgery
transfusion

Point-of-care whole-blood Intraoperative Consider platelet

platelet function analysis bleeding ? transfusion

Fig. 19.2 Management of antiplatelet agents in emergency neurosurgery (Beshay et al. 2010;
Batchelor and Grayson 2013; Beynon et al. 2013; Li et al. 2013)

unfractionated heparin, but this should be stopped 6 h before surgery. In case of

emergency surgery, VKA therapy can be reversed without delay using prothrombin
complex concentrates (PCC) and vitamin K.

19.1.3.7 New Oral Anticoagulants

This new family includes factor Xa inhibitors (apixaban, rivaroxaban) and direct
thrombin inhibitors (dabigatran). These anticoagulants have all shown similar
results in preventing primary and secondary ischemic stroke in atrial fibrillation,
including a lower incidence of spontaneous ICH. There are concerns, however,
about the reversal of these drugs, which seems to be more difficult than with vitamin
K antagonists (Mittal and Rabinstein 2012).
19 Perioperative Hemostasis in Neurosurgery 339

19.1.3.8 Thrombolytics
Intravenous thrombolysis for myocardial infarction or pulmonary embolism shows
a quite low incidence of spontaneous ICH (less than 2 %) (Patel and Mody 1999).
However, the incidence is higher following thrombolysis for ischemic stroke: rates
between 2.4 and 10.7 % have been described following intravenous thrombolysis,
7.8–15.4 % following intra-arterial mechanical plus chemical thrombolysis, and
6.3–9.9 % following intra-arterial procedures following intravenous thrombolysis
(Mokin et al. 2012). This can be explained by the increased fragility of ischemic
brain tissue, particularly due to the early disruption of the blood-brain barrier.
In contrast, modern thrombolytic agents (alteplase) have very short half-lives, and
there is usually no use in providing antagonization. Association with other medica-
tions which interfere with hemostasis and coagulation seems, of course, to increase
the risk of bleeding.
Spinal complications are rare after thrombolytic therapy and usually present as
epidural hematoma (Clark and Paradis 2002).

19.1.4 Neurosurgical Techniques

In addition to bleeding induced by surgery itself, certain neurosurgical techniques

can be responsible for hemostatic disturbances. Patient positioning can induce
bleeding as the upright position causes modifications to intracranial dynamics.
Excessive cerebrospinal drainage and intraoperative mechanical brain shifting also
contribute to bleeding. Decompressive surgery can also be responsible for a danger-
ous increase in blood flow that may lead to hemorrhagic complications in the edem-
atous brain area.

19.2 Evaluation of Hemostatic Changes

in Neurosurgical Patients

19.2.1 Clinical Evaluation of Hemostatic Disturbances

in Neurosurgical Patients

The anatomical specificities of the central nervous system can lead to diagnostic and
therapeutic difficulties, as even a small volume of blood can have dramatic conse-
quences, and the diagnosis of bleeding can be delayed because of a lack of obvious
hemorrhagic exteriorization. Sometimes, the first sign of a bleeding disorder will be
a neurological deterioration in the patient. When available, the patient’s medical
history will be invaluable. Preexisting hemostatic defects can be detected at a pre-
anesthetic consultation, and some authors have proposed standardized question-
naires to evaluate coagulation on admission (Koscielny et al. 2004). In some
situations, hemostatic perturbations can be discovered during surgery. This is par-
ticularly true in emergency situations, with comatose or sedated patients, or with
unknown coagulation diseases. Thus, the surgeon’s appreciation of potential bleed-
ing and hemostasis constitutes precious information that should not be neglected.
340 J. Picard et al.

Multidisciplinary, intraoperative communication and cooperation are essential to

manage hemostatic disorders in the operating room in a proper and timely fashion.
The surgeon’s opinion will be helpful in guiding hemostatic therapy and blood
product transfusion. The brain has the particularity of being the only organ locked
in a non-expandable box.
Postoperative hemorrhagic complications are most frequent in the first 6 h
following surgery (Taylor et al. 1995), so when possible, waking the patient will be
essential for a neurological follow-up that will provide precious information.

19.2.2 Classic Biological Tests

Classic hemostatic monitoring comprises activated partial thromboplastin time

(aPTT), INR, platelets, and fibrinogen. Nevertheless, these conventional tests only
monitor the initiation phase of coagulation and normal results cannot exclude a
perioperative hemorrhagic complication.
Abnormal plasmatic coagulation tests have been shown to be associated with the
progression of traumatic intracranial hemorrhage (Allard et al. 2009), but their use
has never been properly validated. A more complete monitoring of hemostasis may
be helpful for choosing a therapeutic strategy.
Recent European guidelines on the management of bleeding following major
trauma recommend that “routine practice to detect post-traumatic coagulopathy
include the early, repeated and combined measurement of prothrombin time (PT),
aPTT, fibrinogen and platelets.” However, they also suggest that PT and aPTT
should not be used alone to guide hemostatic therapy and that thromboelastometry
could be performed to assist in the characterization and treatment of posttraumatic
coagulopathy (Spahn et al. 2013). These considerations can be reasonably extended
to the perioperative management of bleeding patients.

19.2.3 Point-of-Care Assessment of Hemostasis

Not enough attention is paid to the complex pathophysiology and kinetics of acute
coagulopathy: this is partly due to the limitations with usual hemostasis assays. In
addition to the routine coagulation parameters, viscoelastic assays (ROTEM®/
TEG®) can give an overall understanding of the coagulation status.
Thromboelastometry/thromboelastography appears to be useful in the treatment of
bleeding trauma patients and provides information about the speed and quality of
clot formation (Spahn et al. 2013). They are performed in whole blood and thus
provide clinically relevant data. Thromboelastometry assays are increasingly used
to guide transfusion strategy; however, data on patients with isolated brain injury
are lacking. A recent publication detailed thromboelastometric patterns of isolated
brain-injured patients, but there are no prospective data on the subject (Schöchl
et al. 2011).
19 Perioperative Hemostasis in Neurosurgery 341

D1 = admission
Severe TBI

FIBTEM S 2010-06-19 01:29 2: APRES FIBRI EXTEM S 2010-06-19 01:25 2: APRES FIBRI

CT: 54 s CFT: -s α: 54° CT: 67 s CFT: 115 s α: 68°

A10: 9 mm A20: 10 mm MCF: 10 mm A10: 49 mm A20: 57 mm MCF: 60 mm

Fig. 19.3 Thromboelastometric (ROTEM) profile of a patient with severely traumatic brain injury
on day 1 (hemorrhagic complication: extensive hemorrhagic brain contusions)

Thromboelastometry/thromboelastography is also an attractive technique for

investigating the prothrombotic evolution of surgical patients. In a retrospective
analysis of 152 critically ill surgical patients, Kashuk et al. (2009) reported that the
presence of hypercoagulability – as identified by thromboelastography (r-TEG) –
was predictive of thromboembolic events. A systematic review of the literature to
investigate r-TEG’s accuracy in predicting postoperative thromboembolic events
concluded that more prospective studies were needed (Dai et al. 2009). The ability
to predict thromboembolic events early is particularly significant for neurosurgical
patients (Figs. 19.3 and 19.4).
POC whole-blood impedance aggregometry (Multiplate®) can detect the effects
of aspirin, clopidogrel, and GP IIb/IIIa receptor blockers (Weber et al. 2008). It can
also be used to detect unknown hemostatic disorders in comatose patients or to
assess coagulation in patients treated with interfering medications. Indeed, AP
drug-mediated dysfunction cannot be detected by platelet count.
The availability of repeated and rapid POC tests can guide intraoperative thera-
peutic management and goal-directed hemostatic therapy. This approach has been
shown to reduce blood requirements in cardiovascular surgery and liver transplanta-
tion (Görlinger 2006). More recently, the use of thromboelastometry/
342 J. Picard et al.

Day 4
Pulmonary
embolism

FIBTEM S 2010-06-22 14:32 2: EMBOLIE PULM EXTEM S 2010-06-22 14:29 2: EMBOLIE PULM

CT: 64 s CFT: 83 s α: 82° CT: 64 s CFT: 66 s α: 80°

A10: 28 mm A20: 30 mm MCF: 31 mm A10: 60 mm A20: 67 mm MCF: 69 mm

Fig. 19.4 Thromboelastometric (ROTEM) profile of a patient with severely traumatic brain injury
on day 4 (thromboembolic evolution: bilateral pulmonary emboli)

thromboelastography has been reported in pediatric neurosurgery and after trau-

matic brain injury (Luostarinen et al. 2012; Kunio et al. 2012).

19.3 Management of Hemostasis in Neurosurgery

19.3.1 Blood-Derived Products

There are no evidence-based recommendations on the intraoperative use of blood-

derived products in neurosurgery. For a detailed description of the various blood-
derived or pharmacological products, we refer to Chaps. 9, 10, and 11. Here, we will
focus on the particularities of their use in a neurosurgical context.

19.3.1.1 Platelets
Thrombocytopenia is directly associated to mortality and adverse outcome in traumatic
intracranial hemorrhage patients (Allard et al. 2009). General recommendations are to
maintain a platelet level greater than 100,000/μL, but a platelet count below 175,000/
19 Perioperative Hemostasis in Neurosurgery 343

μL has been correlated to greater intracranial hemorrhage progression (Schnüriger

et al. 2010). Chan et al. (1989) showed an increase in postoperative hematoma forma-
tion when platelet count went below 124,000/μL in the immediate postoperative period.
Risk of bleeding was greater in acute than in chronic thrombocytopenia.

19.3.1.2 Fibrinogen
European guidelines on the management of bleeding following trauma recom-
mend treatment with fibrinogen concentrate or cryoprecipitate if significant bleed-
ing is accompanied by a plasma fibrinogen level below 1.5–2.0 g/L. The
development of thromboelastometric assays has focused attention on the role of
fibrinogen. It plays a central role in the coagulation process and the literature sug-
gests that its administration could reduce blood loss and requirements for blood-
derived products in both cardiovascular surgery and trauma (Karlsson et al. 2008;
Fenger-Eriksen et al. 2008).
Nevertheless, good-quality multicentered randomized trials are lacking, and it is
currently not known whether the administration of high doses of fibrinogen is asso-
ciated with an increased thromboembolic risk.

19.3.1.3 Fresh Frozen Plasma and Prothrombin

Complex Concentrate
There are no recommendations specific to neurosurgery concerning the administra-
tion of either fresh frozen plasma (FFP) or PCC, but infusion of blood-derived
products will always be associated with volume load, which can lead to brain
swelling. Except the reversal of VKA therapy, there is no evidence-based recom-
mendation for the use of PCC in a neurosurgical setting. Retrospective analyses of
goal-directed protocols for thromboelastometry-guided fibrinogen and PCC
administration have shown favorable survival rates (Schöchl et al. 2010), but data
in neurosurgery and prospective trials are needed to establish the role of PCC
administration in this context.

19.3.2 Pharmacological Hemostatic

Interventions in Neurosurgery

19.3.2.1 Tranexamic Acid

Tranexamic acid competitively inhibits plasminogen binding to the fibrin which
maintains clot stability. In a meta-analysis of 18 trials, the administration of
tranexamic acid has been associated with a reduction in blood loss in elective sur-
gery patients (Henry et al. 2007) and has recently been the subject of debate about
reducing transfusion requirements in brain trauma (Perel et al. 2012). There are
many case reports on the use of tranexamic acid in spinal (Cravens et al. 2006) or
intracranial surgery (Sorimachi et al. 2005), to reduce either blood loss or hema-
toma growth, but controlled trials are lacking.
Nevertheless, if hyperfibrinolysis is either detected or suspected, the administra-
tion of tranexamic acid could be helpful in controlling bleeding.
344 J. Picard et al.

19.3.2.2 Recombinant Activated Factor VII

Initially used to treat critical bleeding in hemophilic patients, recombinant activated
factor VII (rFVIIa) has been successfully used in non-hemophilic patients.
According to the cell-based coagulation model, rFVIIa enhances hemostasis by
binding both exposed tissue factor at the injury site and activated platelets to pro-
duce thrombin (Grounds 2003). In neurosurgery, rFVIIa has been used during cra-
niotomies for traumatic subdural or epidural hematomas, subarachnoid hemorrhage,
and tumor resection or to treat warfarin-associated intracranial hemorrhage (Lin
et al. 2003). Many case reports describe the correction of coagulation parameters in
bleeding patients after rFVIIa administration, but the results of randomized clinical
trials do not support its systematic administration for spontaneous intracranial
bleeding. Mayer et al. (2005) reported on 399 patients with spontaneous intracranial
hemorrhage who randomly received either a placebo or different doses of rFVIIa.
They found the lowest increase in the volume of hemorrhage in the group given the
highest dose of rFVIIa (160 μg/kg) in the first 4 h. However, a greater incidence of
serious thromboembolic complications was observed in that group than in the pla-
cebo group. Further, large, controlled randomized clinical trials are necessary to
determine the role of rFVIIa in the treatment of spontaneous intracranial bleeding.
The data available concerning traumatic, surgical, and drug-induced bleeding essen-
tially consist of case reports and retrospective studies. So the off-label use of rFVIIa
cannot be considered a conventional therapy in neurosurgery and should be reserved
to uncontrolled refractory bleeding.

19.3.2.3 Deferoxamine
Iron can induce brain damage. Deferoxamine – an iron chelator – has been shown
to reduce hemoglobin-induced edema in a rat model (Nakamura et al. 2004). It has
also been shown to reduce brain atrophy and improve neurological function after
intracranial hemorrhage in the rat (Okauchi et al. 2010). There are nevertheless no
clinical studies published.

19.4 Future Management of Hemostasis

in Neurosurgical Patients

19.4.1 Early Hemostatic Goal-Directed

Therapy in Neurosurgery

The mechanisms of hemorrhage and coagulopathy in neurosurgical patients are

multifactorial, complex, and dynamic. The traditional biological tests have been
surpassed. Damage control hematology is an emerging concept, and the ability to
detect and treat coagulopathy early is essential to the management of neurosurgical
patients.
Thromboelastometry/thromboelastography and whole-blood impedance
aggregometry are advantageous POC tools that offer the clinician early information
on both the hemorrhagic and procoagulant tendencies in complex situations. The
19 Perioperative Hemostasis in Neurosurgery 345

development of algorithms based on POC information and confirmed by classic

laboratory tests will certainly help in the future.

19.4.2 From Bleeding to Clotting

Bleeding remains the most serious threat to neurosurgical patients, but the problem
is certainly more complex when the early and massive activation of coagulation
processes leads rapidly to a hypercoagulable state. Abrahams et al. (2002) studied
the evolution of coagulability during neurosurgical procedures and found increased
coagulability from the induction of anesthesia and skin incision through to intraop-
erative and postoperative periods (Abrahams et al. 2002). Interestingly, these
changes were more pronounced in patients undergoing craniotomy than in patients
undergoing spinal procedures.
Thromboembolic complications are known to be more frequent in neurosurgi-
cal patients. Classic risk factors including immobility, malignancy, trauma, and a
delayed introduction of thromboprophylaxis certainly do play a role in the increased
number of thromboembolic events observed in these patients, but they are not the
only mechanisms. There is growing evidence that a hypercoagulable state can
develop perioperatively in neurosurgical pathologies and interventions. Goobie
et al. (2001) evaluated coagulation by using thromboelastography (TEG) data from
30 pediatric patients undergoing craniotomy; they found that peri- and postoperative
hypercoagulable TEG profiles showed shortened coagulation times and increased
maximal amplitude of clot strength, compared to preoperative profiles.
Experimental investigations have shown that thrombin is responsible for
increased brain edema and neuronal death, and the intracerebral injection of throm-
bin inhibitors, such as argatroban, has been shown to significantly reduce edema in
a rat model of ICH (Kitaoka et al. 2002); thus, supporting the concept that clotting
and bleeding states are closely linked.

19.4.3 The Forgotten Secondary Brain Injury?

Neurosurgical bleeding is probably one of the most dreaded complications and in

the field of neurocritical care, one of the most complex and fascinating problem.
Pathophysiological mechanisms of brain injury, and hemostatic cascades trig-
gered by attacks on the central nervous system, tend to show that the same processes
that lead to hemorrhagic complications will also lead to a hypercoagulable state and
thromboembolic events.
Just as hypotension, anemia, hypoxia, hypoglycemia, hypercapnia, and hyper-
thermia are all now recognized as secondary factors that can worsen a primary brain
injury, coagulopathy must also be considered as a potential contributing factor to
poor outcomes. Many useful tools, currently in the development stage, will soon
help clinicians to give an even earlier diagnosis and treatment of coagulopathy: the
forgotten secondary brain injury.
346 J. Picard et al.

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Bleeding Management in Elective
Orthopedic Surgery 20
Oliver M. Theusinger

20.1 Introduction

Perioperative blood loss remains an important problem in elective orthopedic surgery

(hip, knee, and spine surgery). For many years, allogenic blood transfusions were the
standard approach to treating diminished hemoglobin (Hb) levels. The inherent risks
of homologous transfusions persist despite all efforts to minimize them. Transmission
of infections, transfusion-related acute lung injury (TRALI) or febrile reactions, red
blood cell (RBC) transfusion-related immunomodulation, and increased mortality,
morbidity, and adverse outcome have all been proven (Dodd 1992; Kopko and Holland
1999; Musallam et al. 2011; Spahn and Goodnough 2013).
The costs of RBC transfusions are largely underestimated. The reported price of
one unit of packed RBC varies between USD 270 and 780, depending on the inclu-
sion of costs related to storage, laboratory analyses (cross-matching tests, antibody
tests, etc.), and prolonged hospital stays. In Switzerland, the cost of one unit of
packed RBC administered in relation to surgery is estimated at close to USD 700
without taking into consideration transfusion-related complications, which have
been estimated to cost around USD 1,000 (Shander et al. 2007, 2010; Ferraris et al.
2012).
Special attention should therefore not only be given to the costs of alternatives to
blood transfusions but also at their possible surgery-specific drawbacks and accep-
tance by orthopedic surgeons. While the experience and skills of the surgeon are
among the most important factors influencing intraoperative blood loss (Ishii and
Matsuda 2005; Moonen et al. 2006), they are also the factors that cannot be man-
aged by any other team member. Adequate hemostasis therefore remains the “gold
standard” technique for eliminating potential complications. Its impact on

O.M. Theusinger, MD
Institute of Anesthesiology, University of Zurich, University Hospital Zurich,
Rämistarsse 100, Zurich 8091, Switzerland
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 351

DOI 10.1007/978-3-642-55004-1_20, © Springer-Verlag Berlin Heidelberg 2015
352 O.M. Theusinger

transfusion decisions is evident: blood that is not lost does not have to be replaced.
Preoperative anemia, which varies from 20 to 51 %, has been identified as another
major issue. The World Health Organization (WHO) has defined this as a Hb level
≤12 g/dL in women and ≤13 g/dL in men, which corresponds to a hematocrit (Hct)
of ≤36 % in women and ≤39 % in men (Rosencher et al. 2003; Theusinger et al.
2007; Kendoff et al. 2011). This has been shown to be an independent risk factor for
increased 30-day mortality and major morbidity in all surgical patients (Musallam
et al. 2011). In up to 30 % of patients, iron deficiency is the cause of anemia and
should be corrected at least 4 weeks prior to surgery in order to achieve optimal
results (Theusinger et al. 2007). Optimizing Hb mass before orthopedic surgery, as
well as limiting intraoperative blood loss, is associated with improved outcomes
after 90 days (Kotze et al. 2012).

20.2 Alternatives to Allogenic Blood Transfusions

A series of alternative methods for reducing or avoiding allogenic blood transfusions

in orthopedic surgery have been described. These include identification of transfusion
triggers for RBCs, pre-donation of autologous blood, iron substitution, administration
of erythropoiesis-stimulating agents (ESA), adaptation of perioperative medication,
body temperature adjustments, goal-directed transfusions, hypotensive epidural anes-
thesia, normovolemic hemodilution, platelet gel and fibrin sealant, autologous retrans-
fusion indirect retransfusion of patients’ shed blood (Cell Saver/C.A.T.S), and direct
retransfusion of patients’ shed blood (ABT, Bellovac).

20.2.1 Identification of Transfusion Triggers

The indications for RBC transfusions are controversial, and their liberal use versus
their more restricted use is largely discussed. Current literature tends to support a
more restrictive use, with Hb concentrations of 6–8 g/dL or awaiting physiological
triggers (Klein et al. 2007).

20.2.1.1 Hemoglobin-Based Transfusion Triggers

The guidelines from the American Society of Anesthesiologists (ASA) and the
American College of Physicians (ACP) recommend RBC transfusion for Hb levels
below 6–10 g/dL (Carson et al. 2012). Transfusions in situations where the Hb level
is higher than 10 g/dL are indicated in rare situations, whereas transfusions for lev-
els below 6 g/dL seem to be nearly always indicated. In Europe, a Hb target range
of 7–9 g/dL is largely accepted, even in cases of major trauma (Marik and Corwin
2008). However, Hb levels alone do not always justify transfusion. In the literature,
Hb levels below 6.4 g/dL have been associated with impaired cognitive function,
and Hb levels below 4.8 g/dL were associated with a mortality of 50 % (Weiskopf
et al. 2003). For this reason, clinical parameters, including hemodynamic status,
should be evaluated individually (Spence 1997; Madjdpour and Spahn 2005).
20 Bleeding Management in Elective Orthopedic Surgery 353

20.2.1.2 Physiological Transfusion Triggers

Physiological transfusion triggers can be used as a guide and these have been defined
as tachycardia, hypotension, oxygen extraction greater than 50 %, mixed venous
oxygen pressure of less than 32 mmHg, an increase of lactate, and electrocardiogram
changes. The level of shock, the hemodynamic response to resuscitation, and the
actual blood loss in the hemodynamically unstable patient should all be integrated
into the indication for RBC transfusions. In any case, RBC transfusions should be
used restrictively as clinical outcome has been shown to be improved by more
restrictive transfusion triggers (Earley et al. 2006; Claridge 2002).

20.2.2 Preoperative Autologous Blood Donation

This method was a standard for many years but is barely used nowadays, as there is
a poor cost-benefit relationship for the patient. Patients donate one or more units of
their own blood preoperatively (4–6 weeks) and are allowed a recovery period of
4 weeks prior to surgery. The units are stored in a blood bank and then retransfused
preoperatively. Patients have been shown to become anemic due to their donation
(Vamvakas and Pineda 2000). Several studies have shown that pre-donation is no
longer recommended in elective orthopedic surgery (Tartter et al. 1986; Theusinger
et al. 2007) because such risks as transfusion reactions, circulatory overload, bacterial
contamination, clerical errors, and negative outcome rates have all been demon-
strated (Goldman et al. 1997).
The cost-effectiveness has also been discussed as more than 45 % of donated
blood is discarded and patients become anemic due to this technique (Goldman
et al. 1997; Habler and Messmer 1997; Franchini et al. 2008).

20.2.3 Preoperative Intravenous Iron Therapy

Anemia related to iron deficiency is the most common type of anemia among
patients scheduled for elective orthopedic surgery (prevalence of up to 30 %)
(Theusinger et al. 2007). Preoperative iron supplements have been proposed in
order to elevate Hb levels (Weiss and Goodnough 2005) as they can be substituted
orally and parenterally.
After significant blood loss, there is a fivefold increase of the erythropoietic
response following intravenous (i.v.) iron administration (Weiss and Goodnough
2005). This, in combination with erythropoietin (EPO), has been shown to be asso-
ciated with a decrease in mortality due to reduced transfusion and infection rates
(Cuenca et al. 2004, 2005, 2006).
Iron therapy was found to be generally safe and effective, especially high molecu-
lar weight iron. Ferric carboxymaltose (Ferinject®, Vifor Int., St. Gallen, Switzerland)
has been shown to be well tolerated, with no safety concerns (Kulnigg et al. 2008) for
dosages up to 1 g of i.v. iron administered every 15 min. Life-threatening anaphylactic
reactions have been described for solutions containing dextran (Chertow et al. 2006),
354 O.M. Theusinger

while minor reactions to Feraheme® (ferumoxytol) injection (AMAG Pharmaceuticals®,

Inc., Waltham, MA, USA) can be of concern. Issues of dosage (502 mg of iron can be
given to the patient in one dose) and a pH of between 6 and 8 could be of concern
(Macdougall et al. 2014).
Iron substitution alone decreases endogenous erythropoietin reserves (Theusinger
et al. 2007), while EPO administration alone increases the risk for thrombotic inci-
dents (Franchini et al. 2008). For these reasons, the combination of iron and EPO is
recommended and should be the gold standard (Goodnough et al. 2000; Coyne et al.
2007; Dahl et al. 2008).
An average patient requires 1 g of iron, whereas the cost for treatment with ferric
carboxymaltose, for example, would be close to USD 300. This has been shown to
be cheaper than one unit of RBC (Shander et al. 2010). Acceptance by surgeons is
optimal, as no further involvement is required from their side.

20.2.4 Administration of Erythropoiesis-Stimulating

Agents (ESA)

Erythropoietin is a glycoprotein hormone mainly produced in the kidneys. It acts as

a growth factor for erythrocyte progenitor cells, promotes their proliferation, and
accelerates the development of reticulocytes (Jelkmann 2008). It is an excellent
choice in order to avoid allogenic blood transfusions in anemic patients undergoing
major elective surgery (Faris et al. 1996; Goodnough 1996; Schmidt et al. 1998;
Rohling et al. 2000; Couvret et al. 2004; Cuenca et al. 2006).
In 2005, Rosencher et al. showed that one to two doses of erythropoietin were
sufficient to increase Hb to non-anemic levels in orthopedic patients (Chun et al.
1997; Rosencher et al. 2005). This treatment costs USD 550 to 1,100. Care should
be taken at all times and EPO should not be administered if patients have a known
personal or familial history of thromboembolic events, severe hypertension, or an
allergy to the agent or other ingredients. Furthermore, pregnancy or breastfeeding
are contraindicated. Finally, neocytolysis is a recently discovered concern. In this
physiological process, a rapid fall in erythropoietin levels has a negative influence
on erythropoiesis and triggers neocytolysis. The extent of this phenomenon’s
relevance in the context of EPO therapy needs to be further investigated (Rice and
Alfrey 2005; Alfrey and Fishbane 2007).
Very recently, a new generation of ESAs called continuous erythropoiesis receptor
activators (CERA) has been designed. They have a longer elimination half-life and
different binding characteristics than previous ESAs, leading to benefits such as a
significant increase in the level of Hb within 2 weeks (Kakimoto-Shino et al. 2014).

20.2.5 Adaptation of Perioperative Medication

Patients undergoing surgery are getting older and are on a variety of medications. While
it was usual to discontinue anticoagulants such as vitamin K antagonists or aspirin sev-
eral days before surgery, discontinuing clopidogrel and aspirin in patients with unstable
20 Bleeding Management in Elective Orthopedic Surgery 355

coronary perfusion and/or recently implanted stents before elective orthopedic surgery
is strongly contraindicated (Spahn et al. 2006, 2007; Chassot et al. 2007a, b).
Recommendations promote aspirin as a lifelong therapy, whereas clopidogrel should be
used only as long as the coronary stents are not fully endothelialized. This usually takes
6–24 weeks depending on the technique used (Chassot et al. 2007a, b). The hemorrhagic
risk due to antiplatelet therapy is modest: 2.5–20 % more blood loss with aspirin and
30–50 % with the combination of aspirin and clopidogrel (Chassot et al. 2007a, b).
Nonsteroidal painkillers (NSAID) are widely used for pre- and postoperative
analgesia and might adversely affect hemostasis after the surgery. They should be
stopped at least 24 h prior to surgery. NSAR inhibit prostaglandin synthesis and
particularly block cyclooxygenase (COX), which is the central enzyme in the pro-
cess of prostaglandin formation. COX-2-selective NSAR have no undesirable COX-
1-related side effects such as impaired platelet aggregation and prolonged bleeding
time or consecutive increased blood loss during surgery. If NSAR are considered for
postoperative pain relief, COX-2-selective ones should be used (Slappendel et al.
2002; Weber et al. 2003). The costs of optimizing perioperative medication are
negligible, but close attention should be paid to this issue during the preoperative
surgical and anesthesiology consultations.

20.2.6 Intraoperative Body Temperature

Body temperature during surgery affects platelet aggregation and bleeding time.
The pathophysiological effect of hypothermia on platelet activation/adhesion is due
to the inhibition of the interaction between von Willebrand factor and the platelet
glycoprotein Ib-IX-V complex. It also slows down the metabolic rate of coagulation
factor enzymes. A decrease of 1.5 °C is associated with increased blood loss of
about 50 % during total hip replacement (Schmied et al. 1996; Winkler et al. 2000).
Maintenance of physiological body temperature is therefore an obligation, and all
efforts should be taken to achieve this goal.

20.2.7 Goal-Directed Transfusions

The principle of goal-directed transfusion is to optimize the coagulation pathway by

replacing coagulation factors identified as being missing or diminished. Fibrinogen,
factor XIII, and the prothrombin complex (the concentrate of factors II, VII, IX, X,
antithrombin III, and protein C) improve coagulation and minimize the blood loss
(Fries et al. 2005, 2006; Theusinger et al. 2014). Point-of-care coagulation monitor-
ing devices are essential. Rotational thromboelastometry (ROTEM®) has been shown
to be useful (Theusinger and Levy 2013) in determining the causes of hemorrhage.
Tests are performed using whole blood and allow conclusions to be made about the
entire clotting process, fibrinolysis, and platelet function at bedside speed (Theusinger
and Levy 2013). In combination with a transfusion algorithm, this has been shown
not only to decrease transfusion requirements during surgery but also to be cost-
effective (Shore-Lesserson et al. 1999; Spalding et al. 2007; Theusinger et al. 2014).
356 O.M. Theusinger

20.2.8 Antifibrinolytic Agents

Okamoto and coworkers began searching for substances that inhibit the action of
plasmin during the 1950s. One of 200 lysin derivates studied was tranexamic acid
(trans-4-aminomethylcyclohexane-1-carboxylic acid, or TXA) (Okamoto et al.
1997). Its use has been shown to have significant beneficial blood-sparing effects
in elective surgery (Henry et al. 2007), while a dose of 1 g reduced bleeding and
blood loss for elective knee and hip arthroplasty (Aguilera et al. 2013; Delanois
and Mont 2013). Costs and side effects are low at this dose, suggesting that a
generalization of the use of antifibrinolytic agents in orthopedic surgery might be
possible.

20.2.9 Hypotensive Epidural Anesthesia (HEA)

The technique of HEA is as yet not widely carried out for perioperative blood man-
agement in orthopedics. Nevertheless, it has been shown to be an effective method
for reducing perioperative blood loss (Niemi et al. 2000). HEA aims to achieve an
epidural dermatome block (at least as far as the T2 level) and to establish a suffi-
ciently extensive and dense block of the cardioacceleratory fibers of the thoracic
sympathetic chain. Bradycardia is usually prevented by using a continuous i.v. infu-
sion of a low-dose epinephrine solution. This leads to reduced arterial pressure but
maintains heart rate, central venous pressure, stroke volume, and cardiac output
within normal ranges. Mean arterial blood pressure can be lowered to 50 mmHg
resulting in a reduction of intraoperative (Nelson and Bowen 1986) and postopera-
tive blood loss, as seen in several orthopedic trials (Juelsgaard et al. 2001; Tenholder
and Cushner 2004; Eroglu et al. 2005). HEA seems, therefore, to be an attractive
alternative for certain specific patients and situations.

20.2.10 Normovolemic Hemodilution

The principle of normovolemic hemodilution is based on replacing 2–4 units of the

patient’s whole blood with acellular fluids (e.g., crystalloids). The advantage of this
procedure is that fewer valuable oxygen carriers (e.g., RBC) are lost in cases of
bleeding due to the artificial dilutional anemia. Additionally, fresh whole blood is
instantly available for retransfusion. This method has been shown to reduce the
need for allogenic blood transfusion in different fields of surgery (Terada et al.
2001; Matot et al. 2002; Wong et al. 2002; Habler et al. 2004), including orthopedic
surgery (Goodnough et al. 1999; Bennett et al. 2006). Contraindications for this
technique are severe anemia, hemorrhagic shock related to trauma, severe sepsis,
respiratory failure, and myocardial insufficiency (Morgan et al. 2002).
The estimated costs seem to be minimal (about USD 30) compared to other
procedures (Monk et al. 1999). It has to be acknowledged, however, that hemodilu-
tion—when using hydroxyethyl starch (HAES/HES)—can lead to diffuse intraop-
erative bleeding (capillary bleeding) due to the reduced platelet aggregation caused
20 Bleeding Management in Elective Orthopedic Surgery 357

by colloids. In procedures where a well-controlled hemostasis is mandatory, normo-

volemic hemodilution might not be the ideal choice from a surgical point of view
and particular care should be taken about HES usage (Kind et al. 2013).

20.2.11 Platelet Gel and Fibrin Sealant

Platelet gel is manufactured from platelet-rich plasma, which is obtained by seques-

tration of autologous whole blood by using a blood cell separator. Treatment
involves direct application of concentrated platelets and their growth factors
(TGF-ß = platelet-derived growth factor) and has been proven to have favorable
effects on the wound healing cascade (Mustoe et al. 1987; Pierce et al. 1989;
Wrotniak et al. 2007). Platelet gel is cheap (about USD 24 per unit of blood seques-
trated), the work required is minimal, and its efficiency in orthopedic surgery has
been well described. Furthermore, Lincoln et al. suggested that it has antibacterial
properties due to its high concentrations of leukocytes and granulocytic neutrophils
which contain myeloperoxidase (Lincoln et al. 1995).
Fibrin sealants, also known as fibrin glues, are plasma-derived surgical hemo-
static agents. Two major components are usually present: fibrinogen and thrombin.
Fibrin sealants can be applied to the wound surface using a dual-syringe system in
either a liquid or an aerosol form. Their improved hemostatic effects have been
shown in both animal and human models (Mankad and Codispoti 2001), with clini-
cal efficiency described in cardiothoracic surgery, cosmetic surgery, and neurosur-
gery (Kjaergard and Fairbrother 1996; Mankad and Codispoti 2001). A few studies
have been published in orthopedic surgery (Levy et al. 1999; Wang et al. 2001)
using a non-autologous cryoprecipitate-based fibrinogen. Besides the improved
hemostatic effect, a lower incidence of postoperative wound healing disturbances
(Everts et al. 2006), fewer infections, and a shorter length of stay were all described
(Pierce et al. 1989). However, the costs for these products are not negligible:
1 ml of fibrin glue is used for 10 cm2 of wound surface at a price of USD 175
(Baxter®, Deerfield, IL, USA).
The use of these hemostatic agents is complementary to decreasing the need for
allogenic blood transfusions. They are not a replacement for diligent surgical hemo-
stasis and should be used judiciously to improve the surgical outcome (Mankad and
Codispoti 2001).

20.2.12 Autologous Retransfusion

There are two different methods of autologous retransfusion. Suctioned blood is

either washed mechanically before being given back to the patient (indirect retrans-
fusion) or it is filtered before retransfusion (direct procedure).

20.2.12.1 Indirect Retransfusion

Two examples of indirect retransfusion systems are the discontinuous autotransfu-
sion system (DATS, “Cell Saver®” system, Haemonetics Corp, Braintree, MA, USA)
358 O.M. Theusinger

and the continuous autotransfusion system (CATS, “C.A.T.S ®” system, Fresenius,

Bad Homburg, Germany). Both systems centrifuge blood, divide corpuscular ele-
ments according to their density, and wash these with a physiological liquid (e.g.,
normal saline) (Dai et al. 2004).
The difference between the two methods is that in the discontinuous setting, each
cycle processes a fully loaded blood reservoir, whereas the continuous system is
almost independent of the blood volume (priming volume 30 mL). Another advantage
of the continuous system is that smaller centrifugal forces are used to separate eryth-
rocytes. Furthermore, a higher percentage of residual fat particles is removed, which
is a relevant concern in orthopedic surgery. Leukocytes, on the other hand, are better
removed by the discontinuous system (Dai et al. 2004). The quality of these washed
RBCs is at least comparable to that of stored blood cells (McShane and Martin 1987).
The major contraindication to the use of indirect retransfusion is bacterial con-
tamination of suctioned wound blood; tumor surgery is only a relative contraindica-
tion (Beck-Schimmer et al. 2004). Intraoperative cell salvage has been proven to be
an effective method to avoid allogenic blood transfusion (Spahn and Casutt 2000).
Using indirect retransfusion systems in orthopedic patients significantly reduces the
need for allogenic blood transfusions from 70 to 23 % (Heddle et al. 1992).
The high costs associated with this indirect retransfusion technique (USD 2,400
for Cell Saver®, Haemonetics Corp, Braintree, MA, USA) might suggest that its
intraoperative use be reserved for dedicated and specific surgery only.

20.2.12.2 Direct Retransfusion

Postoperative drainage can be used for the direct retransfusion (e.g., Bellovac
ABT®, Astra Tech, Vienna, Austria) of filtered shed blood. This method has gained
popularity in the field of orthopedic surgery as it is cost-effective and easy to use.
Concerns over the safety of unwashed, filtered shed blood have been tempered by
recent studies (Healy et al. 1994; Habler and Messmer 1997; Habler et al. 2004)
showing that autologous retransfusion is safe provided the correct protocols are fol-
lowed. These include abiding by maximum transfusion volumes, a blood loss over
250 ml, and a retransfusion time within 6 h of surgery, thereby minimizing any
hematological or immune reactions (Henry et al. 2002). Six hours postoperatively,
the system can still be used as a regular low-vacuum drain.
Different studies have shown the benefits (easy handling, low work load, low
cost at around USD 100, reduced hospital stay) of autologous retransfusion in elec-
tive orthopedic surgery, especially after hip and knee replacements (Healy et al.
1994; Goodnough et al. 2000, 2003; Juelsgaard et al. 2001; Henry et al. 2002;
Jelkmann 2008). Nevertheless, a few trials have described failings in this safe sys-
tem (Ishii and Matsuda 2005) and an increase in complication rates of 10 % (febrile
reactions or tachycardia) after the retransfusion of unwashed wound drainage blood
after total hip arthroplasty (Reize and Wulker 2007).
Retransfusion of shed blood is most effective if all lost blood can be collected
and given back, as in total knee arthroplasty, where tourniquets are used during
surgery. In hip arthroplasty, where blood loss occurs mostly during surgery, this
system does not seem to be the ideal solution (Juelsgaard et al. 2001), although
20 Bleeding Management in Elective Orthopedic Surgery 359

some studies have still reported a positive effect (Juelsgaard et al. 2001; Henry et al.
2002; Goodnough et al. 2003).

Conclusions
Concerns regarding the safety and high costs of allogenic blood products have
led to increased research and efforts to implement patient-blood management
programs in orthopedic surgery. A multidisciplinary approach to optimizing the
care of patients who might need transfusions should be an obligation for patients
undergoing orthopedic procedures. Both an individualized evaluation of the
patient and clinical management of the transfusion decision-making process are
necessary (including the application of appropriate indications), as are the mini-
mization of blood loss and optimization of the patient’s red cell mass. The need
to reduce allogenic blood transfusions and healthcare costs while ensuring that
blood components are available for the patients who need them is a cornerstone
of appropriate team work.
Anemic patients (women, Hb <12 g/dL; men, Hb <13 g/dL: WHO) should be
treated preoperatively with i.v. iron and EPO as this is the optimal method for
preparing a patient for elective surgery (Goodnough et al. 2000; Coyne et al.
2007; Dahl et al. 2008; So-Osman et al. 2014a, b).
The use of intraoperative platelet gel and fibrin sealant may be an adequate
option as they improve hemostatic effects, lower the incidence of postoperative
wound healing disturbances, present fewer infections, and lead to shorter hospi-
tal stays (Cuenca et al. 2004).
Intraoperative salvage is effective in patients where excessive blood loss
>1.5 L is expected (Goodnough et al. 1999). Due to the high costs associated
with these systems, their utility should be critically assessed before surgery.
Postoperative salvage is still debated, with some controversy regarding possible
side effects. So far, most of the concerns have been proven wrong and the method
itself is inexpensive and easy to use (Healy et al. 1994; Goodnough et al. 2000, 2003;
Juelsgaard et al. 2001; Henry et al. 2002; Cuenca et al. 2004, 2005; Jelkmann 2008).
Finally, it is not only important for surgeons and anesthesiologists to have
early knowledge of the patient’s preoperative Hb level and the expected blood
loss during surgery, but they should also have detailed knowledge about the dif-
ferent alternatives available for reducing the need for allogenic blood products.
All hospitals should adapt their methods with regard to the type of surgery to be
performed and to their financial possibilities.

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Perioperative Coagulation in Neuraxial
and Peripheral Nerve Blocks 21
Kyle Kirkham and Eric Albrecht

21.1 Introduction

The occurrence of hemorrhagic complications from the performance of neuraxial

and peripheral anesthesia are rare events, making estimates of their incidence chal-
lenging. The most dreaded hemorrhagic complication following regional anesthetic
techniques is the development of a symptomatic spinal hematoma with the concur-
rent risk of neurological ischemia and permanent paralysis. While spontaneous spi-
nal hematoma can occur in even healthy patients, medical anticoagulant therapy
increases the risk significantly. An extensive review of the literature examined 61
cases of spinal hematoma associated with neuraxial regional anesthesia and found
that 68 % involved impaired coagulation, most commonly heparin or low molecular
weight heparin (LMWH) (Vandermeulen et al. 1994). One quarter of procedures
were identified as being challenging, with bleeding identified at the time of needle
or catheter placement. The overall incidence of spinal hematoma after neuraxial
blockade is unknown; however, commonly quoted frequencies are calculated to be
less than 1 in 150,000 epidural and 1 in 200,0000 spinal procedures (Tryba 1993).
However, it may be as high as 1 in 3,600 procedures for the highest risk groups
(Moen et al. 2004). Risk factors contributing to this supplementary risk include
increased age, female sex, history of excessive bruising or bleeding, continuous
catheter technique, large needle gauge, multiple passes, and moderate or difficult
needle placements (Horlocker et al. 1995).

K. Kirkham, MD, FRCPC

Department of Anaesthesia and Pain Management,
Toronto Western Hospital, University of Toronto,
399 Bathurst Street, Toronto, Ontario, M5T 2S8, Canada
E. Albrecht, MD, DEAA (*)
Department of Anesthesiology, Centre Hospitalier Universitaire Vaudois
and University of Lausanne, Rue du Bugnon 45, 1011 Lausanne, Switzerland
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 365

DOI 10.1007/978-3-642-55004-1_21, © Springer-Verlag Berlin Heidelberg 2015
366 K. Kirkham and E. Albrecht

Given that most of these factors are either unmodifiable or unpredictable at the
start of a procedure, most of the attention placed on the prevention of hemorrhagic
complications has been towards coagulopathies induced by anticoagulant or anti-
thrombotic medication. The 2010 American Society of Regional Anesthesia and
Pain Medicine (ASRA) guidelines on regional anesthesia and antithrombotic med-
ications summarized a total of 26 case reports of hemorrhagic complication: 13
were associated with peripheral or plexus nerve blocks and antithrombotic therapy,
while 13 others occurred without concurrent antithrombotic therapy (Horlocker
et al. 2010). The majority of serious outcomes in this series were related to major
hemorrhage, which is theoretically more easily managed than a neuraxial hema-
toma. However, this series demonstrated that hospital admission may be prolonged
by this outcome, discomfort may be significant, transient neurological deficits may
occur, and consequences may be severe enough to result in death (Maier et al.
2002).
When deciding whether to proceed with a regional technique, consideration must
be given to the site of needle placement and to the consequences of a hemorrhagic
complication specific to that site. Current guidelines therefore advocate caution when
considering peripheral or plexus regional techniques in cases involving anticoagulated
patients. ASRA’s formal recommendation is that these techniques be considered
equivalent to neuraxial procedures (Horlocker et al. 2010). The European Society of
Anaesthesiology (ESA) similarly suggests that deep blocks, including lumbar plexus
and paravertebral blocks as well as the removal of indwelling catheters, should be
considered under neuraxial guidelines (Gogarten et al. 2010) if there is a newer one.
In general, a cautious approach is justified for any patient on anticoagulant medica-
tion. Even superficial procedures like axillary or popliteal neural blockade, where
accompanying vessels are directly compressible, should be carefully weighed up from
a risk-benefit perspective and where reasonable medication should be withheld for
appropriate time periods before needle or catheter placement.

21.2 Anticoagulants and Regional Anesthesia

21.2.1 Antiplatelet Agents

Antiplatelet medications include a broad range of agents with significantly different

implications for the performance of regional anesthesia. As a class, this group
includes aspirin and other nonsteroidal anti-inflammatory drugs (NSAID); the thi-
enopyridine derivatives, most notably clopidogrel and ticlopidine; and the GP IIb/
IIIa platelet receptor antagonists, including eptifibatide, tirofiban, and abciximab.
Each of these groups differs greatly in its pharmacological impact on platelet aggre-
gation and function and must therefore be examined separately when considering a
patient for a regional anesthetic technique.
The Collaborative Low-dose Aspirin Study in Pregnancy, published in 1994
(CLASP Lancet 1994), was conducted to investigate the management of pre-
eclampsia. Of those patients randomized to receive aspirin, approximately 750
21 Perioperative Coagulation in Neuraxial and Peripheral Nerve Blocks 367

Table 21.1 Guideline recommendations for antiplatelet agents

ESA guidelinesa ASRA guidelinesb
Time before procedure/ Time after Time before procedure/ Time after
catheter removal procedure catheter removal procedure
Aspirin Not specified Not specified None None
NSAID In isolation, no adjustment required In isolation, no adjustment required
Clopidogrel 7 days After catheter 7 days
removal
Ticlopidine 10 days After catheter 14 days
removal
Abciximab 48 h 24–48 h
Tirofiban/ 8–10 h 4–8 h
eptifibatide
a
Gogarten et al. (2010)
b
Horlocker et al. (2010)

continued their dose until at least 1 day prior to delivery, resulting in only one occur-
rence of traumatic cannula placement in the intervention group vs. two in the control
group and no spinal hematoma. While 3 of the 61 cases described by Vandermeulen
et al. (1994) were using NSAID concurrently, prospective case series have failed to
demonstrate an increased risk associated with continuing aspirin or NSAID during
the performance of neuraxial procedures (Horlocker et al. 1995, 2002).
As a result, NSAID dosing alone does not require adjustment for the purpose of
regional anesthesia. However, the balance of evidence from case reports suggests that
combining nonselective NSAID with other forms of thromboprophylaxis increases
the risk of major hemorrhagic complications (Ruff and Dougherty 1981; Moen et al.
2004). The practical implication of this observation is that a cautious approach should
be taken, as reflected in current guidelines. These limit postoperative use of NSAID
therapy to COX-2 selective agents if the administration of thromboprophylaxis is
anticipated, and patients on pre-procedure combination therapy should have their non-
selective NSAID withheld for 12–24 h prior to the planned procedure.
Thienopyridine derivatives have been associated with increased bleeding in sur-
gical settings and are generally considered contraindications for regional anesthe-
sia. The pharmacokinetics of these agents determines the recommendations for safe
time periods before invasive procedures. There is consensus that clopidogrel should
be discontinued 7 days prior to a regional anesthetic procedure (see Table 21.1).
Ticlopidine has a variable half-life that depends on the duration of its administra-
tion, and there is disagreement between European and North American recommen-
dations. The ESA minimum recommended period is 10 days (Gogarten et al. 2010),
whereas ASRA guidelines recommend 14 days (Horlocker et al. 2010). These
agents have, for example, been associated with both neuraxial and retroperitoneal
hematoma after lumbar plexus blockade.
Antagonist agents of the platelet GP IIb/IIIa receptor include abciximab, eptifi-
batide, and tirofiban. They have considerably different durations of effect on platelet
function, with a return to normal function requiring only 4–8 h after eptifibatide or
368 K. Kirkham and E. Albrecht

tirofiban, but a minimum of 24–48 h after abciximab therapy. The antiplatelet effect
of these agents is profound: it is prudent to target the upper limits of these ranges
when planning the removal of an indwelling catheter and to carefully monitor neu-
rological function afterward. In addition to their intrinsic activity, these agents gen-
erate a risk of significant thrombocytopenia that may last beyond their
pharmacological duration (Berkowitz et al. 1997). As such, it is recommended that
a platelet count be performed for any patient who has received a GP IIb/IIIa
inhibitor.

21.2.2 Unfractionated Heparin

The administration of low-dose subcutaneous unfractionated heparin (UFH), pri-

marily for the purpose of thromboprophylaxis, has a considerable accumulated
body of practice. Overall, there is little evidence to suggest a significant increase in
risk associated with the performance of regional anesthetic techniques in patients
who are receiving this therapy. Liu and Mulroy (1998) summarized the early, pub-
lished experience of neuraxial anesthesia in the presence of subcutaneous UFH and
found no epidural hematomas in over 9,000 cases. When administered subcutane-
ously, a 1–2 h delay exists before peak anticoagulant effect. Some authors therefore
advise a delay of 4–6 h before needle placement. Controversy exists as to whether
any interval is necessary however, given the low perceived risk of complications in
current North American guidelines; these do not advocate any specific delay when
daily doses of 5,000 U are administered twice daily (Horlocker et al. 2010).
Higher daily doses or more frequent dosing intervals carry a potential, but uncer-
tain, increased risk. European recommendations for prophylactic dosing include
withholding heparin therapy for a minimum of 4–6 h prior to a regional procedure,
with a further delay to 8–12 h in a setting of therapeutic subcutaneous dosing; the
re-initiation of therapy should be delayed for 1 h after completion of the
procedure.
Systemic intraoperative, intravenous heparinization, for indications such as vas-
cular surgery, carries a potential significant impact on the risk of neuraxial compli-
cations. For patients who have undergone a regional anesthetic technique,
intraoperative i.v. heparin should be delayed a minimum of 1 h after needle or cath-
eter placement. In the setting of a traumatic needle placement, most authors advo-
cate a risk-benefit discussion between the patient and surgical team to determine
whether to continue with the procedure at all (Liu and Mulroy 1998). European
guidelines (Gogarten et al. 2010) suggest an even more cautious approach where
possible, including delaying heparinization for 6–12 h and, when possible, post-
ponement of the operation.
The removal of an indwelling catheter should be considered the equivalent to an
invasive procedure and similar delays to therapy are recommended. In addition, due
to the potential for patients to develop heparin-induced thrombocytopenia (HIT), a
platelet count is advisable prior to needle placement for any patient who has received
therapy for greater than 4–5 days (Linkins et al. 2012) (Table 21.2).
21 Perioperative Coagulation in Neuraxial and Peripheral Nerve Blocks 369

Table 21.2 Guideline recommendations for unfractionated heparins

ESA guidelinesa ASRA guidelinesb
Time before procedure/ Time after Time before procedure/ Time after
catheter removal procedure catheter removal procedure
Prophylaxis 4–6 h 1h No delay
(<15,000 IU/day) (<10,000 IU/day)
Therapeutic 8–12 h 1h Not established
S.C.
Intravenous 4 h and normal 1h 2–4 h 1h
laboratory values
Traumatic Delay low-dose therapy 1–2 h; delay Individual patient risk-benefit
needle intraop heparinization 6–12 h; discussion with surgical team
placement consider surgical delay
a
Gogarten et al. (2010)
b
Horlocker et al. (2010)

21.2.3 Low Molecular Weight Heparin

The performance of regional anesthesia in cases using low molecular weight hepa-
rins (LMWH) deserves special consideration for three reasons. Firstly, in many cen-
ters, LMWH has replaced UFH or oral anticoagulants as the thromboprophylaxis of
choice. As a result, significant numbers of patients are exposed to this class of medi-
cation annually. Secondly, traditional coagulation tests such as activated partial
thromboplastin time (aPTT) and activated clotting time (ACT) are unaffected by
LMWH, making monitoring challenging. Thirdly, the introduction of LMWH, par-
ticularly in North America, had a demonstrable impact on the reported number of
hemorrhagic complications from neuraxial needle placement in a relatively short
period of time. Between 1993 and 1998, 60 cases of spinal hematoma were reported
after the introduction of LMHW to the United States (Horlocker et al. 2010). It has
been estimated that this represented a frequency of approximately 1 in 3,100 epi-
dural catheter procedures and 1 in 40,800 spinal procedures (Schroeder 1998).
These observations contrasted with prior European experience where, in one exam-
ple, Bergqvist et al. (1992) pooled 9,013 neuraxial patients receiving LMWH from
11 studies and found no incidence of hematoma. This geographical difference may
partially be accounted for by different dosing regimen, with North American
patients often receiving twice-daily dosing.
The increased risk of twice-daily dosing is reflected in both current North
American and European guidelines. Recommendations include delaying needle
placement or catheter removal for a period of 10–12 h after prophylactic once-daily
dosing and then restarting therapy for a minimum of 2–4 h after the procedure.
Initiation of postoperative therapy should begin no earlier than 6–8 h after needle
placement. Twice-daily or therapeutic dosing should be withheld for a minimum of
24 h before a regional procedure or the removal of an indwelling catheter. In this
setting, therapy may be restarted a similar 2–4 h after the procedure. However,
ASRA guidelines further recommend delaying the initiation of postoperative
370 K. Kirkham and E. Albrecht

Table 21.3 Guideline recommendations for low molecular weight heparins

ESA guidelinesa ASRA guidelinesb
Time before
procedure/catheter Time after Time before procedure/ Time after
removal procedure catheter removal procedure
Pre-procedure 12 h 4h 10–12 h 2h
LMWH
Higher dose or 24 h 4h 24 h 2h
twice daily
Postoperative Once-daily dosing: delay LMWH for
LMWH 6–8 h
Twice-daily dosing: delay LMWH for
24 h and remove catheter 2 h
pre-therapy
Traumatic needle Consider delaying therapy for 24 h
placement
a
Gogarten et al. (2010)
b
Horlocker et al. (2010)

twice-daily dosing by 24 h after a neuraxial technique, as well as removing indwell-

ing catheters 2 h before therapy begins.
As described above, the concurrent administration of thromboprophylaxis may
increase the hemorrhagic risk of otherwise benign antiplatelet agents like NSAID.
Thus careful attention should be paid to the complete medical history of these
patients to ensure that no other agents which might increase the risk of a serious
complication (beyond that considered in these recommendations) are being co-
administered. The risk of HIT associated with LMWH is real but uncommon, with
some series failing to show any significant incidence of this condition (Warkentin
et al. 1995) (Table 21.3).

21.2.4 Vitamin K Antagonists

The administration of vitamin K antagonists, particularly warfarin for perioperative

thromboprophylaxis, remains common in many centers in North America. As such,
there remains considerable interest in the optimal management of these medica-
tions, the specifics of their monitoring, and which levels of anticoagulation place
patients at increased risk during regional anesthetic procedures. All recommenda-
tions are strongly opposed to performing procedures on patients who are therapeuti-
cally anticoagulated. However, there has been some relevant debate in recent
literature regarding how strict recommendations should be, particularly with respect
to the initiation of treatment.
Generally, levels of factors II, VII, IX, or X below 40 % of the normal have been
quoted as posing a high risk of bleeding (Raj et al. 2004). This level is felt to occur
around an international normalized ratio (INR) of 1.5; however, the differing half-
lives of each factor determine their relative level when this laboratory result is
21 Perioperative Coagulation in Neuraxial and Peripheral Nerve Blocks 371

Table 21.4 Guideline recommendations for warfarin

ESA guidelinesa ASRA guidelinesb
Time before Time before Time after procedure
procedure/catheter Time after procedure/catheter (may initiate therapy
removal procedure removal pre- or post-procedure
Initiation of After Catheter removal
therapy catheter INR ≤1.4
removal INR <3.0 with no
other agents and
neuromonitoring
Preexisting INR ≤1.4 4–5 days and
therapy normal INR
a
Gogarten et al. (2010)
b
Horlocker et al. (2010)

reached. North American guidelines recommend that preexisting therapy be stopped

4–5 days before a regional technique and that the INR be normalized. For newly
initiated therapy, concurrent administration of medication affecting hemostasis is
discouraged, the INR should be monitored daily, and neurological function exam-
ined routinely. Indwelling catheters should preferably be withdrawn with the INR
<1.5, but an INR <3.0 may be permissible in the presence of otherwise normal
hemostasis and appropriate monitoring (Horlocker et al. 2010). Several case series
demonstrate that INR values in this higher range are likely to be safe during the
initiation phase of therapy (Parvizi et al. 2006; Liu et al. 2011), although a cautious
approach is justified.
Reversal of vitamin K antagonists may be accelerated using oral or intravenous
vitamin K supplementation or may be clinically reversed through the administration
of prothrombin complex concentrates or plasma. In most centers the administration
of plasma or plasma-derived products would be supported if required for urgent
surgery, but not specifically for the purpose of performing an elective or semi-
elective regional anesthetic technique (Table 21.4).

21.2.5 Anti-Xa Agents and Direct Thrombin Inhibitors

This class of medication has recently expanded, with new agents in development
and approved for clinical use. Many of these drugs present unique challenges to the
regional anesthesiologist. The anti-Xa drug with the longest history, in both Europe
and North America, is fondaparinux, but the introduction of rivaroxaban, apixaban,
and others has led to an increasing number of patients presenting for chronic antico-
agulation. The half-lives of these agents are typically long (allowing for once-daily
dosing), but are varied: fondaparinux near 20 h and rivaroxaban closer to 6 h. The
literature supporting periprocedural guidelines is developing. Recommendations are
typically cautious and based directly on what is known of the agents’ pharmacology.
For example, the manufacturer of the univalent direct thrombin inhibitor dabigatran
372 K. Kirkham and E. Albrecht

Table 21.5 Guideline recommendations for anti-Xa agents

ESA guidelinesa ASRA guidelinesb
Time before procedure/ Time after Time before procedure/ Time after
catheter removal procedure catheter removal procedure
Fondaparinux 36–42 h 6–12 h Single injection, atraumatic needle
(2.5 mg daily) placement or alternate prophylaxis.
Avoid indwelling catheters
Rivaroxaban 22–26 h 4–6 h
(10 mg daily)
Apixaban 26–30 h 4–6 h
(2.5 mg BID)
Dabigatran Contraindicated 6h
(150–220 mg)
Argatroban 4h 2h Recommend against neuraxial
techniques
Hirudins 8–10 h 2–4 h Recommend against neuraxial
(e.g., lepirudin, techniques
desirudin)
a
Gogarten et al. (2010)
b
Horlocker et al. (2010)

suggests that regional procedures should be contraindicated in patients receiving it.

It is recommended that physicians who anticipate encountering these agents famil-
iarize themselves with their individual pharmacology, as specific considerations
exist for each one. To illustrate this, dabigatran is up to 80 % renally cleared and
clearance half-time may be greatly affected in cases of renal insufficiency; the lack
of any monitoring test makes prediction of adequate reversal challenging.
In a series of patients receiving fondaparinux 2.5 mg thromboprophylaxis post-
operatively, 1,631 patients underwent neuraxial or deep peripheral regional anesthe-
sia and no major hemorrhagic complications were noted. However, first doses were
administered 6–12 h after surgery, while treatment was withheld for 36 h before
surgery, and restarted 12 h after indwelling catheter removal (Singelyn et al. 2007).
Ultimately, little clinical evidence has been reported and extreme caution is recom-
mended, particularly when considering a neuraxial technique. Table 21.5 summa-
rizes current guideline recommendations.

21.2.6 Thrombolytics

Thrombolytics, like the exogenous plasminogen activators streptokinase or anistre-

plase, are only administered in emergency situations and thus often unpredictably
for the regional anesthesiologist. If this situation is encountered after performance
of a regional technique, vigilance is necessary and frequent neurological examina-
tions should be performed to assess for the possibility of a hemorrhagic complica-
tion. Consideration should be made for leaving indwelling catheters in situ until
thrombolytic activity has ceased.
21 Perioperative Coagulation in Neuraxial and Peripheral Nerve Blocks 373

References
Bergqvist D, Lindblad B, Matzsch T (1992) Low molecular weight heparin for thromboprophy-
laxis and epidural/spinal anaesthesia – is there a risk? Acta Anaesthesiol Scand 36:605–609
Berkowitz SD, Harrington RA, Rund MM et al (1997) Acute profound thrombocytopenia after
c7E3 Fab (Abciximab) therapy. Circulation 95:809–813
CLASP Collaborative Group (1994) CLASP: a randomized trial of low-dose aspirin for the pre-
vention and treatment of pre-eclampsia among 9364 pregnant women. Lancet 343:619–629
Gogarten W, Vandermeulen E, Van Aken H et al (2010) Regional anaesthesia and antithrombotic
agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol
27:999–1015
Horlocker TT, Wedel DJ, Schroeder DR et al (1995) Preoperative antiplatelet therapy does not
increase the risk of spinal hematoma associated with regional anesthesia. Anesth Analg
80:303–309
Horlocker TT, Bajwa ZH, Ashraf Z et al (2002) Risk assessment of hemorrhagic complications
associated with nonsteroidal anti-inflammatory medications in ambulatory pain clinic patients
undergoing epidural steroid injection. Anesth Analg 95:1691–1697
Horlocker TT, Wedel DJ, Rowlingson JC et al (2010) Regional anesthesia in the patient receiving
antithrombotic or thrombolytic therapy, American Society of Regional Anesthesia and Pain
Medicine evidence-based guidelines (third edition). Reg Anesth Pain Med 35:64–101
Linkins L-A, Dans AL, Moores LK et al (2012) Treatment and prevention of heparin-induced
thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American
College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(2
Suppl):e495S–e530S
Liu SS, Mulroy MF (1998) Neuraxial anesthesia and analgesia in the presence of standard heparin.
Reg Anesth Pain Med 23(6 Suppl 2):157–163
Liu SS, Buvanendran A, Viscusi ER et al (2011) Uncomplicated removal of epidural catheters in
4365 patients with international normalized ratio greater than 1.4 during initiation of warfarin
therapy. Reg Anesth Pain Med 36:231–235
Maier C, Gleim M, Weiss T et al (2002) Severe bleeding following lumbar sympathetic blockade
in two patients under medication with irreversible platelet aggregation inhibitors. Anesthesiology
97:740–743
Moen V, Dahlgren N, Irestedt L (2004) Severe neurological complications after central neuraxial
blockades in Sweden 1990–1999. Anesthesiology 101:950–959
Parvizi J, Viscusi ER, Harrison GF et al (2006) Can epidural anesthesia and warfarin be coadmin-
istered? Clin Orthop Relat Res 456:133–137
Raj PP, Shah RV, Kaye AD et al (2004) Bleeding risk in interventional pain practice: assessment,
management, and review of the literature. Pain Physician 7:3–51
Ruff RL, Dougherty JH (1981) Complications of lumbar puncture followed by anticoagulation.
Stroke 12:879–881
Schroeder DR (1998) Statistics: detecting a rare adverse drug reaction using spontaneous reports.
Reg Anesth Pain Med 23(Suppl 2):183–189
Singelyn FJ, Verheyen C, Piovella F et al (2007) The safety and efficacy of extended thrombopro-
phylaxis with fondaparinux after major orthopedic surgery of the lower limb with or without a
neuraxial or deep peripheral nerve catheter: the EXPERT study. Anesth Analg
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Tryba M (1993) Epidural regional anesthesia and low molecular heparin: Pro. [German].
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Anesth Analg 79:1165–1177
Warkentin TE, Levine MN, Hirsh J et al (1995) Heparin-induced thrombocytopenia in patients
treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med
332:1330–1335
 Part III
Post-operative Hemostasis
Coagulation Disorders in Intensive
Care Patients 22
Marcel Levi

22.1 Introduction

Critically ill patients commonly suffer from coagulation abnormalities (Levi and
Opal 2006). A myriad of altered coagulation parameters is often detectable, such as
thrombocytopenia, longer global coagulation times, reduced levels of coagulation
inhibitors, or high levels of fibrin split products. Each of these clotting derange-
ments may derive from a variety of different pathophysiological mechanisms. Some
patients may have a marked coagulopathy, yet it can go largely undetected when
measured using routine coagulation assays. Proper identification of the underlying
cause for these coagulation abnormalities is required since different coagulation
disorders may necessitate different diagnostic and therapeutic management strate-
gies. This chapter reviews the most frequently occurring coagulation abnormalities
in patients in intensive care units (ICUs). Emphasis is put on the differential diagno-
sis, the underlying molecular and pathogenetic pathways, and the appropriate diag-
nostic and therapeutic interventions.

22.2 Incidence

The incidence of thrombocytopenia (platelet count <150 × 109/l) in critically ill

patients is 35–44 % (Vanderschueren et al. 2000). A platelet count of <100 × 109/l is
seen in another 30–50 % of patients. A longer global coagulation time, such as pro-
thrombin time (PT) or the activated partial thromboplastin time (aPTT), occurs in
14–28 % of ICU patients (Levi and Opal 2006).
ICU patients with coagulation defects have a four to five times higher risk of
bleeding than patients with a normal coagulation status (Vanderschueren et al.

M. Levi, MD
Department of Vascular Medicine and Internal Medicine, Academic Medical Center,
University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
e-mail: [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 377

DOI 10.1007/978-3-642-55004-1_22, © Springer-Verlag Berlin Heidelberg 2015
378 M. Levi

2000). The risk of intracerebral bleeding in critically ill patients during ICU admis-
sion is relatively low (0.3–0.5 %), but 88 % of patients with this complication have
platelet counts <100 × 109/l. Moreover, a decrease in platelet count may indicate
ongoing coagulation activation, which contributes to microvascular failure and
organ dysfunction. Early identification of these patients is crucial to the provision
of adequate supportive care (Ahmed et al. 2009; Schultz 2009). Regardless of the
cause, thrombocytopenia is an independent predictor of ICU mortality in multi-
variate analyses, with various studies showing a relative risk of 1.9–4.2 (Fig. 22.1)
(Strauss et al. 2002; Vanderschueren et al. 2000). Other coagulation test abnormali-
ties frequently observed in ICU patients include elevated fibrin split products and
reduced levels of coagulation inhibitors. Fibrin split products, such as D-dimer,
were detectable in 42 % of a consecutive case series of ICU patients, in 80 % of
trauma patients, and in 99 % of patients with sepsis (Bernard et al. 2001; Shorr
et al. 2002). Low levels of coagulation inhibitors, such as antithrombin and protein
C, are found in 40–60 % of trauma patients and 90 % of sepsis patients (Bernard
et al. 2001).

22.3 Coagulation and Inflammation in Critically Ill Patients

The simultaneous and interdependent activation of inflammation and coagulation is

important in the pathogenesis of many systemic inflammatory states that can be found
in critically ill patients. Endothelial cells and natural anticoagulant pathways have a
central position in the interaction between coagulation and inflammation pathways;
the restoration of defective anticoagulant pathways in patients with sepsis has there-
fore received considerable attention (Levi and van der Poll 2008). There is ample
evidence that there exists extensive crosstalk between inflammation and coagulation,

1,400 50

1,200
40
Number of patients

1,000
Mortality

800 30

600 20
400
10
200

0 0
<50 50-100 100-150 >150
Platelet count (×109/I)

Fig. 22.1 Distribution of nadir platelet count (black bars) and survival (striped bars) in a pooled
analysis of four clinical studies of consecutive groups of patients admitted to an ICU (From Levy
and Opal (2010) with permission)
22 Coagulation Disorders in Intensive Care Patients 379

whereby inflammation not only leads to activation of coagulation, but coagulation

also markedly affects inflammatory activity (Levi et al. 2008). Procoagulant activity is
regulated by three key anticoagulant pathways: antithrombin, the protein C/thrombo-
modulin system, and tissue factor pathway inhibitor (Esmon 2001). Notably, activated
protein C (APC) appears to play a central role in the pathogenesis of sepsis and associ-
ated organ dysfunction (Griffin et al. 2007). There is ample evidence that an insuffi-
cient functioning of the protein C pathway contributes to the derangement of
coagulation in sepsis (Esmon 1987; Levi et al. 2001). The circulating zymogen pro-
tein C is activated by the endothelial cell-bound thrombomodulin once this is acti-
vated by thrombin (Esmon 1987). APC acts in concert with its cofactor protein S and
is able to proteolytically degrade the activated cofactors V (FVa) and VIII (FVIIIa)
which are essential to coagulation; hence, it is an effective anticoagulant. The endo-
thelial protein C receptor not only accelerates activation of protein C several times
over but also serves as a receptor for APC, and the binding of APC to this receptor
may amplify its anticoagulant and anti-inflammatory effects (Esmon 2000). In patients
with sepsis, plasma levels of the zymogen protein C are low or very low due to
impaired synthesis, consumption, and degradation by proteolytic enzymes, such as
neutrophil elastase (Eckle et al. 1991; Mesters et al. 2000; Vary and Kimball 1992).
Furthermore, a significant downregulation of thrombomodulin, caused by pro-inflam-
matory cytokines such as tumor necrosis factor-α and interleukin-1, has been demon-
strated, resulting in diminished protein C activation (Faust et al. 2001; Nawroth and
Stern 1986). Low levels of free protein S may further compromise an adequate func-
tion of the protein C system. In plasma, 60 % of the cofactor protein S is complexed
to a complement regulatory protein, C4b-binding protein (C4bBP). As a consequence
of the acute phase reaction in inflammatory diseases, increased levels of C4bBP in
plasma may result in a relative deficiency of protein S, which further contributes to a
procoagulant state during sepsis. Finally, but importantly, the endothelial protein C
receptor has been shown to be downregulated in sepsis, and this may negatively affect
the function of the protein C system (Taylor et al. 2000). Interestingly, all three anti-
coagulant systems are located at the endothelial surface, where they can direct both
anticoagulant and anti-inflammatory functions. During inflammation-induced activa-
tion of coagulation, the functions of all three pathways may be impaired (Levi et al.
2004). Pro-inflammatory cytokines and chemokines, as well as endothelial cell per-
turbation, affect all physiological anticoagulant mechanisms, and vice versa, activated
coagulation proteases and physiological anticoagulants can modulate inflammation
via specific cell receptors.

22.4 Causes of Thrombocytopenia

There are many causes of thrombocytopenia in critically ill patients. Table 22.1
summarizes the most frequently occurring diagnoses.
Sepsis is a clear risk factor for thrombocytopenia in critically ill patients, and the
severity of sepsis correlates with the decrease in platelet count (Mavrommatis et al.
2000). The main factors contributing to thrombocytopenia in patients with sepsis
380 M. Levi

Table 22.1 Differential diagnosis of thrombocytopenia in the ICU

Differential Relative
diagnosis incidence (%) Additional diagnostic clues
Sepsis 52.4 Positive (blood)cultures, positive sepsis criteria,
hematophagocytosis in bone marrow aspirate
DICa 25.3 Prolonged aPTT and PT, increased fibrin split products,
low levels of physiological anticoagulant factors
(antithrombin, protein C)
Massive blood loss 7.5 Major bleeding, low hemoglobin, longer aPTT and PT
Thrombotic 0.7 Schistocytes in blood smear, Coombs-negative hemolysis,
microangiopathy fever, neurologic symptoms, renal insufficiency
Heparin-induced 1.2 Use of heparin, venous or arterial thrombosis, positive HIT
thrombocytopenia test (usually ELISA for heparin–platelet factor IV
antibodies), rebound of platelets after cessation of heparin
Immune 3.4 Antiplatelet antibodies, normal or increased number of
thrombocytopenia megakaryocytes in bone marrow aspirate, thrombopoietin
(TPO) decreased
Drug-induced 9.5 Decreased number of megakaryocytes in bone marrow
thrombocytopenia aspirate or detection of drug-induced antiplatelet
antibodies, rebound of platelet count after cessation of drug
Seven major causes of thrombocytopenia (platelet count <150 × 109/l) are listed. Relative incidences
are based on two studies in consecutive ICU patients. Patients with hematological malignancies
were excluded.
a
Patients with sepsis and DIC are classified as DIC

are impaired platelet production, increased platelet consumption or destruction, or

platelet sequestration in the spleen or on the endothelial surface. In patients with
sepsis, impaired platelet production within the bone marrow may seem contradic-
tory to the high levels of platelet production-stimulating pro-inflammatory cyto-
kines (such as tumor necrosis factor-α and interleukin-6) and high concentrations of
circulating thrombopoietin. These cytokines and growth factors should theoretically
stimulate megakaryopoiesis in the bone marrow (Folman et al. 2000). However,
marked hemophagocytosis may occur in a significant number of patients with sep-
sis. This pathological process consists of active phagocytosis of megakaryocytes
and other hematopoietic cells by monocytes and macrophages, due hypothetically
to their stimulation by high levels of macrophage colony-stimulating factor in sepsis
(Francois et al. 1997). Platelet consumption probably also plays an important role in
patients with sepsis, due to ongoing generation of thrombin (which is the most
potent activator of platelets in vivo) in its most fulminant form, known as dissemi-
nated intravascular coagulation (see below). Platelet activation, consumption, and
destruction may also occur at the endothelial site as a result of the extensive endo-
thelial cell–platelet interaction in sepsis, although this may vary between different
vascular beds in various organs (Levi and Lowenberg 2008).
Heparin-induced thrombocytopenia (HIT) is caused by a heparin-induced anti-
body that binds to the heparin–platelet factor IV complex on the platelet surface
(Warkentin et al. 2003). This may result in massive platelet activation, and as a
consequence, a consumptive thrombocytopenia and arterial and venous thrombosis
22 Coagulation Disorders in Intensive Care Patients 381

occur. A consecutive series of critically ill ICU patients who received heparin
revealed an incidence of 1 % in this setting (Verma et al. 2003). Unfractionated
heparin carries a higher risk of HIT than low molecular weight heparin (LMWH).
Thrombosis may occur in 25–50 % of patients with HIT (with fatal thrombosis in
4–5 %) (Warkentin 2003). The diagnosis of HIT is based on the detection of HIT
antibodies in combination with the occurrence of thrombocytopenia in a patient
receiving heparin, with or without concomitant arterial or venous thrombosis. It
should be mentioned that the commonly used ELISA (enzyme-linked immunosor-
bent assay) for HIT antibodies has a high negative predictive value (100 %), but a
very low positive predictive value (10 %) (Verma et al. 2003). The gold standard for
the diagnosis of HIT is a sensitive platelet activation assay; however, this test is not
routinely available. Normalization of the number of platelets 1–3 days after discon-
tinuation of heparin may further support the diagnosis of HIT.
The category of thrombotic microangiopathies encompasses syndromes such as
thrombotic thrombocytopenic purpura, hemolytic–uremic syndrome, severe malig-
nant hypertension, chemotherapy-induced microangiopathic hemolytic anemia, and
the HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count)
(Moake 2002). A common pathogenetic feature of these clinical entities appears to
be endothelial damage, causing platelet adhesion and aggregation, thrombin forma-
tion, and impaired fibrinolysis. The multiple clinical consequences of this extensive
endothelial dysfunction include thrombocytopenia, mechanical fragmentation of
red blood cells with hemolytic anemia, and obstruction of the microvasculature of
various organs such as the kidneys and the brain (leading to renal failure and neuro-
logic dysfunction, respectively). Despite this common final pathway, the various
thrombotic microangiopathies have different underlying etiologies. Thrombotic
thrombocytopenic purpura is caused by congenital or acquired (autoimmune) defi-
ciency of von Willebrand factor-cleaving protease (ADAMTS13); this results in
endothelial cell-attached ultra-large von Willebrand multimers that readily bind to
platelet surface glycoprotein Ib and cause platelet adhesion and aggregation (Tsai
2003). In hemolytic–uremic syndrome, a cytotoxin released upon infection with a
specific serogroup of gram-negative microorganisms (usually E. coli serotype
O157:H7) is responsible for endothelial cell and platelet activation. In case of
malignant hypertension or chemotherapy-induced thrombotic microangiopathy,
direct mechanical and chemical damages to the endothelium are, respectively, pre-
sumed responsible for the enhanced endothelial cell–platelet interaction. A diagnosis
of thrombotic microangiopathy relies upon the combination of thrombocytopenia,
the Coombs-negative hemolytic anemia, and the presence of schistocytes in the
blood smear. Additional information can be achieved by measurement of
ADAMTS13; however, low levels of ADAMTS13 may occur in all forms of throm-
botic microangiopathy (van den Born et al. 2008).
Drug-induced thrombocytopenia is another frequent cause of thrombocytopenia
in an ICU setting (Stephan et al. 1999). It may be caused by drug-induced myelo-
suppression, such as that caused by cytostatic agents or by immune-mediated mech-
anisms. Drug-induced thrombocytopenia is a difficult diagnosis in an ICU setting as
patients are often exposed to multiple agents and have numerous other potential
382 M. Levi

reasons for platelet depletion. Drug-induced thrombocytopenia is often diagnosed

based upon the timing of the initiation of a new agent in relation to the development
of thrombocytopenia, after exclusion of other possible causes. A rapid restoration
of the platelet count observed after discontinuation of a suspected agent is highly
suggestive of drug-induced thrombocytopenia.

22.5 Causes of Prolonged Global Coagulation Times

It is important to emphasize that global coagulation tests, such as PT and aPTT, are
a poor reflection of in vivo hemostasis. However, these tests are a convenient method
of quickly estimating the concentration of one or at times multiple coagulation
factors for which each test is sensitive (Table 22.2) (Greaves and Preston 2001).
In general, coagulation tests will take longer if coagulation factor levels are below
50 %. This is relevant since the coagulation factor levels needed for adequate hemo-
stasis are somewhere between 25 and 50 % (Edmunds 2001).
Longer global coagulation tests may be due to a deficiency of one or more coagu-
lation factors. In addition, but more rarely, the presence of an inhibiting antibody
with a major in vivo relevance (such as in acquired hemophilia), but a clinically
insignificant laboratory phenomenon, should be considered. The presence of lupus
anticoagulant may cause a longer aPTT and can be associated with thrombocytope-
nia as well. Paradoxically, lupus anticoagulant may dramatically increase the risk of
thrombosis. The presence of an inhibiting antibody can be confirmed using a simple
mixing experiment. As a general rule, if a longer global coagulation test cannot be
corrected by mixing 50 % of patient plasma with 50 % of normal plasma, then an
inhibiting antibody is likely to be present.

Table 22.2 Differential diagnosis of abnormal global coagulation times

Test result Cause
PT prolonged, Factor VII deficiency
normal aPTT Mild vitamin K deficiency
Mild liver insufficiency
Low doses of vitamin K antagonists
Normal PT, aPTT Factor VIII, IX, or XI deficiency
prolonged Use of unfractionated heparin
Inhibiting antibody and/or antiphospholipid antibody
Factor XII or prekallikrein deficiency (no relevance for in vivo coagulation)
PT and aPTT Factor X, V, and II or fibrinogen deficiency
prolonged Severe vitamin K deficiency
Use of vitamin K antagonists
Global clotting factor deficiency
Synthesis: liver failure
Loss: massive bleeding
Consumption: DIC
Levi and Opal (2010)
22 Coagulation Disorders in Intensive Care Patients 383

In the vast majority of critically ill patients, deficiencies of coagulation factors

are acquired, and we will not discuss the various congenital coagulation defects
here. In general, deficiencies in coagulation factors may be due to impaired synthe-
sis, massive loss, or increased turnover (consumption). Impaired synthesis is often
due to liver insufficiency or vitamin K deficiency. Vitamin K deficiency may be
caused by poor nutrition in combination with the use of antibiotics that affect intes-
tinal flora and thereby bacterial vitamin K production. PT is highly sensitive to
both conditions since this test is very dependent on the plasma levels of factor VII
(a vitamin K-dependent coagulation factor with the shortest half-life of the clotting
factors). Liver failure may be differentiated from vitamin K deficiency by measur-
ing factor V, which is not vitamin K dependent. In fact, factor V plays an important
role in various scoring systems for severe acute liver failure (Bailey et al. 2003).
Uncompensated losses of coagulation factors may occur after massive bleeding,
for example, in trauma patients or patients undergoing major surgical procedures.
It is particularly common in patients with major blood loss where intravascular
volume is rapidly replaced with crystalloids, colloids, and red blood cells without
simultaneous administration of coagulation factors. The resulting depletion coagu-
lopathy may persist and exacerbate bleeding. In addition, transfusion in these
patients may lead to systemic activation of inflammatory processes and may con-
tribute to further coagulation derangements (Vlaar et al. 2009). In hypothermic
patients (e.g., trauma patients), measurements from global coagulation tests may
underestimate coagulation in vivo since laboratory test-tube assays are standard-
ized and performed at 37 °C to simulate normal body temperature. Consumption
of coagulation factors may occur within the framework of disseminated intravas-
cular coagulation (see below). In complicated cases, various causes for longer
global coagulation times may exist at once, and the cause can also change over
time. For example, multi-trauma patients will often present with a loss of coagula-
tion factors due to severe bleeding, but they can later develop a consumption
coagulopathy due to disseminated intravascular coagulation (DIC) that is a conse-
quence of a systemic inflammatory response. Coagulopathy may ensue from
trauma-induced liver injury and acute hepatic failure with resultant impaired
coagulation factor synthesis.
Some anticoagulant agents will also lengthen global coagulation times.
Unfractionated heparin lengthens aPTT, but confusingly, LMWH has no such effect
(or only a very modest one). Vitamin K antagonists cause a reduction in vitamin
K-dependent coagulation factors, resulting in an initial lengthening of PT, followed
by lengthening of both PT and aPTT.

22.6 Disseminated Intravascular Coagulation

DIC occurs in a substantial proportion of consecutive intensive care patients. It is a

syndrome caused by systemic intravascular activation of coagulation that may be
secondary to various underlying conditions (Levi and ten Cate 1999). The forma-
tion of microvascular thrombi, in concert with inflammatory activation, may cause
384 M. Levi

failure of the microvasculature and thereby contribute to organ dysfunction (Wheeler

and Bernard 1999). Ongoing and insufficiently compensated consumption of plate-
lets and coagulation factors may pose a risk of bleeding, especially in perioperative
patients or patients who need to undergo invasive procedures. Thrombin generation
proceeds via the (extrinsic) tissue factor/factor VIIa route concomitant with depres-
sion of the inhibitory mechanisms of thrombin generation, such as the antithrombin
III and protein C and S systems (Levi et al. 2008). Impaired fibrin degradation, due
to high circulating levels of plasminogen activator inhibitor 1, further enhances
intravascular fibrin deposition.
Patients with DIC have a low or rapidly decreasing platelet count, longer global
coagulation tests, low plasma levels of coagulation factors and inhibitors, and
increased markers of fibrin formation and/or degradation, such as D-dimer or fibrin
degradation products (Levi et al. 2009). Coagulation proteins with a marked acute
phase behavior, such as factor VIII or fibrinogen, are usually not decreased or may
even increase. Thus fibrinogen, although one of the commonly advocated laboratory
tests for the diagnosis of DIC, is not a very reliable marker for DIC, except in very
severe cases, although sequential measurements can provide some insight. There is
no single laboratory test with sufficient accuracy for the diagnosis of DIC. However,
its diagnosis may be made using a simple scoring system based on a combination of
routinely available coagulation tests (Taylor et al. 2001). In a number of prospective
validation studies, the sensitivity and specificity of this DIC score were found to be
above 95 and 98 %, respectively. Furthermore, this DIC score was found to be a
strong and independent predictor of mortality in a large series of patients with
severe sepsis (Dhainaut et al. 2004). Recent research points to a prominent associa-
tion between activated coagulation as a result of inflammation or tissue damage and
preexisting metabolic derangements, such as diabetes mellitus (Hermanides et al.
2009; Levi et al. 2008).

22.7 Management of Coagulation Abnormalities

in Intensive Care Patients

The primary focus of attention in the treatment of a clinically relevant coagulopathy

should clearly be directed towards the adequate management of the underlying con-
dition. Nevertheless, in addition to a proper treatment for the underlying disorder,
supportive measures for the treatment of coagulation defects are also often required.
For patients with a platelet count of <30–50 × 109/l, accompanied by bleeding or
at high risk of bleeding, and in patients with a platelet count <10 × 109/l, regardless
of the presence or absence of bleeding, most guidelines advocate a platelet transfu-
sion. Platelet concentrates usually contain a mixture of platelets from the blood
donations of 5–6 donors (equal to 5–6 units), although in some parts of the world
(notably the USA), single-donor transfusion has become the usual practice due to a
presumed decrease in side effects and potential for antibody formation. Platelet
transfusion is particularly effective in patients with a thrombocytopenia due either
to impaired platelet production or increased consumption; disorders of enhanced
22 Coagulation Disorders in Intensive Care Patients 385

platelet destruction (e.g., immune thrombocytopenia) may necessitate alternative

therapies, such as steroids or human immunoglobulin. Some causes of thrombocy-
topenia may require specific measures. HIT (or suspected HIT) requires immediate
cessation of heparin and initiation of an alternative anticoagulant treatment, e.g.,
with danaparoid, thrombin inhibitors, or fondaparinux (Hirsh et al. 2004). Vitamin
K antagonists should be avoided in the initial treatment of HIT since these agents
may cause skin necrosis. In patients with a thrombotic microangiopathy due to
antibody-induced low levels of ADAMTS13, plasma exchange and immunosup-
pressive treatment should be initiated; in cases of congenital ADAMTS13 defi-
ciency, plasma infusion suffices (Moake 2002).
Fresh or frozen plasma contains all the coagulation factors and may be used to
make up the congenital or acquired deficiencies of these clotting factors. In most
centers, the current best practice guidelines advocate the use solvent- or detergent-
treated plasma, which may provide better protection against the transmission of
blood-borne infections, but may also include a lower recovery of coagulation factors
(Hellstern et al. 2002). Most consensus guidelines indicate that plasma should only
be transfused in cases of bleeding or situations with a high risk of bleeding; it should
not be based on laboratory abnormalities alone. For more specific therapy or if the
transfusion of large volumes of plasma is not advisable, fractionated plasma of puri-
fied coagulation factor concentrate is available. Prothrombin complex concentrates
(PCC) contain the vitamin K-dependent coagulation factors II, VII, IX, and X.
Hence, these concentrates may be used if immediate reversal of vitamin K antagonist
treatment is required. PCC may also be used if a replenishment of all the coagulation
factors is necessary and large volumes of plasma may not be tolerated. In some cases,
administration of purified coagulation factor concentrates, such as fibrinogen
concentrate, may be helpful.
Pro-hemostatic treatment can be used as an adjunctive treatment in patients with
significant blood loss (Mannucci and Levi 2007). De-amino-8-D-arginine vasopres-
sin (DDAVP, desmopressin) is a vasopressin analogue that induces the release of the
contents of the endothelial cell-associated Weibel–Palade bodies, including von
Willebrand factor (vWF). Hence, the administration of DDAVP results in a marked
increase in the plasma concentration of vWF (and associated coagulation factor
VIII) and, by as yet unexplained additional mechanisms, a potentiation of primary
hemostasis. DDAVP has proved to be effective in the care of patients with von
Willebrand’s disease and mild hemophilia A, but also of patients with uremic
thrombocytopathy and other defects in primary hemostasis (Mannucci 1997).
Antifibrinolytic agents, such as lysine analogues (ε-aminocaproic acid or
tranexamic acid), may also be helpful in the prevention or control of bleeding, in
particular if hyperfibrinolysis is thought to be the major contributor to the hemo-
static defect. Antifibrinolytic therapies may also compensate for other coagulation
defects. Antifibrinolytic agents have been found effective in preventing blood loss and
reducing transfusion in patients undergoing major surgical procedures, and they are
relatively safe (Levi et al. 1999; Porte et al. 2000). A large, international, controlled
multicenter trial recently showed that the use of the antifibrinolytic agent tranexamic
acid reduced mortality in trauma patients with excessive blood loss (Shakur et al. 2010).
386 M. Levi

Recombinant factor VIIa (rFVIIa) is a pro-hemostatic agent that has been

licensed for the treatment of patients with hemophilia and antibodies inhibiting
factors VIII or IX. A very large number of case series have reported successful use
of rFVIIa in patients with other types of coagulation defects or in patients with
major bleeding due to surgery or trauma; however, the number of successful con-
trolled clinical trials is still limited. Initial trials in patients with intracranial hemor-
rhage and trauma were promising; however, the benefit of rFVIIa on clinically
relevant outcome parameters in these settings was not confirmed, and the incidence
of thrombotic complications slightly increased (Levi 2012). A meta-analysis of all
the controlled trial data on rFVIIa examined the thromboembolic event rate outside
the approved label indications (Levi et al. 2010). Arterial thromboembolic rates were
higher in rFVIIa-treated (5.5 %) than placebo-treated (3.2 %) patients. Venous
thromboembolic rates were comparable between rFVIIa-treated (5.3 %) and placebo-
treated (5.7 %) patients. In rFVIIa-treated patients, 2.9 % experienced coronary arte-
rial thrombotic events compared to 1.1 % with placebo. Arterial thromboembolic
rates were highest in patients over 65 years old (9.0 % vs 3.8 %) and particularly in
patients over 75 years old (10.8 % vs 4.1 %). Therefore, until ongoing clinical trials
and further safety data on critically ill patients become available, the off-label use of
rFVIIa can only be justified in cases of life-threatening bleeding, when all other
conventional treatments have failed (Mannucci and Levi 2007).
Supportive treatment of the coagulopathy associated with DIC is a complex issue
(Levi et al. 2009). Administration of anticoagulants may theoretically be beneficial,
but their efficacy has never been proved in clinical trials. Restoration of dysfunc-
tional physiological anticoagulant pathways by administration of antithrombin
concentrate or (activated) protein C has beneficial effects on laboratory parameters,
but the efficacy of this approach for clinically relevant outcome parameters has yet
to be confirmed. In initial trials with patients with severe sepsis, recombinant human
APC (drotrecogin alpha activated) was effective (Bernard et al. 2001); however, a
recently completed placebo-controlled trial in patients with severe sepsis and septic
shock was prematurely stopped due to the lack of any significant benefit from APC
(Ranieri et al. 2012). The manufacturer of APC subsequently decided to withdraw
the product from the market, which has resulted in a revision of current guidelines
for the treatment of DIC (Thachil et al. 2012). Interestingly, in all studies, the
relative efficacy of APC in the subgroup of patients with DIC was higher than in
those without DIC, and patients treated with APC had a more rapid resolution of
DIC than placebo-treated patients (Dhainaut et al. 2004).
Soluble thrombomodulin represents a new alternative option for the treatment of
DIC. In an initial phase III, randomized, double-blind clinical trial involving 234
patients with DIC, the administration of soluble thrombomodulin had a significantly
better effect on bleeding manifestations and coagulation parameters than heparin,
but the mortality rate at 28 days was similar in both study groups (Saito et al. 2007).
DIC was resolved in 66.1 % of the thrombomodulin group, compared to 49.9 % of
the heparin group (difference 16.2 %; 95 % confidence interval 3.3–29.1). Patients
in the thrombomodulin group also showed a more marked improvement in the clini-
cal course of bleeding symptoms. Soluble thrombomodulin was recently evaluated
22 Coagulation Disorders in Intensive Care Patients 387

in a phase II/III clinical study involving 750 patients with sepsis and disseminated
intravascular coagulation. Twenty-eight-day mortality was 17.8 % in the thrombo-
modulin group and 21.6 % in the placebo group. Markers of coagulation activation
were lower in the thrombomodulin group than in the placebo group. There were no
differences between the groups in bleeding or thrombotic events.

Conclusions
Coagulation abnormalities occur frequently in critically ill patients and may have
a significant impact on the outcome. Treatment of ICU patients should be directed
primarily at their underlying condition, but an adequate explanation for the coag-
ulation abnormalities of these critically ill patients, together with supportive
therapy, may also be required. Deficiencies in platelets and coagulation factors in
bleeding patients or patients at risk of bleeding can be made up by transfusion of
platelet concentrate or plasma products, respectively. In addition, pro-hemostatic
treatment may be beneficial in cases of severe bleeding, whereas restoring physi-
ological anticoagulant pathways may be helpful in patients with sepsis and DIC.

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Perioperative Thromboprophylaxis
23
Marc Aldenkortt and Marc Licker

23.1 Introduction

The term “hemostasis” originally referred to a sequence of events aimed at mini-

mizing blood loss by forming a clot at the site of vessel injury. In 1958, Astrup first
alluded to the concept of “hemostatic balance,” by which clot formation following
tissue injury orchestrates its own destruction (Astrup 1958). Under normal blood
flow conditions, endothelial cells continuously release vasodilatory and anti-aggre-
gant substances (e.g., nitric oxide and prostacyclin) while providing a protective
barrier that separates blood cells and plasma proteins from highly reactive com-
ponents within the layers of the vascular wall. Vascular endothelial cells, platelets,
natural inhibitors of coagulation, and the fibrinolytic system all participate in main-
taining blood fluidity (Tanaka et al. 2009).
Following endothelial disruption due to trauma or surgery, local exposure of tis-
sue factor and the activation of platelets and coagulation factors trigger a sequence
of events. This involves platelet adhesion to subendothelial elements, further plate-
let aggregation, generation of large amounts of thrombin, and ultimately, formation
of a “platelet–red cell–fibrin” thrombus that seals off the hemorrhagic vascular leak
(Fig. 23.1) (Schenone et al. 2004). Under certain physiological conditions, the over-
whelming thrombosis induced by excessive activation of the hemostatic process
outside the traumatic area is counteracted by systemic antithrombotic activity (e.g.,
protein C, protein S), local activation of fibrinolysis, and the dilution effects of
blood flow (Wolberg et al. 2012).
In the perioperative period, venous thrombus formation results from an imbalance
between local and systemic procoagulants/anticoagulants as well as between pro- and

M. Aldenkortt • M. Licker (*)

Department of Anaesthesiology, Pharmacology and Intensive Care,
University Hospital of Geneva, Rue Gabrielle-Perret-Gentil,
Geneva CH-1211, Switzerland
e-mail: [email protected]; [email protected]

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 391

DOI 10.1007/978-3-642-55004-1_23, © Springer-Verlag Berlin Heidelberg 2015
392 M. Aldenkortt and M. Licker

TF VIIa
X IX

VIIIa
IXa
Va
Xa
Activated
Platelets
Prothrombinase
Complex

IIa

Fibrinogen Fibrin

Fig. 23.1 Cell-based activation of the coagulation cascade (primary and secondary hemostasis)
upon endothelial injury (TF tissue factor; coagulation factors and their activated forms IIa, Va, X/
Xa, VIIa, and IX/IXa)

antifibrinolytic activity. According to Virchow, three key phenomena – venous stasis,

vascular injury, and hemostatic abnormalities – are responsible for this imbalance
(Table 23.1). Patients with cancer are particularly prone to developing venous throm-
bosis since tumoral cells release procoagulant substances (White et al. 2007).

23.2 Venous Thromboembolism (VTE)

23.2.1 Definition

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are considered two
manifestations of the same anatomo-clinical entity, namely, venous thromboembo-
lism (VTE). Venous thrombi are predominately composed of red blood cells, plate-
lets, and leukocytes, all bound together by fibrin. PE is the third most common
cause of hospital-related death, and it is the most common preventable cause of
hospital-related death.

23.2.2 Prevalence

The highest risk of DVT occurs in the first postoperative week, but it remains important
up to 3–6 weeks following major thoracoabdominal or orthopedic procedures (White
et al. 2003). In the absence of antithrombotic prophylaxis and if screened by contrast
venography, duplex ultrasound, or fibrinogen labeling, the prevalence of asymptomatic
23 Perioperative Thromboprophylaxis 393

Table 23.1 Pathogenic mechanisms of venous thrombosis

Venous stasis Vascular wall injury Hemostatic abnormalities
Impairment of blood flow Endothelial disruption Blood cell activation
Patient-related factors
Pregnancy, postpartum Inflammatory infiltration Procoagulant tumor
Cancer Infiltration by tumor Polyglobulia, dehydration
Arterial aneurysm Hyperhomocysteinemia Hyperfibrinogenemia
Previous deep vein Previous deep vein thrombosis Inherited thrombophiliaa
thrombosis Myeloproliferative disorder
Obesity (>20 % ideal Antiphospholipid/lupus-like Antiphospholipid/lupus-like
body weight) anticoagulant antibodies anticoagulant antibodies
Congestive heart failure Sepsis, severe infection
Varicose veins Post-trauma/surgical inflammation
Bed rest, prolonged sitting
Advanced age
Procedure-related factors
Immobilization, paralysis Surgical incision, trauma Hormonal/chemotherapy
Mechanical ventilation Venous puncture Steroids
Central venous catheter Heparin-induced Heparin-induced thrombocytopenia
Pacemaker wires thrombocytopenia
Tourniquet
a
Thrombophilic factors are found in 25–50 % of patients with VTE (factor V Leiden mutation;
prothrombin 2020 mutation; deficiency of antithrombin, of protein C, or of protein S; and/or
antiphospholipid syndrome)

DVT can be as high as 40–80 % following total knee arthroplasty (TKA) or total hip
arthroplasty (THA) and 15–30 % following major abdominal surgery (Stringer et al.
1989; White et al. 2003). Pain or tenderness at palpation is a characteristic symptom of
DVT that may be accompanied by local swelling, erythema, and increased warmth, as
well as the presence of dilated veins (collaterals) on the chest wall or legs. The preva-
lence of symptomatic VTE has largely decreased over the last four decades because of
important changes in perioperative surgical care, including less invasive surgery and
earlier ambulation. Following major joint surgery, the rate of symptomatic VTE events
has declined from 15 to 30 % prior to 1980 (without prophylaxis) to less than 2 % after
2000 (with prophylaxis) (Januel et al. 2012). Ethnicity, geographical location, and life-
style may also influence the prevalence of VTE. In major orthopedic surgery, the rate
of proximal DVT diagnosed by venography exceeds 20 % in Western countries but is
less than 10 % in Asian countries (Kanchanabat et al. 2011).

23.2.3 Time Course and Cost Implications

Most thrombi start in the calf and have few clinical consequences if they remain
confined below the knee. The probability that calf DVT will extend to involve the
proximal iliofemoral and/or visceral veins, and subsequently cause PE, increases
with the severity and persistence of the initiating prothrombotic stimulus.
Alternatively, the fresh thrombus may dissolve by activation of the fibrinolytic
394 M. Aldenkortt and M. Licker

system, or the granulation tissue may invade the occlusive blood clot which can
later be recanalized. Although the patency of the vessel can be restored, destruction
of the venous valves results in chronic venous hypertension and secondary varices.
Studies investigating the spontaneous evolution of untreated proximal DVT are
scarce, but they do suggest a risk of post-thrombotic syndrome (leg swelling, ten-
derness, and ulcers) in 25–50 % and of clinical PE in 10–40 % of cases (Huber et al.
1992). Importantly, about 10 % of PE are rapidly fatal as a result of acute heart
failure – the right ventricle being unable to face the sudden elevation of afterload if
thrombi occlude more than two thirds of the pulmonary vasculature. In patients
surviving an acute PE episode, pulmonary perfusion normalizes in about two thirds
of patients, while in 4–6 %, relapsing embolization of small clots from persisting
DVT may lead to chronic pulmonary hypertension (Pengo et al. 2004).
From an economic standpoint, VTE increase the global burden on both the
healthcare system and individuals by up to USD 1.5 billion a year in the USA and
EUR 3.07 billion in the European Union (Oger 2000; Dobesh 2009). In Europe, the
cost of VTE in orthopedic surgery has been estimated at EUR 8,265 per patient,
thereby doubling the average cost of orthopedic inpatient care (Ollendorf et al.
2002). More recently, the risk-adjusted total healthcare cost, including the benefi-
ciary’s cost share over 1 year, was found to be USD 13,500 higher in patients with
a VTE (versus without a VTE) following TKA (Baser et al. 2011).

23.3 Assessment of VTE Risk Factors

The concept of primum non nocere applies to VTE prophylaxis as it does to all areas
of medicine. Each patient should be assessed and treated on an individual basis and
balance maximal antithrombotic efficacy against minimal bleeding, while taking
into account patient convenience.
Several models of VTE risk assessment have been published, namely, those
developed by Caprini, Rogers, Cohen, and Kucher (Caprini et al. 2001; Cohen et al.
2005; Kucher et al. 2005; Rogers et al. 2007). Each of these models encompasses a
list of exposure risk factors (presenting illness or procedure) and predisposing risk
factors (genetic and clinical characteristics). The Caprini score was validated in a
large retrospective study on a sample of general, vascular, plastic, and urological
surgery patients (Table 23.2) (Bahl et al. 2010). Patient and surgical risk factors are
summed to produce a cumulative score which falls into one of four levels of risk,
with a growing incidence of VTE: low risk (VTE ~2 %) if the total score is 0–1,
moderate risk (VTE ~5–10 %) if the score equals 2, high risk (VTE 20–40 %) if the
score is 3–4, and very high risk (VTE ≥40 %) if the score is ≥5.
Alternatively, the American College of Chest Physicians’ (ACCP) guidelines
stratify the risks of VTE according to the type of procedure (orthopedic, pelvic/
abdominal, cardiac, thoracic, or intracranial/spinal) and to some disease character-
istics (trauma, cancer) (Falck-Ytter et al. 2012; Gould et al. 2012a). Though simple,
this approach fails to provide an individualized approach to risk assessment and
thromboprophylaxis.
Table 23.2 Assessment of the risk of venous thromboembolism
Risk factor 1 pt 2 pts 3 pts 5 pts
Age 41–60 years old 61–74 years old ≥75 years old
Procedure/trauma Minor surgery Arthroscopy, laparoscopy Elective major lower limb
(>45 min) arthroplasty (hip, knee)
Major surgery (>45 min) Multiple trauma (<1 month)
Hip, pelvis, or leg fracture
Central venous access Acute spinal cord injury (<1 month)
Functional status Bed rest (medical patient) Immobilizing plaster cast
(<1 month)
Confined to bed (>72 h)
Physical status COPD Cancer
CHF or AMI
23 Perioperative Thromboprophylaxis

Pregnancy or postpartum (<1 month)

Sepsis
Obesity (BMI >25)
Varicose veins
History DVT/PE (patient or family) Stroke (<1 month)
Major surgery (<1 month)
Inflammatory bowel disease
Recurrent abortion, unexplained
stillborn infant
Hemostasis Facteur V Leiden
Lupus anticoagulant
Prothrombin 20210A
Anticardiolipin antibodies
Hyperhomocysteinemia
HIT thrombopenia
Modified from Caprini et al. (2001)
395
396 M. Aldenkortt and M. Licker

The risk of bleeding should be carefully balanced against the need for pharmaco-
logical VTE prophylaxis, given the dire consequences of blood loss (hemorrhagic
shock) and compressive hematoma requiring homologous transfusion and/or reop-
eration (Chee et al. 2008). In addition to surgical characteristics (site, extent, and
duration), assessing the risk of bleeding should also consider the following: the
patient and family history (excessive bleeding after tooth extraction, surgery/trauma,
or abortion/delivery); the presence of renal failure, liver disease, or peptic ulcer; and
the concomitant use of anticoagulant/antiplatelet drugs. The average cost incurred
by major bleeding averages USD 113 per patient receiving anticoagulant medica-
tion (Muntz et al. 2004).

23.4 Strategies for Perioperative Thromboprophylaxis

23.4.1 Non-pharmacological Approach

A multimodal thromboprophylaxis approach should be tailored to the patient’s indi-

vidual risk level. Besides the administration of antithrombotic drugs, other simple
measures need to be considered, particularly in patients with a high risk of bleeding
and in the early phase following surgery. These include fast-track anesthesia, early
patient mobilization, and the use of mechanical methods that are deemed suitable
(Table 23.3). Among patients undergoing major joint replacement, multimodal
thromboprophylaxis including regional anesthesia, intermittent compression, and
aspirin (in low risk patients) was associated with the lowest mortality rate – this was
compared with potent anticoagulant drugs such as heparin derivatives, fondaparinux
or rivaroxaban (Poultsides et al. 2012).

Table 23.3 General recommendations to minimize the risk of perioperative thromboembolism

Preoperative consultation
Assess the risk of VTE and bleeding (patient and procedure factors)
Consider discontinuation of procoagulant drugs (e.g., contraceptives, steroids)
Consider discontinuation of antiplatelet/anticoagulant drugs
Inform the patient about VTE risk, choice of thromboprophylaxis, early rehabilitation plan
Intraoperative period
Minimally invasive surgery and fast-track anesthesia protocol
Hemodynamic optimization, avoid dehydration
Transfusion protocol
Consider regional analgesic techniques
Spontaneous or assisted mode ventilation
Postoperative period
Regional anesthesia blocks, multimodal analgesia
Early extubation, patient mobilization
Early removal of indwelling catheters (arterial and central venous lines, urinary catheter) and
drainage tubes
23 Perioperative Thromboprophylaxis 397

23.4.2 Anesthetic Technique and Early Ambulation

Inadequate pain management, intestinal dysfunction, and immobilization have been

recognized among the main factors delaying postoperative recovery. Reducing tis-
sue injury by minimally invasive surgical procedures, improving tissue oxygen
delivery by hemodynamic optimization, and multimodal analgesic approaches are
all key components of fast-track protocols that may influence Virchow’s triad and
reduce the risk of VTE.
Interestingly, regional anesthetic techniques, particularly continuous epidural anal-
gesia, have been associated with a reduction in perioperative blood loss and VTE
(Roderick et al. 2005; Mauermann et al. 2006). Antithrombotic effects have also been
attributed to a greater inhibition of the inflammatory reaction, enhanced venous return
owing to spontaneous ventilation and sympatholytic effects, and better quality analge-
sia allowing pain-free deambulation (Hahnenkamp et al. 2002; Delis et al. 2004).

23.4.3 Mechanical Prophylaxis

First reported in 1980, continuous passive motion (CPM) is an external motorized

device that enables a joint to move passively through a preset arc of motion.
Although continuous passive motion has been shown to enhance functional recov-
ery and reduce the length of hospital stay following TKA, there are currently insuf-
ficient data supporting its effectiveness in preventing DVT (Heron et al. 2001).
British guidelines advocate a systematic use of elasticated compressive stockings
(ECS) in all hospitalized surgical patients (day and night), from their admission
until return to a normal level of mobility.1 When fitted and used properly, they
increase blood flow velocity, reduce the risk of venous wall dilation and intimal tear,
improve venous valve function, and may reduce coagulability, all of which contrib-
ute to minimize the risk of venous thrombosis. The optimal length of ECS (thigh
versus calf length) is still unresolved, but problems are more common with the
thigh-length stockings and in overweight patients.
Overall, ECS can reduce the risk of VTE by as much as 50–66 % (Phillips et al.
2008; Khaw et al. 1993). The main contraindication is the presence of peripheral
vascular disease. Given the fourfold increased risk (5.3 % versus 1.2 % without
ECS) of local complications (breaks ulcers, blisters, and necrosis), it is recom-
mended that ECS be removed daily for a skin inspection.
Intermittent pneumatic compression devices (IPC) comprise a pair of inflatable
sleeves wrapped either around the entire leg or only below the knee and attached to
a small bedside electric pump. The sleeves are inflated alternately or sequentially,
first around the lower leg and then the upper, to “milk” the blood from the leg and
increase venous flow. IPC is thought to facilitate mobilization and reduce the risk of
venous thrombosis by enhancing microcirculatory flow, reducing soft tissue swell-
ing, and stimulating the release of intrinsic fibrinolytic substances (Windisch et al.

1
www.nice.org.uk/guidance/index.
398 M. Aldenkortt and M. Licker

2011; Urbankova et al. 2005). A recent systematic review indicated that IPC pro-
vided sufficient prophylaxis for the majority of gynecology patients undergoing
benign surgery; in comparison with no prophylaxis, IPC has been shown to reduce
DVT by 60 % (relative risk 0.40, 95 % CI 0.29–0.56; p < 0.05) (Rahn et al. 2011).
Direct comparison between ECS and IPC has failed to demonstrate a significant
superiority of either method, although IPC was associated with lower DVT rates in
three out of ten studies (Morris and Woodcock 2010). Since IPC and ECS are not as
effective as antithrombotic drugs, these devices should be used as support to phar-
macological prophylaxis, as a sole therapy in low-risk patients, or if drugs are con-
traindicated (e.g., early postoperative period, increased risk of bleeding) (Kakkos
et al. 2008). The ACCP guidelines assign a 2A recommendation to the use of com-
bination prophylaxis in the highest-risk group since the rate of DVT can be reduced
from 19 % with pharmacological prophylaxis alone to less than 4 % with combined
modalities (Kakkos et al. 2012). Unfortunately, compliance with IPC is question-
able and studies on the optimal device are still lacking.

23.4.4 Pharmacological Prophylaxis

Following the success of aspirin, vitamin K antagonists (VKA), and heparin in pre-
venting thrombotic events, several parenterally administered anticoagulants (hirudin
analogues, argatroban) have been developed for patients with heparin-induced
thrombocytopenia (HIT) and antithrombin deficiency (Fig. 23.2). More recently, oral

TF VIIa
1940s
ORAL PARENTERAL
Oral Vitamine K Antagonists
X IX
Vit K Antagonist

Factors Fondaparinus
VIIIa
II, VII, IX, X IXa AT
1980s
SC Low Molecular Weight Heparin Va Danaparoid
Xa
1990s Activated AT
IV Direct Thrombin inhibitors Rivaroxaban Platelets
(Desirudin, Bivalirubin) Apixaban Prothrombinase AT
2002 Complex LMWH
IV Indirect inhibitors of factors Xa Aspirin, clopidrogel UFH
(Fondaparinus, Danaparoid) prasugrel

2004
IIa Desirudin
Oral direct inhibitors of Thrombin Dabigatran Bivalirubin
(Dabigatran)
2008
Oral direct inhibitors of factor Xa
(Rivaroxaban)
Fibrinogen Fibrin

Fig. 23.2 Common antithrombotic drugs: historical development and site of action in the coagu-
lation cascade
23 Perioperative Thromboprophylaxis 399

formulations of direct thrombin inhibitor (DTI) and anti-factor Xa have emerged;

these have the advantages of a more predictable anticoagulant response, low potential
of drug or dietary interaction, greater specificity (with no requirement for antithrom-
bin binding), and no need for routine patient monitoring (Fareed et al. 2012; Bauer
et al. 2011). Another advantage of novel antithrombotic drugs is the absence of
rebound thrombin generation following discontinuation of unfractionated heparin
(UFH), low-molecular-weight heparin (LMWH), or VKA that may lead to a hyper-
coagulable condition. Hereafter, we present some of the key features of common
antithrombotic drugs used in perioperative medicine (Table 23.4).

23.4.4.1 Aspirin
Aspirin causes an irreversible inhibition of cyclooxygenase, an essential enzyme for the
production of thromboxane A2, a powerful stimulant of platelet aggregation. Thus, aspi-
rin produces an effective anti-aggregant action for the platelet’s entire lifespan. Although
platelets play a role in the initiation and propagation of VTE, aspirin (even at a high
dose) is less effective than heparin derivatives in preventing VTE. Current guidelines,
therefore, do not recommend thromboprophylaxis by aspirin alone, except in patients at
risk of bleeding. Patients receiving aspirin to prevent cardiovascular thrombotic events
(atrial fibrillation, prior myocardial infarct or stroke, or vascular stent implantation), but
requiring noncardiac surgery, may continue aspirin around the time of surgery, instead
of stopping it 7–10 days preoperatively (Grade 2C) (Douketis et al. 2012).

23.4.4.2 Vitamin K Antagonists

23.4.4.2.1 Mechanism of Action
Coumarin derivative drugs such as warfarin (Coumadin®), acenocoumarol
(Sintrom®), and phenprocoumon (Marcoumar®) act indirectly, requiring 3–5 days to
reach therapeutic effectiveness. Indeed, these VKA inhibit epoxide reductase in the
liver and interfere with the synthesis of coagulation factors (II, VII, IX, X, protein C,
and protein S), thereby preventing new thrombus formation. Within 24 h of oral
administration, prothrombin time (PT) lengthens as factor VII concentration drops
rapidly, but an antithrombotic effect is not achieved until after 72–96 h because of
the longer half-lives of the other vitamin K-dependent coagulation factors.

23.4.4.2.2 Pharmacokinetics
Rapidly absorbed from the gastrointestinal tract after oral intake, VKA have high
bioavailability and reach maximal blood concentrations about 90 min after admin-
istration. Warfarin has a longer half-life (36–42 h), circulates highly bound to
plasma proteins, and accumulates in the liver where the two isomers are metaboli-
cally transformed. Acenocoumarol has a lower degree of digestive absorption and a
shorter half-life (8–12 h), with up to 36 % of the drug being retrieved inert in the
stool. Phenprocoumon has 100 % bioavailability and a very long half-life (5–6 days).
The dose–response of VKA may vary up to tenfold between individuals and two-
to threefold within an individual. The cytochrome P450 complex (e.g., CYP2C9,
CYP3A4) has become clearly established as the predominant catalyst responsible
for the metabolism of its more potent S-enantiomer and its activity may be
Table 23.4 Common antithrombotic drugs
400

Route and Half-life

Substance Hemostasis frequency of and time to peak
(brand name) target administration concentration Elimination Monitoring Reversal
Anti-vitamin K Factors II, VII, Oral, OD 8–12 h and 1–4 h Liver, kidney INR 2.0–3.0 Vitamin K PTCC, FFP
(Sintrom, Warfarin) IX, X; protein (S) (2.0–2.5 if
S and C 36–72 h and bleeding risk)
1–4 h (W)
Unfractionated Factors Xa, IIa IV (continuous) or 3–4 h Reticuloendothelium (aPTT, anti-Xa, Protamine
heparin (1:1; +AT) SC (TID) 30–90 min (kidney, liver) [heparin])
Low-molecular- Factors Xa, IIa SC, OD, or BIDa 5–10 h Kidney (aPTT, anti-Xa (Protamine)
weight heparin (2:1 or 4:1; 3–4 h [0.5–1])
+AT)
Danaparoid (Orgaran) Factor Xa (IV) SC, BID 25 h Kidney Not required None (plasmapheresis)
(+AT) 4–5 h (anti-Xa)
Fondaparinux Factor Xa (IV) SC, OD 17–21 h Kidney Not required None
(Arixtra) (+AT) 25 min (anti-Xa)
Desirudin Factor IIa SC 1–3 h Kidney (80–90 %) (Ecarine CT, None (PTCC, HF)
2h aPTT)
Bivalirudin (Angiox) Factor IIa IV 25 min Kidney (Ecarine CT, (PTCC, HF)
aPTT)
Dabigatran (Pradaxa) Factor IIa Oral, BID 12–17 h Kidney (80 %) Not required None (FFP, PTCC, Pl)
2–4 h (TT)
Rivaroxaban (Xarelto) Factor Xa Oral, OD 5–11 h Kidney (65 %), liver Not required None (PTCC, VIIa)
2–4 h (anti-Xa)
Apixaban (Eliquis) Factor Xa Oral, OD 8–15 h Liver, kidney (25 %) Not required None (PTCC, VIIa)
0.5–2 h (anti-Xa)
BID twice daily, FFP fresh frozen plasma, HRA hip replacement arthroplasty, IV intravenous, KRA knee replacement arthroplasty, LMWH low-molecular-
weight heparin, OD once daily, PTCC prothrombinic complex concentrate, SC subcutaneous, TID three times a day
a
Dosage adjustment (e.g., enoxaparin: 40 mg/day, if body weight <150 kg and CrCl >30 ml/min; 30 mg/day, if <150 kg and CrCl 10–29 ml/min; 30 mg twice
M. Aldenkortt and M. Licker

a day, if >150 kg and CrCl >30 ml/min)

23 Perioperative Thromboprophylaxis 401

influenced by the patient’s health status, genetic polymorphisms (VKORC1) and

mutations, diet, and drugs (Carlquist and Anderson 2011). In the USA, Coumadin
is the second most commonly mismanaged therapeutic drug, requiring more than
40,000 emergency room visits per year, resulting in about USD 40–60 million in
additional medical costs per year (Budnitz et al. 2006).

23.4.4.2.3 Monitoring
Because of the large variability of plasma concentration and the unpredictability of
VKA, regular monitoring of their effect on coagulation is of utmost importance. The
international normalized ratio (INR) is the gold standard test for VKA monitoring,
and the targeted range should be within 2.0–3.0 (or a closer range, 2.0–2.5, in patients
at risk of bleeding). The INR is a mathematically transformed or calculated value
converting PT in seconds to a standard ratio value. Theoretically, the INR eliminates
the differences in sensitivity of various PT reagents. However, the INR may not elim-
inate all of the PT assay’s variables, requiring adjustment to make the reagent’s INR
more accurate with regard to a specific local instrument in a local laboratory.

23.4.4.2.4 Reversal
In anticipation of elective surgery and to reverse a mildly elevated INR, withholding
VKA for 3–4 days is indicated, perhaps complemented with the administration of
oral vitamin K (Keeling et al. 2011). In patients with life-threatening bleeding,
administration of vitamin K, fresh frozen plasma (FFP), prothrombin complex con-
centrates (PCC, including the 4 coagulation factors: II, VII, IX, and X), or even
recombinant activated factor VII (rfVIIa) may be justified (Wozniak et al. 2012).

23.4.4.2.5 Indications and Contraindications

VKA are mainly indicated in vascular and major orthopedic surgery (TKA, THA).
Patients undergoing arterial infra-inguinal surgery, and needing to maintain venous
graft patency, are more likely to benefit from VKA treatment than from platelet inhibi-
tors (Geraghty and Welch 2011). Compared with LMWH, treatment with VKA is less
efficient in preventing DVT (RR = 1.51, 95 % CI 1.27, 1.79) and associated with a
similar incidence of serious bleeding events (Mismetti et al. 2004; Muntz et al. 2004).
Treatment is initiated at relatively high doses (warfarin 5–10 mg or <5 mg in
debilitated patients) in combination with UFH or LMWH (first 2 days), and there-
after, the drug dosage is tapered according to INR monitoring. The narrow therapeu-
tic index and an unpredictable dose–response relationship may cause unexpected
bleeding complications or insufficient anticoagulation. VKA should not be pre-
scribed during pregnancy or to uncooperative patients (i.e., dementia, alcoholism).

23.4.4.3 Heparin and Its Derivatives

23.4.4.3.1 Unfractionated Heparin
Commercially available UFH preparations are derived from bovine lung or porcine
intestinal mucosa; they consist of heterogeneous mixtures of branched chains of glycos-
aminoglycans. The molecular weights of these sulfated molecules range from 5,000 to
30,000 Da, with a mean molecular weight of 15,000 Da (~45 monosaccharide chains).
402 M. Aldenkortt and M. Licker

Mechanism of Action
UFH produces its major anticoagulant effect by irreversibly inactivating thrombin
(IIa) and activated factor X (factor Xa) through an antithrombin-dependent mecha-
nism with an anti-factor Xa to anti-factor IIa ratio of 1:1. Antithrombin (AT) is a
native anticoagulant protein that inactivates several clotting factors (IXa, Xa, XIIa,
and thrombin). Only one third of an administered dose of UFH binds to AT, while
the remaining fraction has a minimal anticoagulant effect. The UFH–AT complex is
100–1,000 times more potent as an anticoagulant than AT alone (Hirsh et al. 2001).
The UFH–AT complex, through its action on thrombin, not only prevents fibrin
formation but also inhibits thrombin-induced activation of factors V, VIII, and IX as
well as platelets. Thereby, it prevents further growth and propagation of the throm-
bus, but it is unable to inactivate thrombin or factor Xa within a formed clot. In
vitro, the high-molecular-weight heparin fraction also binds to platelets and von
Willebrand factor; depending on the experimental settings, it can either induce or
inhibit platelet aggregation.

Pharmacokinetics
After subcutaneous (s.c.) injection, bioavailability is dose dependent, ranging
from 30 % at lower doses to as much as 70 % at higher doses, and its anticoagu-
lant effect lasts around 1–2 h. Heparin is mainly cleared via internalization in
endothelial cells and macrophages (heparinase and sulfatase), a small part being
cleared by the kidney.
Pharmacokinetic limitations of heparin are related to its propensity to bind to
positively charged surfaces (plastic tubing), macrophages, endothelial cells, osteo-
clasts, and circulating proteins; this results in a poorly predictable response.
Heparin’s half-life is prolonged with increasing dosages and in patients with renal
failure, whereas it can be decreased or increased in patients with liver impairment.
Importantly, acutely ill patients may require higher doses of UFH to achieve an
antithrombotic effect, given increased binding to inflammatory cells and proteins as
well as to deficient levels of AT (heparin resistance).

Monitoring
Anticoagulation with heparin can easily be monitored by measuring activated par-
tial thromboplastin time (aPTT) or anti-Xa activity and, in a cardiac surgery setting
or in a catheterization laboratory, by measuring activated clotting time (ACT).
Monitoring is not required for the purpose of thromboprophylaxis.

Reversal
Protamine sulfate is considered the treatment of choice for patients who develop
significant bleeding complications while on UFH. This basic protein 5-kDa cationic
polypeptide binds to negatively charged UFH, thereby neutralizing its antithrombin
effect while incompletely reversing factor Xa inhibition.
One UI of protamine neutralizes one UI of heparin. Potentially life-threatening
adverse effects such as hemodynamic collapse, bronchospasm, and pulmonary
hypertension may exceptionally occur in susceptible patients (prior exposure to
protamine, fish allergies, and vasectomy). With high doses of protamine, increased
23 Perioperative Thromboprophylaxis 403

bleeding has been associated with dose-dependent reductions in thrombin

generation.

Indications and Contraindications

Heparin was the first anticoagulant to prove its effectiveness in preventing VTE
(Kakkar et al. 1972; Geerts et al. 2008; Gould et al. 2012b). Given as an s.c. fixed
low dose of 5,000 U every 8 or 12 h, UFH is an effective, safe form of thrombopro-
phylaxis, reducing the risk of VTE by 60–70 % in at-risk surgical patients.
Limitations of UFH include (1) the inability of heparin to deactivate factor Xa in the
prothrombinase complex or thrombin bound to fibrin, (2) HIT, and (3) osteopenia
caused by heparin-induced stimulation of osteoclasts after prolonged administration
(>6 months).
HIT is the most serious prothrombotic, drug-induced problem. It occurs in 0.2–
0.8 % of patients as a result of antibodies directed towards platelet factor IV, leading
to platelet activation with thrombin generation and ultimately vascular thrombosis
(Shantsila et al. 2009). Hence, patients treated with UHF should have their platelet
counts monitored every 1–2 days. A diagnosis of HIT should be considered if that
count drops by more than 50 % or to <100,000/mm within the 5–10 days of treat-
ment initiation, particularly in patients previously exposed to heparin. A benign
form of thrombocytopenia occurs in 10–30 % of patients starting within the first day
of heparin therapy, with the platelet count remaining stable or reversing to normal
even though UFH therapy continues.

23.4.4.3.2 Low-Molecular-Weight Heparin

LMWH is derived from heparin by chemical or enzymatic depolymerization to yield
fragments (>18 saccharide units) with molecular weights ranging from 1,000 to
10,000 Da (average MW of 4,500–5,000 Da). Currently, LMWH (enoxaparin,
Lovenox®; dalteparin, Fragmin®; tinzaparin) has largely replaced UFH as a frontline
therapy in preventing VTE following surgery; they have similar efficacy and an improved
safety profile (Akl et al. 2008). Compared with UFH, the risk of developing HIT and
HIT complicated by VTE can be reduced by 76 % (Junqueira et al. 2012). Moreover, the
risk of major bleeding is markedly attenuated in patients receiving LMWH compared
with those receiving UFH or fondaparinux (−48 %) (Muntz et al. 2004).

Mechanism of Action
Compared with UFH, LMWH has a reduced ability to deactivate thrombin as it can-
not bind to AT and thrombin simultaneously. The anti-factor Xa to anti-factor IIa
ratio is between 2:1 and 4:1 (Hirsh et al. 2001). Compared with UFH, LMWH has
a smaller effect on platelet function and platelet adhesion, therefore interfering less
with primary hemostasis.

Pharmacokinetics
Because LMWH binds less to plasma proteins and cells, they exhibit a more predict-
able dose–response relationship. Following a single s.c. injection of LMWH, absorp-
tion is almost complete, plasma activity peaks after 3 h, the elimination half-life
approximates 4 h, whereas the mean residence time of anti-Xa activity is about 6 h,
404 M. Aldenkortt and M. Licker

independent of the dose (20–80 mg) (Turpie 1998). Following repeated s.c. doses,
there is no evidence of accumulation or alterations in distribution and clearance.
In pregnant women, LMWH does not cross the placental barrier, as detected by
anti-factor Xa activity. LMWH is weakly metabolized in the liver, and relatively small
amounts are eliminated by the kidneys. The dosage of LMWH should be adjusted to
body weight rather than on a fixed regimen, particularly in obese subjects.

Monitoring
Measurement of aPTT can only serve as an indicator of overdosage. Monitoring is
not necessary for the prevention of VTE nor is it generally in therapeutic anticoagu-
lation, except in three situations: renal failure, obesity, and pregnancy. In these
patients, the anti-Xa level should be monitored, with a target range of 0.5–1.1 U/ml.

Reversal
Protamine sulfate can be used to reverse the effects of LMWH (1:1 ratio) although
this antagonizing effect is neither complete nor predictable.

Indications and Contraindications

LMWH has become the anticoagulant of choice for the prevention of venous throm-
bosis following major orthopedic and thoracoabdominal surgery, as well as after
major trauma. This is due to its favorable risk–benefit profile and ease of use;
LMWH is at least as effective and safe as UFH.
The timing and dose of the first LMWH injection differ between Europe and
North America. In Europe, 40 mg LMWH (enoxaparin) is usually given 12 h preop-
eratively, while in North America, 30 mg is administered twice daily, starting
12–24 h postoperatively.

23.4.4.3.3 Fondaparinux: Arixtra®

Mechanism of Action
Fondaparinux is a small synthetic pentasaccharide, derived from heparin. By a
mechanism similar to LMWH, its high affinity for AT produces an indirect selective
anti-Xa activity. Fondaparinux does not inhibit factor Xa bound to the prothrombi-
nase complex thrombin (Petitou et al. 2009).

Pharmacokinetics
After s.c. application, fondaparinux exhibits almost 100 % bioavailability. The drug
is eliminated via renal filtration, and its half-life is about 17–21 h (Nagler et al.
2012). In vitro studies show no cross-reactivity with HIT antibodies. Given its pre-
dictable antithrombotic effects and prolonged half-life, fondaparinux can be admin-
istered safely once a day (2.5 mg).

Monitoring
Monitoring fondaparinux is not routinely necessary. In certain situations, such as
acute renal failure, a chromogenic anti-Xa heparin assay or a specific drug assay can
be performed (pentasaccharide target 0.14–0.19 mg/l).
23 Perioperative Thromboprophylaxis 405

Reversal
Protamine sulfate and FFP fail to antagonize fondaparinux-induced antithrombotic
effects, and there is limited evidence that recombinant factor VII could be used to
stop fondaparinux-related bleeding, although it was found to normalize lengthened
coagulation assays (Dzik 2012).

Indications and Contraindications

Fondaparinux is specifically indicated to prevent VTE following major joint sur-
gery. Its efficacy is comparable to LMWH, and it does not cause more clinically
relevant hemorrhages (Turpie et al. 2002).
Fondaparinux is contraindicated in patients with severe renal impairment (CrCl
<30 ml min−1), low body weight (<50 kg), or those at high risk of bleeding (Nagler
et al. 2012). In patients treated with antiplatelet drugs or those receiving neuraxial
anesthesia/analgesia, a safe delay should be considered before initiating thrombo-
prophylaxis with fondaparinux (Gogarten et al. 2010).

23.4.4.3.4 Danaparoid: Orgaran®

Mechanism of Action
Danaparoid sodium is a mixture of partially depolymerized glycosaminoglycan.
AT-mediated danaparoid catalyzes the deactivation of factor Xa (Wilde and
Markham 1997). There is also an AT and heparin cofactor II-mediated inhibition
of thrombin. However, the ratio of anti-Xa to anti-IIa activity is more than 22:1.
Danaparoid inhibits thrombus formation with approximately the same potency as
heparin but shows greater efficacy at inhibiting the expansion of preformed
thrombi.

Pharmacokinetics
After s.c. administration, the absolute bioavailability of danaparoid sodium
approaches 100 %, and the time to reach peak plasma anti-Xa activity levels is
approximately 4–5 h (Wilde and Markham 1997). Elimination is mainly via renal
filtration and biological half-life activity approximates 25 h.

Monitoring
No routine monitoring is requested. Under special circumstances (i.e., renal failure),
the anti-Xa level should be determined.

Reversal
No agent can reverse the effect of danaparoid. In acute bleeding situations, plasma-
pheresis has been shown to effectively reduce the plasma anti-Xa levels (Dzik).

Indications and Contraindications

The substance is in clinical use for thrombosis prophylaxis in orthopedic, abdomi-
nal, and thoracic surgery. Given its low cross-reactivity with heparin–platelet factor
IV, it is also a suitable alternative in patients with HIT. Danaparoid is more expen-
sive than LMWH and is no longer marketed in the USA.
406 M. Aldenkortt and M. Licker

23.4.4.4 Direct Thrombin Inhibitors

23.4.4.4.1 Hirudin Analogues
Mechanism of Action
Unlike UFH and LMWH, direct thrombin inhibitors (DTI) do not require any inter-
action with an endogenous cofactor. The antithrombotic action results from the spe-
cific binding of free soluble and fibrin-bound thrombins. This prevents fibrin
formation as well as thrombin-mediated activation of factors V, VIII, XI, and XIII
and thrombin-induced platelet aggregation (Greinacher and Warkentin 2008). Since
their chemical structure differs from that of heparin, hirudin analogues do not inter-
act with HIT antibodies.
Currently, four parenteral DTI have been approved for use as anticoagulants in
the USA: lepirudin, desirudin, bivalirudin, and argatroban.
Hirudin was originally isolated from the leech salivary gland and was used as the
first parenteral anticoagulant for humans in 1909. Desirudin (Revasc®) and lepiru-
din (Refludan®) are developed by recombinant technology (65 amino acids; molec-
ular weight, 6980 Da). Binding of desirudin to thrombin is irreversible and 10 times
weaker than for hirudin.
Bivalirudin (Angiox®) is an engineered 20-amino acid, bivalent analogue of hiru-
din with a thrombin inhibition activity nearly 800 times weaker than that of hirudin
(Van De Car et al. 2010). Its reversible binding with thrombin contributes to a
decreased risk of bleeding.

Pharmacokinetics
After s.c. administration, desirudin reaches maximum plasma concentrations after
1–3 h, has a terminal half-life of 2 h, and is primarily excreted by the kidneys (80–
90 %) (Graetz et al. 2011). After intravenous (i.v.) injection, bivalirudin has an
immediate onset of action with therapeutic ACT achieved within 5 min and a half-
life of 25 min. It is mainly cleared by proteolytic cleavage and hepatic metabolism;
20 % of the dose is eliminated by the kidneys.

Monitoring
For perioperative thromboprophylaxis, monitoring is not deemed necessary even in
patients with moderate renal impairment (ClCr of 30–60 ml/min). An aPTT assay
should be performed on patients with severe renal dysfunction and for therapeutic
anticoagulation (target aPTT ratio between 1.5 and 2.5). An alternative to aPTT is
the ecarin clotting time assay (ECT), which reflects anti-factor II activity.

Reversal
There is no specific antidote available. Hirudin-induced bleeding can be partially
reversed by PCC and hemofiltration, hollow-fiber filters, and high- and low-flux
polysulfone dialysers (Dzik).

Indications and Contraindications

Hirudin derivatives are mainly used in patients with HIT, as an alternative to UFH
or LMWH. Desirudin (s.c.) is the only fixed dose DTI approved in Europe and
North America for postoperative prevention of VTE in major orthopedic surgery. In
23 Perioperative Thromboprophylaxis 407

these patients, after 8–12 days of treatment, desirudin (15 mg/day, started preopera-
tively) was found superior to UFH (5,000 UI s.c. three times daily, started preopera-
tively) or LMWH (40 mg enoxaparin s.c. once daily), while showing a similar
safety profile (Salazar et al. 2010; Eriksson et al. 1997a, b).
In 2005, the US Food and Drug Administration approved bivalirudin as an alter-
native anticoagulant to heparin in patients undergoing percutaneous coronary inter-
ventions. Dose adjustments of bivalirudin are necessary in patients with moderate
renal insufficiency, and it is contraindicated in severe renal impairment. Because of
its narrow therapeutic window and its potential for increased bleeding events, lepi-
rudin’s use as an anticoagulant is limited.

23.4.4.4.2 Dabigatran: Pradaxa®

Mechanism of Action
Dabigatran etexilate is an orally active, double prodrug that is rapidly converted into
dabigatran by plasma esterase. It is a low-molecular-weight molecule (472 Da) that
acts as a specific, potent, and reversible direct thrombin inhibitor (Schulman and
Majeed 2012).

Pharmacokinetics
After oral administration, dabigatran has a low bioavailability (<10 %), independent
of the dose of the prodrug. The time to maximum plasma concentration is 1.25–
2.5 h, and its half-life is about 12–14 h (Schulman and Majeed 2012). The drug is
neither metabolized, induced, nor inhibited by cytochrome P450 drug-metabolizing
enzymes. Renal excretion is the primary elimination pathway. The remainder under-
goes conjugation with glucuronic acid to form acyl glucuronides, which are excreted
via the bile.

Monitoring
Given its predictable and consistent anticoagulant effects, treatment with dabigatran
does not require routine coagulation monitoring or dose titration. Thrombin time
(TT) is the assay most responsive to dabigatran in the clinically relevant plasma
concentration range, whereas the aPTT and PT are the least so. Longer blood coagu-
lation parameters (aPTT, PT,) occur in parallel with increasing concentrations of
dabigatran.

Reversal
No specific antidote exists. Blood products (FFP, PCC, platelets) remain the main-
stay of treatment in case of overdose or bleeding (Dzik). Maintaining enforced
diuresis and dialysis may be attempted as the drug binds weakly to plasma proteins
(Kaatz et al. 2012).

Indications and Contraindications

A cost–utility analysis from the UK National Health Service indicated that dabiga-
tran (220 mg/day) was more effective and less expensive than enoxaparin (40 mg)
in patients undergoing total knee or hip replacements (TKR or THR). In three, large,
phase III RCT (RE-MODEL, RE-NOVATE, and RE-NOVATE II), oral dabigatran
408 M. Aldenkortt and M. Licker

(150 and 220 mg once daily) initiated postoperatively was shown to be non-inferior
to s.c. enoxaparin sodium (40 mg once daily, initiated prior to surgery) with regard
to the incidence of total VTE events and all-cause mortality in patients undergoing
TKR or THR surgery (Burness and McKeage 2012). A meta-analysis of 14 studies
indicated that DTI (ximelagatran, dabigatran, and desirudin) were equally effective
to VKA and LMWH in the prevention of major VTE following major joint surgery.
However, they were associated with a higher mortality and more frequent bleeding
(except desirudin) (Salazar et al. 2010).
In North America and Europe, dabigatran is licensed for thromboprophylaxis in
total knee and hip arthroplasty (TKA and THA), whereas in Switzerland, it is exclu-
sively licensed for the prevention of stroke and systemic embolism in patients with
atrial fibrillation.

23.4.4.5 Oral Anti-factor Xa Agents

23.4.4.5.1 Rivaroxaban: Xarelto®
Mechanism of Action
Rivaroxaban is an orally active oxazolidone molecule that directly and reversibly
inhibits free factor Xa, as well as clot-bound and prothrombinase complex-bound
factor Xa.

Pharmacokinetics
After oral ingestion (10 mg), rivaroxaban has an 80–100 % bioavailability, with
peak plasma concentrations reached in 2–4 h, and an elimination half-life of 5–9 h
or 9–13 h in the elderly (Weinz et al. 2009). Rivaroxaban is extensively bound to
plasma proteins, it undergoes metabolic degradation in the liver, and it is mainly
eliminated through renal filtration (Eriksson et al. 2009).

Monitoring
Monitoring the antithrombotic effect of rivaroxaban is unnecessary, and no assay
has yet been validated. It is of note that increasing plasma–drug concentrations cor-
relates with longer PT and the inhibition of factor Xa activity.

Reversal
PCC were found to neutralize the anticoagulant effect of rivaroxaban in healthy
volunteers. Likewise, partial reversal of longer PT and bleeding time was achieved
after the administration of rfVIIa (Eerenberg et al. 2011).

Indications and Contraindications

Compared with LMWH, rivaroxaban has been shown to be slightly superior in pre-
venting VTE in patients presenting atrial fibrillation and those undergoing major
orthopedic surgery (RR 0.48, CI 0.31–0.75). It also showed significant cost savings
(USD 465–533 per surgical case) (Duran et al. 2012; Gomez-Outes et al. 2012).
However, the risk of clinically relevant bleeding could be higher than with LMWH
23 Perioperative Thromboprophylaxis 409

(RR 1.25, 95 % CI 1.05–1.49) (Gomez-Outes et al. 2012). Rivaroxaban has been

licensed for these specific indications in North America and several European
countries.

23.4.4.5.2 Apixaban: Eliquis®

Mechanism of Action
Apixaban is a highly selective, reversible, direct inhibitor of factor Xa. It shows
moderate selectivity for clot-bound factor Xa versus free factor Xa and also inhibits
thrombin generation.

Pharmacokinetics
After oral administration, apixaban has 50 % bioavailability, with peak plasma con-
centration reached after 0.5–3 h, and an elimination half-life of 12–15 h if it is given
once daily or 8–11 h if given twice daily (Eriksson et al. 2009). The drug mainly
undergoes hepatic oxidation into a phenol compound and is excreted in the bile;
25 % is eliminated via the kidneys. It has a low potential for drug–drug
interaction.
The recommended dose is 2.5 mg orally, twice daily.

Monitoring
Apixaban does not interfere with platelet aggregation, while it shows a slight dose-
dependent lengthening of INR and aPTT. No routine monitoring is required for
thromboprophylactic purposes.

Reversal
There are no specific reversal agents. Guidelines merely recommend supportive
treatment in cases of drug-associated bleeding, including the administration of
blood products (FFP, PCC) and activated charcoal if drug ingestion was within the
last couple of hours (Dzik) (Kaatz et al. 2012).

Indications and Contraindications

Compared with enoxaparin, apixaban was found equally effective in lowering the
risk of VTE (RR 0.82, 95 % CI 0.41–1.64), while it slightly attenuated the risk of
bleeding (RR 0.82, CI 0.69–0.98) (Gomez-Outes et al. 2012). In Switzerland, apix-
aban is licensed for the prevention of VTE in major orthopedic surgery (TKA and
THA). Its main contraindication is renal failure.
To date, clinicians and patients must make trade-offs between personal conve-
nience, risk reduction in thrombosis versus increased risk of bleeding (at higher
dosage), and the higher costs of these newer agents (rivaroxaban CHF 5/day; apixa-
ban CHF 10/day). Overall, treatment with factor Xa inhibitors is expected to prevent
four instances of symptomatic DVT per 1,000 patients treated (95 % CI, 3–6 fewer
events) but may increase major bleeding by two more events per 1,000 patients
(95 % CI, 0–4 more events) than LMWH (Neumann et al. 2012).
410 M. Aldenkortt and M. Licker

23.5 Evidence-Based Guidelines for Perioperative

Thromboprophylaxis

The US Agency for Healthcare Research and Policy has ranked the prevention of
VTE as the most valuable patient safety practice, given its cost-effectiveness and
benefit–risk ratio. In many countries, thromboprophylaxis serves as a quality indi-
cator of hospital health care. However, there is still a large gap between official
recommendations and medical practice since compliance with guidelines varies
from 13.3 to 94 % (Gomez-Outes et al. 2012; Cohen et al. 2008). In addition,
although many at-risk patients do not receive adequate prophylaxis, there is also
evidence to suggest that low-risk patients being prescribed thromboprophylaxis
comprises another important problem (Bikdeli and Sharif-Kashani 2012).
Dissemination of information through professional and social networks will
enhance global awareness of the importance of VTE. Methods such as computer-
based decision systems and preprinted orders have been shown to be most effective in
optimizing compliance with thromboprophylactic guidelines. Finally, periodic audits
focusing on outcome data and treatment adhesion, with feedback to nursing and medi-
cal teams, may reinforce consistent use of VTE prophylaxis (Galante et al. 2012).
Since 2010, guidance on VTE prophylaxis in surgical patients has been issued by
a number of medical organizations: the ACCP (February 2012), the American
College of Physicians (ACP, November 2011), the Scottish Intercollegiate Guideline
Network (SIGN, December 2010), and the UK National Institute for Health and
Clinical Excellence (NICE, January 2010). Although these recommendations are
based upon data derived from large RCT, several issues deserve further clarification,
including the role of screening for asymptomatic DVT, the best timing for the initia-
tion of pharmacological prophylaxis, the optimal duration of prophylaxis in high-
risk patients, and the indications for newer anticoagulant agents.
The plethora of official recommendations can be confusing, if not overwhelm-
ing. For the sake of clarity, we summarize the available effective methods of throm-
boprophylaxis for specific surgical categories taking into account the risk of
bleeding and VTE (Table 23.5) (Darvall and Bradbury 2012; Falck-Ytter et al.
2012; Gould et al. 2012a; Muntz and Michota 2010; Deitelzweig et al. 2008).
In very-low-risk patients (expected incidence of VTE <0.5 %), early ambula-
tion following the intervention will suffice, with no need for any specific pharma-
cological or mechanical prophylaxis. In low-risk patients (VTE ~1.5 %), ECS or
IPC devices should be applied during the period of patient immobilization.
Moderate-risk patients (VTE ~3 %) should benefit from LMWH, UFH, or
mechanical prophylaxis. In high-risk patients (VTE ~6 %), dual prophylaxis
should be instituted with GES or IPC combined with LMWH or UFH. If concerns
are raised about the potentially devastating consequences of bleeding (e.g., hem-
orrhagic shock, intracranial or ocular surgery), then mechanical prophylaxis
should be used alone. For instance, for every 1,000 neurosurgical patients who
receive prophylactic doses of UFH or LMWH, 91 VTE events can be prevented
but at the expense of 7 intracranial hemorrhagic events and 28 more cases of
minor bleeding (Hamilton et al. 2011).
Table 23.5 Evidence-based guidelines for perioperative prophylaxis of venous thromboembolism
Grade of
Type of surgery Thromboprophylactic method evidence Duration of TP
Very-low-risk VTE <0.5 %
Caprini score 0 No prophylaxis, early ambulation 1B –
Same day surgery (hernia repair)
Orthopedic procedure <30 min
Repair of small fractures
Isolated lower leg injuries + immobilization Mechanical prophylaxis 2C
Low-risk VTE ~1.5 %
Caprini score 1–2 Mechanical prophylaxis 2C Hospital stay or until free ambulation
General surgery, gynecological surgery,
laparoscopic surgery
23 Perioperative Thromboprophylaxis

Moderate risk VTE ~3 %

Caprini score 3–4 UFH, LMWH, or fondaparinux (if low risk of major 2B Start within 12–24 h postop, for
bleeding) 7–10 days
Mechanical prophylaxis (if high risk of bleeding) 2C
Bariatric surgery One of the following options, with/without MP Start within 12–24 h postop, for
UFH 5,000 s.c., tid 7–10 days
LMWH enoxaparin 40 mg s.c. od or bid (BMI <50)
LMWH enoxaparin 60 mg s.c. od or bid (BMI >50)
+/− mechanical prophylaxis
Cardiac surgery (no VTE risk factors) Mechanical prophylaxis 2C Start within 12–24 h postop, for
Or UFH or LMWH (if low risk of bleeding) 2C 7–10 days
Thoracic surgery (no VTE risk factors) Mechanical prophylaxis, if high risk of bleeding 2C
Neurosurgery (no VTE risk factors) Mechanical prophylaxis 2C Start within 12–24 h postop, for
Spinal surgery (no VTE risk factors) Or UFH or LMWH (if low risk of bleeding) 2C 7–10 days
Major trauma (no VTE risk factors)
(continued)
411
Table 23.5 (continued)
412

Grade of
Type of surgery Thromboprophylactic method evidence Duration of TP
High risk VTE ~6 %
General or abdominal, pelvic surgery UFH or LMWH 1B Start (2–12 h before or) 12–24 h postop,
Thoracic surgery + VTE risk factors UFH or LMWH + mechanical prophylaxis 2C ≥7–10 days, 30 days if cancer (1B)
(low bleeding risk) 2C
Neurosurgery + VTE risk factors Mechanical prophylaxis + LMWH or UFH (if low 2C Start 24–48 h postop, if low risk of
Spinal surgery + VTE risk factors bleeding risk) intracranial/spinal bleeding
Major trauma + VTE risk factors (e.g., Mechanical prophylaxis if no lower leg injury 2C Start 24–48 h postop, if low risk of
spinal/brain injury) Mechanical prophylaxis + UFH or LMWH (if low 2C intracranial/spinal bleeding
bleeding risk)
If UFH and LMWH are contraindicated, choose one of
following
Aspirin 2C
Fondaparinux 2C
Total hip or knee arthroplasty (THA, TKA) Consider one of the following options Start ≥12 h preop or ≥12 h postop
Hip fracture surgery (HFS) LMWH (UFH, adjusted-dose VKA or aspirin) 1B Extend prophylaxis to 10–35 days
(2B/2C) postop or until end of rehabilitation
Fondaparinux 1B, 2B during the hospital stay
Apixaban, rivaroxaban, or dabigatran 1B, 2B
Mechanical prophylaxis 1C
LMWH is preferred over other drugs 2C
Dual prophylaxis, mechanical + pharmacological
Major orthopedic surgery (e.g., HA, TKA, Consider one of the following options
HFS, spinal surgery)
+ patient uncooperative with injection or Apixaban or dabigatran 1B
mechanical devices Rivaroxaban or adjusted dose of VKA 1B
Major orthopedic surgery + risk of bleeding Consider one of the following options
Mechanical prophylaxis 2C
No prophylaxis
M. Aldenkortt and M. Licker

Mechanical prophylaxis: intermittent pneumatic compression device or elasticated compressive stockings (>18 h/day)
LMWH low-molecular-weight heparin, UFH unfractionated heparin, VKA vitamin K antagonist, TP thromboprophylaxis
23 Perioperative Thromboprophylaxis 413

In bariatric surgery, PE has been reported as the most common cause of postop-
erative death, accounting for 30 % of all deaths in the International Bariatric Surgery
Registry. Hence, the ACCP task force recommends the routine administration of
UFH, LMH, or fondaparinux, in combination with optimally used IPC. Weight-
adjusted doses of antithrombotic drugs should be prescribed in order to achieve a
consistent VTE risk reduction, although the incidence of major bleeding increases
in parallel (Becattini et al. 2012).
In major orthopedic, abdominal, or pelvic surgery, prophylaxis with UFH,
LMWH, VKA, or fondaparinux should be continued beyond the hospital stay
(4 weeks instead of 5–7 days) or until appropriate recovery of function (Kakkar
et al. 2008; Rasmussen et al. 2009). Special attention must be given to elderly
patients due to their higher prevalence of comorbidities, renal dysfunction, and
impaired functional capacity. Peptic ulcer, hemophilia, or von Willebrand disease,
as well as the use of antiplatelet drugs, makes thromboprophylaxis a particular chal-
lenge. Moreover, central neuraxial blockade should be performed to a dedicated
time frame: a spinal or epidural needle should only be inserted 8–12 h after the last
s.c. dose of UFH or 18 h after a once daily dose of LMWH (Gogarten et al. 2010;
Horlocker et al. 2010a).

Conclusions
Arterial and venous thromboembolic events commonly occur after surgery and
cause potentially preventable morbidity and mortality. Current evidence-based
management strategies have significantly reduced the incidence of VTE, although
there is room for further improvements with the administration of safer anti-
thrombotic agents and the implementation of specific guidelines coupled with
rigorous clinical audits.

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 Part IV
Economic Aspects and Organization
Economic Aspects and Organization
24
Klaus Görlinger and Sibylle A. Kozek-Langenecker

24.1 Introduction: The Costs of Blood

Hospitals have limited financial resources, and transfusion and hemostasis

management must compete with other diagnostic and therapeutic options for the
allocation of funds. At the same time, the costs of blood transfusion continue to
increase dramatically and vary widely between countries and even between hospi-
tals within the same country (Table 24.1) (Abraham and Sun 2012; Toner et al.
2011; Glenngård et al. 2005; Varney and Guest 2003). The total cost of supplying
patients with hemostatic diagnostics and therapies involves a complex bundle of
activity-based costs surrounding the primary supply process, as well as secondary
costs linked to transfusion-associated adverse events (Abraham and Sun 2012;
Shander et al. 2010). These adverse events account for almost 35 % of transfusion-
related costs (Glenngård et al. 2005). Severe bleeding and inappropriate allogeneic
blood transfusion, in particular, are likely to be associated with increased morbidity,
length of hospital stay, and additional secondary hospital costs (Berenson et al.
2010; Bufe et al. 2009; Christensen et al. 2009; Leahy and Mukhtar 2012; Pybus
et al. 2012; Rao et al. 2008; Sarode et al. 2010; Shander et al. 2011; Stanworth et al.
2011a; Stokes et al. 2011). This chapter discusses the primary and secondary cost
implications of hemostatic interventions and transfusion strategies.

K. Görlinger (*)
Department of Anaesthesiology and Intensive Care Medicine, University Hospital Essen,
University of Duisburg-Essen, Duisburg-Essen, Germany
e-mail: [email protected], [email protected]
S.A. Kozek-Langenecker
Department of Anaesthesia and Intensive Care, Evangelical Hospital Vienna, Vienna, Austria

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 421

DOI 10.1007/978-3-642-55004-1_24, © Springer-Verlag Berlin Heidelberg 2015
422 K. Görlinger and S.A. Kozek-Langenecker

24.2 Costs of Bleeding Complications

and Allogeneic Blood Transfusion

In addition to increased hospital costs, bleeding and allogeneic blood transfusion

have been shown to be independently associated with increased morbidity and mor-
tality and longer stays in intensive care units (ICU) and in hospital (Glance et al.
2011; Khan et al. 2007; Marik and Corwin 2008; Murphy et al. 2007; Pereboom
et al. 2009; Sarani et al. 2008; Shander et al. 2007; Spiess et al. 2004; Watson et al.
2009). Blood transfusion costs can be separated into primary or acquisition costs for
allogeneic blood products (paid by the government or the hospital itself), activity-
based costs (including all processing costs, from the indication of blood transfusion
to monitoring effects and for possible adverse events), and secondary costs due to
any transfusion-associated adverse events (Shander 2007). Acquisition costs for allo-
geneic blood products vary widely between countries and are difficult to determine
in those where hospitals do not pay for them directly because governments supply
them “for free” (Table 24.1). However, a hospital’s activity-based blood transfusion
costs are usually 3.2–4.8 times higher than blood product acquisition costs (Shander
et al. 2010). Shander et al.’s analysis of four hospitals showed that annual expendi-
tures on blood and transfusion-related activities, limited to surgical patients, ranged
from USD 1.62 to USD 6.03 million per hospital and were largely related to the
transfusion rate. Some hospitals calculate a virtual internal transfer price which has
to be “paid” by the transfusing department to the blood bank in order to compensate
the blood bank for its activity-based costs (e.g., storage and crossmatching).
Transfusion-associated adverse events such as acute lung injury (ALI),
transfusion-related acute lung injury (TRALI), transfusion-associated circulatory
overload (TACO), transfusion-related immunomodulation (TRIM), nosocomial
infections, and sepsis, as well as ischemic events (myocardial infarction, stroke,
acute renal failure, or multiple organ failure), are all associated with increased sec-
ondary costs for hospitals, governments, health insurance companies, or patients
themselves (Berenson et al. 2010; Glenngård et al. 2005; Stokes et al. 2011).
However, each adverse event and each additional day with mechanical ventilation in
an American ICU increase hospital costs by USD 3,800 to USD 4,000 (Dasta et al.
2005; Kaushal et al. 2007). In the UK, average “return-to-theatre costs” due to
bleeding complications in cardiac surgery have been calculated as GBP 2,617
(Sharples et al. 2006). Christensen et al. analyzed data from the cardiac surgery unit
of the Augsburg Clinic in Germany to determine the relationship between excessive
postoperative hemorrhage in cardiac surgery, patient outcomes, and hospital costs.
Excessive postoperative bleeding, defined as a drainage volume of more than 200 ml
in any 1 of the first 6 h after surgery, was associated with a significantly increased
incidence of adverse events (e.g., fourfold increase of strokes and doubled incidence
of renal failure), doubled length of stay in ICU (3.1 ± 5.0 days versus 5.7 ± 5.3 days),
fourfold increase in patient’s 30-day mortality (5.5 % versus 22.4 %), and doubled
total hospital costs (EUR 8,027 ± 7,557 versus EUR 15,404 ± 8,986 ). When adjusted
for potential confounding factors, the incremental cost of excessive postoperative
hemorrhage was EUR 6,251 (95 % confidence interval: EUR 4,594–7,909)
(Table 24.2) (Christensen et al. 2009). Murphy et al. (2007) reported a more than
Table 24.1 Costs of allogeneic blood products and coagulation factor concentrates in the USA and Europe
24

Author (year) Country Cost calculation PRBC FFP Platelets Cryoprecipitate Fibrinogen PCC rFVIIa
Varney and Guest UK Mean activity- £635 (€1,031) £378 (€614) £347 (€564) £834 (€1,354) – – –
(2003) based costs (NHS
costs)
Glenngård et al. Sweden Societal costs €702 for 2 filtered allogeneic PRBC units – – – –
(2005) (Transfusion reactions accounted for 35 % of
costs)
€598 for 2 autologous PRBC units – – – –
€285 for intraoperative PRBC salvage (>4 – – – –
units)
Agrawal et al. UK Mean activity- £546.12 (€804.86) for transfusion of 2 PRBC units:
(2006) based costs Mean staff costs £37.24 (blood bank £9.68 + ward £27.56); mean costs of disposables £13.25; mean
Economic Aspects and Organization

costs for blood products £287.56; mean costs of wastage £11.86; other derived cost (e.g., hospital stay)
£196.21
Murphy et al. UK Acquisition costs £135.50 £31.50 (€46) £214 (€315) – – – –
(2007) (€200)
Shander et al. USA and Mean acquisition $248.18 in Englewood Hospital Medical Center, Englewood, NJ, USA
(2010) Europe costs $203.47 in Rhode Island Hospital, Providence, RI, USA
$193.70 in Centre Hospitalier Univers. Vaudois, Lausanne, Switzerland
$153.72 in General Hospital Linz, Austria
USA and Mean activity- $1,183.32 in Englewood Hospital Medical Center, Englewood, NJ, USA
Europe based costs $726.05 in Rhode Island Hospital, Providence, RI, USA
$611.44 in Centre Hospitalier Univers. Vaudois, Lausanne, Switzerland
$522.45 in General Hospital Linz, Austria
(continued)
423
Table 24.1 (continued)
424

Author (year) Country Cost calculation PRBC FFP Platelets Cryoprecipitate Fibrinogen PCC rFVIIa
Toner et al. (2011) US Mean acquisition $210.74 ± 37.9 $60.70 ± 20 $533.90 ± 69 – – – –
costs (apheresis)
Median costs for $50.00 ± 120 – – – – – –
mandated onsite per unit
screening
Median storage $68.00± 81 – – – – – –
and retrieval costs per unit
Mean charge to $343.63 ± 135 – – – – – –
patient per unit
Görlinger et al. Germany Virtual internal €85 €65 €250 (pooled – €288/g €126 per €3,203 per 4.8
(2011a, b) and transfer prices platelet conc.) 500 IU mg (240 KIU)
Hanke et al. (2012)
Weber et al. (2012) Germany Acquisition costs €72 0.162 €/g or €231 (pooled – €233 per g €114 per €2,784 per 4.8
€40.50 per platelet conc.) 600 IU mg (240 KIU)
250 ml unit
Abraham and Sun Western Mean activity- €877.69 for 2 – – – – – –
(2012) Europe based costs units
K. Görlinger and S.A. Kozek-Langenecker
Table 24.2 Additional length of stay (LOS) at intensive care unit (ICU), high-dependency unit (HDU), and at hospital (HP), and incremental hospital costs
24

due to bleeding complications in major surgery and acute coronary syndromes (ACS)
Number of Patients with Additional length of stay at ICU/ Incremental costs per
Author (year) Clinical setting, country patients (n) bleeding (%) hospital (HP) (days) hospitalization ($)
Murphy et al. (2007) Cardiac surgery, UK 8,598 57.1 % transfused Hazard ratio for discharge from ICU/ RBC units – relative increase
patients HDU, 0.69 (95 % CI, 0.65–0.72) and in costs; mean (95 % CI)
Any: 57.1 % from HP, 0.63 (95 % CI, 0.60–0.67) at Any: 1.42 (1.37–1.46)
1 unit: 13.6 % any postoperative time 1: 1.11 (1.08–1.14)
2 units: 14.5 % 2: 1.21 (1.18–1.25)
3–4 units:15.2 % 3–4: 1.41 (1.36–1.46)
5–9 units:10.0 % 5–9: 1.81 (1.71–1.90)
>9 units: 3.8 % >9: 3.35 (3.03–3.70)
Rao et al. (2008) Non-ST-segment elevation 1,235 36.8 % Unadjusted
Economic Aspects and Organization

ACS, USA Mild bleeding 1.5 days $7,392

Moderate 9.6 days $31,516
bleeding
Severe bleeding 11.0 days $52,282
Bufe et al. (2009) ACS, Germany 59 – – €5,415
Christensen et al. Cardiac surgery, Germany 1,118 6.4 % 2.6 ICU days €7,377 (unadjusted)
(2009) €6,251 (adjusted)
Berenson et al. (2010) ACS, USA 11,266 8.2 % Increased $48,114 (adjusted)
Stokes et al. (2011) Major surgery, overall, 1,608,923 29.9 % 2.7 ICU/6.0 HP days (1.3–9.6) Adjusted
Canada (7.5–47.4 %) (unadjusted)
Spinal surgery 107,187 15.0 % 1.4 ICU/4.5 HP days $17,279
Vascular surgery 216,199 31.5 % 4.8 ICU/9.3 HP days $15,123
Solid organ surgery 45,687 28.5 % 3.8 ICU/8.1 HP days $13,210
Noncardiac thoracic 142,562 34.3 % 6.4 ICU/9.6 HP days $13,473
surgery
Cardiac surgery 103,829 47.4 % 2.8 ICU/4.8 HP days $10,279
General surgery 362,512 27.5 % 3.6 ICU/7.2 HP days $4,354
425

Knee/hip replacement 246,815 29.8 % 0.1 ICU/1.3 HP days $3,005

Reproductive organ surgery 384,132 7.5 % 0.9 ICU/3.6 HP days $2,805
426 K. Görlinger and S.A. Kozek-Langenecker

40 % increase in overall average hospitalization costs for transfused cardiac surgery

patients over non-transfused patients in the UK. Bufe et al. (2009) demonstrated
that costs caused by bleeding requiring transfusion of ≥2 units of blood products in
an acute coronary syndrome therapy setting increased hospital costs by EUR
5,415 in Germany. Rao et al. (2008) analyzed data from the economic sub-study of
the GUSTO IIb trial in 1,235 American patients with non-ST-segment elevation
acute coronary syndromes to determine the relationship between bleeding, transfu-
sion, length of hospital stay, and hospital costs. As bleeding severity increased,
there was a stepwise increase in length of stay (no bleeding, 5.4 days; mild bleeding,
6.9 days; moderate bleeding, 15.0 days; and severe bleeding, 16.4 days) and unad-
justed total costs (no bleeding, USD 14,282; mild, USD 21,674; moderate, USD
45,798; and severe bleeding, USD 66,564). After adjustment for baseline differ-
ences between patients, each moderate or severe bleeding event increased costs by
USD 3,770, and each transfusion event increased costs by USD 2,080. Another
American study reported that, after adjustment for patient characteristics, in-hospital
acute coronary syndrome-related procedures, and length of stay, patients with
severe bleeding incurred initial hospitalization charges of USD 48,114 higher than
those of patients without bleeding (Berenson et al. 2010). Thus, clinical interven-
tions that can effectively prevent or address severe perioperative or peri-interventional
bleeding reduce transfusion requirements, and transfusion-associated adverse
events are very likely to substantially improve cost-effectiveness (Kozek-
Langenecker et al. 2013).

24.3 Costs of Ischemic and Thromboembolic Events

Both bleeding and allogeneic blood transfusion have been shown to be associated
with an increased incidence of ischemic and thromboembolic events, as well as
in-hospital and posthospital costs (Dobesh 2009; Ruppert et al. 2011; Sharples
et al. 2006; Spiess et al. 2004; Vekeman et al. 2011). Therefore, hemostatic inter-
ventions that can effectively stop microvascular bleeding without increasing the
incidence of ischemic and thromboembolic events are very likely to substantially
improve cost-effectiveness.

24.4 Prophylactic Hemostatic Interventions

with “Universal Hemostatic Agents”

In recent decades, several attempts have been made to find a universal hemo-
static agent capable of ensuring hemostasis during and after major surgery and
trauma, independent of the individual cause of the bleeding. Almost all the drugs
studied in this context either failed to reduce bleeding and transfusion require-
ments if given as prophylaxis or were associated with severe adverse events,
such as acute renal failure or thrombotic/thromboembolic events and even
increased mortality.
24 Economic Aspects and Organization 427

24.4.1 Antifibrinolytics

Aprotinin was withdrawn from the market in November 2007 due to the reported
increased incidence of renal dysfunction and mortality in cardiac surgery patients,
compared to treatment with lysine analogues (Brown et al. 2007; Fergusson et al.
2008; Mangano et al. 2006). Lysine analogues (tranexamic acid or TXA, and
ε-aminocaproic acid) reduce perioperative blood loss and transfusion requirements
and can be highly cost-effective in major orthopedic surgery, cardiac surgery, post-
partum hemorrhage, liver resection and transplantation, and trauma (CRASH-2
Trial C2010; CRASH-2 Trial Collaborators 2011; Ducloy-Bouthors et al. 2011;
Fergusson et al. 2008; Ferrer et al. 2009; Goobie et al. 2011; Greiff et al. 2012;
Gurusamy et al. 2009; Henry et al. 2011; Ickx et al. 2006; Martin et al. 2011;
Molenaar et al. 2007; Novikova and Hofmeyer 2010; Sander et al. 2010; Sukeik
et al. 2011; Rajesparan et al. 2009; Tzortzopoulou et al. 2008). Notably, in the
CRASH-2 study, a reduction in mortality was only observed if TXA was adminis-
tered within 3 h of a trauma. In contrast, prophylactic administration of TXA more
than 3 h after trauma was associated with increased mortality (CRASH-2 Trial
Collaborators 2011). The timing of TXA administration therefore seems to be cru-
cial. During liver transplantation, a targeted therapy of hyperfibrinolysis also pro-
duced a similar reduction of transfusion requirements, which was detected using
viscoelastic tests (thromboelastometry/thromboelastography) (Ickx et al. 2006;
Görlinger et al. 2010). During liver transplantation, therefore, the efficacy and
safety of a prophylactic administration of lysine analogues, compared to a targeted
therapeutic intervention, is still being debated (Schofield et al. 2012). A large, inter-
national, prospective, randomized clinical trial looking at the outcome effects of
TXA in 15,000 women with postpartum hemorrhage is ongoing (Shakur et al.
2010).
However, administration of TXA in patients undergoing major surgery has been
shown to reduce transfusion requirements cost-effectively without significantly
increasing the incidence of deep vein thrombosis (Rajesparan et al. 2009).
Particularly in countries with limited financial resources, lysine analogues have
been shown to significantly save costs and lives (Guerriero et al. 2010). Indeed,
cost-effectiveness analysis based on the CRASH-2 trial data showed that an early
administration of TXA to bleeding trauma patients is likely to be highly cost-
effective in low, middle, and high income settings (Guerriero et al. 2011).

24.4.2 Recombinant Activated Factor VII

According to current literature, the use of recombinant activated factor VII (rFVIIa)
should be restricted to its licensed indications since outside these indications its
effectiveness in reducing transfusion requirements and mortality remains unproven,
but the risks of arterial thromboembolic events and costs are high. All prospective
randomized trials dealing with the prophylactic administration of rFVIIa have failed
to show any effect on mortality (Chavez-Tapia et al. 2011; Dutton et al. 2009;
428 K. Görlinger and S.A. Kozek-Langenecker

Hauser et al. 2010; Levi 2010; Kozek-Langenecker et al. 2013; Simpson et al.
2012). A reduction in the number of transfused packed red blood cells (PRBCs) by
2.6 U and a reduction in the need for massive transfusion (14 % versus 33 %) could
only be demonstrated in severe blunt trauma (Boffard et al. 2005). However, a sec-
ond trauma study, powered for a reduction in mortality, was terminated early since
statistical significance could not be achieved (Dutton et al. 2009; Hauser et al.
2010). From a pharmacoeconomic point of view, the cost of 400 μg/kg rFVIIa
(about EUR 20,000) is extremely high compared to a reduction in transfusion
requirements of 2.6 U of PRBC. Indeed, a cost-effectiveness analysis of using
rFVIIa as an off-label rescue treatment for critical bleeding requiring massive trans-
fusion was recently published. The total cost per life-year gained through massive
transfusion was USD 1,148,000 (95 % CI: USD 825,000–1,471,000), and the incre-
mental cost of rFVIIa as part of that life-saving treatment was USD 736,000 (95 %
CI: USD 527,000–945,000) (Ho and Litton 2012). The incremental costs of rFVIIa
were much greater than the usual acceptable cost-effective limit (< USD 100,000
per life-year) for most patients with critical bleeding. Furthermore, two prospective
randomized trials in patients with intracerebral hemorrhage observed a significantly
increased incidence of arterial thromboembolic complications, including myocar-
dial and cerebral infarction (7 % versus 2 % (p = 0.12) and 10 % versus 1 % (p = 0.01),
respectively) (Mayer et al. 2005; Sugg et al. 2006). A distinct trend to more criti-
cally serious (thromboembolic) adverse events, including stroke, has also been
observed in a prospective randomized study of liver transplantation (placebo 10 %;
60 μg/kg rFVIIa 19 %; 120 μg/kg rFVIIa 12 %; p > 0.05) and cardiac surgery (pla-
cebo 7 %; 40 μg/kg rFVIIa 14 % (p = 0.25); 80 μg/kg rFVIIa 12 % (p = 0.43)) (Gill
et al. 2009; Lodge et al. 2005). Furthermore, the risk of arterial thrombotic compli-
cations (in particular stroke and myocardial infarction) after the “off-label use” of
rFVIIa has been highlighted in several other publications (Howes et al. 2009; Levi
et al. 2010; O’Connell et al. 2006; Simpson et al. 2012). Finally, two recently pub-
lished studies showed that rFVIIa had minimal clinical impact on outcomes for
patients requiring less than 30 units of PRBCs. For patients transfused more than 30
units of PRBCs, differences in 24-h and 30-day mortality suggest that rFVIIa con-
verted early deaths from exsanguination to late deaths from multiple organ failure
(Morse et al. 2011; Nascimento et al. 2011). Therefore, in accordance with the
manufacturer’s recommendations, most recent guidelines recommend not to use
rFVIIa in non-licensed indications (AAGBI 2010; BGMA 2009a; Kozek-
Langenecker et al. 2013; Lin et al. 2012; Rossaint et al. 2010; Stürmer et al. 2011).

24.5 Cell Salvage

Cell salvage has been shown to be cost-effective in minimizing perioperative

transfusion of allogeneic blood products (Carless et al. 2010; Davies et al. 2006;
Wang et al. 2009). A Swedish cost study calculated intraoperative erythrocyte
24 Economic Aspects and Organization 429

salvage to be EUR 285 per transfusion (>4 units). This was comparatively much
lower than the cost of a 2-unit transfusion of filtered allogeneic PRBCs, which was
EUR 598. The administrative costs of preoperative autologous blood donation
were found to be much higher due to the higher logistic and personnel expenses
(Glenngård et al. 2005).

24.6 Implementation of Transfusion and Coagulation

Management Protocols

Implementing transfusion and coagulation management protocols has the potential

to reduce transfusion requirements and transfusion-associated costs in trauma and
major surgery (Görlinger et al. 2013; Kozek-Langenecker et al. 2013; Rotter et al.
2010; Schöchl et al. 2013). In a study including 210 patients, Avidan et al. (2004)
demonstrated that both transfusion protocols guided by routine laboratory testing
and point-of-care (POC) testing were able to reduce transfusion requirements com-
pared to transfusion and coagulation management based on clinical discretion.
However, the turnaround time of conventional coagulation tests measured in a cen-
tralized laboratory is simply too long for their effective use in decision-making for
severely bleeding patients (Davenport et al. 2011; Haas et al. 2012a, b; Toulon et al.
2009). Furthermore, Griffee et al. (2010) showed that massive transfusion protocols
featuring an immediate availability of blood products and multidisciplinary com-
munication reduce mortality and conserve resources. These results have been con-
firmed by other authors. Several before-and-after cohort studies have demonstrated
that the implementation of a massive transfusion or exsanguination protocol in
trauma patients resulted in a significant reduction of overall blood product con-
sumption, post-injury complications, organ failure, mortality, and costs (Cotton
et al. 2008, 2009; Dente et al. 2009; O’Keeffe et al. 2008; Riskin et al. 2009; Vogt
et al. 2012). Accordingly, most recommendations and guidelines on the manage-
ment of severe perioperative bleeding strongly recommend the implementation of
local transfusion and coagulation management protocols (Callum and Rizoli 2012a;
Dzik et al. 2011; Kozek-Langenecker et al. 2013; Rossaint et al. 2010; Stürmer et al.
2011). However, massive bleeding protocols can be based on different concepts,
depending on local availability of diagnostic and therapeutic options, as well as
personal experience (Cotton et al. 2008; Görlinger et al. 2011a, b; Görlinger et al.
2013; James et al. 2012; Johansson 2010, 2012; Johansson et al. 2012; Nunez et al.
2010; Schöchl et al. 2012; Schöchl et al. 2013; Solomon et al. 2012; Spinella and
Holcomb 2009; Theusinger et al. 2012; Waydhas and Görlinger 2009). Large-scale
randomized trials are definitely needed to compare the efficacy, safety, and cost-
effectiveness of these different concepts. However, until these trials are completed,
it is clear that all hospitals having to manage bleeding patients should use a severe
bleeding protocol to ensure a prompt and coordinated response to hemorrhage
(Callum and Rizoli 2012b).
430 K. Görlinger and S.A. Kozek-Langenecker

24.6.1 Formula-Driven Transfusion Protocols

(1:1:1 Ratio Concept)

Current literature does not clarify whether a formula-driven transfusion protocol

reduces or increases hospital costs. Several retrospective and some prospective
cohort studies – mostly performed on military trauma patients – suggest that an
early transfusion of fresh frozen plasma (FFP), in an FFP to PRBC ratio between
1:2 and 1:1, results in reduced 30-day mortality (Dente et al. 2009; Holcomb et al.
2008; Maegele et al. 2008). However, the evidence for this is of low quality since
there is a lack of prospective randomized clinical trials confirming these data
(Cushing and Shaz 2011; Murad et al. 2010; Roback et al. 2010; Schuster et al.
2010; Zehtabchi and Nishijima 2009). Furthermore, other authors did not find a
survival benefit in prospective cohort studies dealing with civilian trauma patients,
nor could they identify a survival bias as the reason for the statistical significance
(Ho et al. 2012; Mitra et al. 2010; Scalea et al. 2008; Snyder et al. 2009). However,
a survival benefit was not demonstrated in most other transfusion populations
besides massive transfusion (Murad et al. 2010; Stanworth et al. 2011b). Rather,
several studies associated transfusion of FFP with a significantly increased inci-
dence of acute lung injury, sepsis, and multiple organ failure, as well as fewer
ventilator-free and ICU-free days in non-massively transfused patients (Borgman
et al. 2011; Inaba et al. 2010; Johnson et al. 2010; Maegele et al. 2008; Sambasivan
et al. 2011; Watson et al. 2009). Therefore, FFP transfusion should be restricted to
massively transfused patients (AAGBI 2010; BGMA 2009b; Kozek-Langenecker
et al. 2013; Liumbruno et al. 2009; Rossaint et al. 2010; Stürmer et al. 2011; Tavares
et al. 2011).

24.6.2 Point-of-Care Testing-Driven Transfusion and

Coagulation Management Protocols (POC-Driven
Goal-Directed Therapy or “Theranostic” Approach)

First-line, goal-directed therapy with coagulation factor concentrates (fibrinogen

and/or prothrombin complex concentrate (PCC)) guided by POC testing (thrombo-
elastometry/thromboelastography and whole blood impedance aggregometry) has
been shown to be effective in reducing transfusion-associated costs in selected
patients in trauma, cardiac surgery, and liver transplantation without increasing the
incidence of thromboembolic events. In principle, these functional hemostatic POC
tests facilitate the optimal management of severe perioperative bleeding by guiding
specific pharmacological or transfusion-based interventions and by allowing physi-
cians to differentiate better between microvascular and surgical bleeding.
Furthermore, they have the ability to reduce allogeneic blood transfusion require-
ments and to decrease re-exploration rates. Since re-exploration for bleeding in
patients after coronary artery bypass surgery is associated with increasing periop-
erative mortality by 4.5 times and increased hospital costs, they have important
implications for overall patient safety and health-care costs (Christensen et al. 2009;
Mehta et al. 2009; Sharples et al. 2006).
24 Economic Aspects and Organization 431

24.6.2.1 Goal-Directed Therapy Guided by Point-of-Care

Testing in Severe Trauma
Several cohort studies have reported decreased allogeneic blood transfusion require-
ments, reduced incidence of multiple organ failure, and improved survival in trauma
patients with massive bleeding when treated with goal-directed hemostatic control
resuscitation (HCR) guided by viscoelastic tests (thromboelastometry/thromboelas-
tography) (Görlinger et al. 2012; Innerhofer et al. 2013; Johansson and Stensballe
2009, 2010; Nienaber et al. 2011; Schöchl et al. 2010, 2011). Indeed, some trauma
centers were able to demonstrate that first-line, goal-directed therapy with fibrinogen
concentrate and PCC has the potential to decrease FFP transfusion requirements by
more than 90 % (Görlinger et al. 2012; Innerhofer et al. 2013; Schöchl et al. 2013).
However, no data on cost-effectiveness are available in this clinical setting.

24.6.2.2 Goal-Directed Therapy Guided by Point-of-Care

Testing in Liver Transplantation
Coagulopathy in patients with critical liver dysfunction is complex. In this patient
population, hemostasis can quickly decompensate to either bleeding or to throm-
bosis, depending on concomitant risk factors (Tripodi and Mannucci 2011;
Schaden et al. 2013; see Sect. 2.2). Both bleeding and thrombosis are associated
with worse outcome and increased hospital costs. However, routine coagulation
tests such as prothrombin time (PT) and the international normalized ration (INR)
are not able to define whether a patient with critical liver dysfunction has hypo- or
hypercoagulability and are not able to predict the risk of bleeding in these patients.
Therefore, prophylactic transfusion of FFP and platelets, due to increased INR or
low platelet count, should be avoided in this patient population. Hemostatic inter-
ventions should only be performed in cases of clinically relevant bleeding.
Notably, patients with liver dysfunction and increased INR are not “auto-antico-
agulated.” In contrast, thrombin generation assays performed in the presence and
absence of thrombomodulin, as well as viscoelastic tests (thromboelastometry/
thromboelastography), indicate that patients with liver dysfunction tend to exhibit
hypercoagulability with the inherent risk of thrombosis. Therefore, thrombopro-
phylaxis should strongly be considered in patients with liver dysfunction, but in
the absence of bleeding (Schaden et al. 2013).
Implementation of transfusion and coagulation management algorithms based
on thromboelastometry has been shown to reduce transfusion requirements,
transfusion-associated adverse events, and transfusion-associated costs in patients
undergoing liver transplantation. Görlinger et al. (2010) published a retrospective
study analyzing the intraoperative use of blood products and coagulation factor con-
centrates, as well as their respective acquisition costs, both before and after imple-
mentation of thromboelastometry-guided, goal-directed, hemostatic therapy in
visceral surgery and liver transplantation. Here, transfusion requirements for
PRBCs, FFP, platelets, and antithrombin concentrate decreased by 60, 89, 58, and
78 %, respectively. At the same time, use of fibrinogen concentrate and PCC
increased approximately tenfold and threefold, respectively. No off-label use of
rFVIIa occurred after implementation of the thromboelastometry-based algorithm.
This resulted in an overall cost saving of EUR 270,167 per year (36 % reduction)
432 K. Görlinger and S.A. Kozek-Langenecker

for allogeneic blood products and coagulation factor concentrates. Balanced against
this were additional costs for thromboelastometry (depreciation costs of three
ROTEM® devices, disposables, and reagents for 2,400 ROTEM® tests per year)
amounting to EUR 16,500 (Görlinger et al. 2010). Over an observation period of ten
years (covering 21,814 visceral surgeries including 1,105 liver transplantations), the
total cost saving amounted to EUR 1.6 million (EUR 1,765,280 of savings on allo-
geneic blood products and coagulation factor concentrates and EUR 165,000 of
additional costs for thromboelastometry) (Goerlinger et al. 2010). Activity-based
costs and secondary costs induced by transfusion-associated adverse events were
not considered in these costs analyses. Similar results have been published by other
groups (Noval-Padillo et al. 2010; Trzebicki et al. 2010; Wang et al. 2010).
Thromboelastometry-based, goal-directed therapy with fibrinogen concentrate and
PCC was not associated with an increased incidence of thromboembolic events
(Kirchner et al. 2012). This is in line with other publications reporting on the low
thrombotic risk of fibrinogen concentrate and PCC, so long as an overdose is
avoided (Grottke et al. 2011; Hanke et al. 2013; Kozek-Langenecker et al. 2011;
Majeed et al. 2012; Manco-Johnson et al. 2009; Sørensen et al. 2011; Warmuth
et al. 2012). Therefore, increased thrombosis-related costs are not to be expected.

24.6.2.3 Goal-Directed Therapy Guided by Point-of-Care

Testing in Cardiovascular Surgery
Implementation of transfusion and coagulation management algorithms based on
thromboelastometry/thromboelastography and whole blood impedance aggregometry
have the potential to reduce transfusion requirements, transfusion-associated adverse
events, thromboembolic events, and hospital costs in cardiovascular surgery.
Shore-Lesserson et al. (1999) were the first to demonstrate (using a prospective
randomized clinical trial) that a POC algorithm based on viscoelastic tests (throm-
boelastography) reduces transfusion incidence and requirements in cardiac sur-
gery. Since then, at least 16 clinical studies (totalizing 8,507 cardiac surgery
patients) have dealt with transfusion protocols in cardiovascular surgery, compar-
ing POC-based algorithms with algorithms based on routine laboratory testing and
clinician discretion or standard of care (Görlinger et al. 2013). All 16 studies dem-
onstrated a reduction in transfusion requirements in the POC group using visco-
elastic tests (TEG® or ROTEM®). The effect size was dependent on the study
population (simple coronary artery bypass graft surgery or complex cardiac/aortic
surgery), the average blood loss, the extent of POC diagnostics (TEG®, ROTEM®,
or ROTEM® plus Multiplate®), and the availability of specific coagulation factor
concentrates such as fibrinogen concentrate, four-factor PCCs, and factor XIII con-
centrate for calculated, goal-directed therapy. POC diagnosis was most effective in
patients undergoing complex cardiac or aortic surgery with detected abnormal
bleeding (Girdauskas et al. 2010; Hanke et al. 2012; Rahe-Meyer et al. 2009a, b;
Weber et al. 2012). Seven studies reported a reduction in the incidence of medias-
tinal re-exploration (Görlinger et al. 2011a; Nuttall et al. 2001; Spiess et al. 1995;
Weber et al. 2012), massive transfusion (Girdauskas et al. 2010; Görlinger et al.
24 Economic Aspects and Organization 433

2011a; Hanke et al. 2012; Weber et al. 2012), and hospital costs (Görlinger et al.
2011a; Hanke et al. 2012; Spalding et al. 2007; Spiess et al. 1995; Weber et al.
2012). Not one study demonstrated increased hospital costs. Off-label use of
rFVIIa – integrated into some algorithms as a rescue therapy if the algorithm’s
hemostatic therapy has failed – was almost completely eliminated in five studies
(Girdauskas et al. 2010; Görlinger et al. 2011a; Hanke et al. 2012; Spalding et al.
2007; Weber et al. 2012). This was certainly important to the cost savings in these
studies and potentially also for a reduction in the incidence of thrombotic/throm-
boembolic events. Only the four most recent studies performed, between 2010 and
2012, demonstrated an actual improvement in patient outcomes in the POC group
(Girdauskas et al. 2010; Görlinger et al. 2011a; Hanke et al. 2012; Weber et al.
2012). These studies used a similar POC coagulation and transfusion management
algorithm, first published in 2007, based on first-line, goal-directed therapy with
fibrinogen concentrate and four-factor PCCs guided by thromboelastometry
(Görlinger et al. 2007). Two studies additionally used whole blood impedance
aggregometry (Görlinger et al. 2011a; Weber et al. 2012). Three of them demon-
strated a reduction in thrombotic/thromboembolic events (Görlinger et al. 2011a;
Hanke et al. 2012; Weber et al. 2012). Furthermore, the randomized clinical trial in
coagulopathic patients undergoing complex cardiac surgery recently published by
Weber et al. (2012) showed significant reductions in postoperative pulmonary dys-
function, postoperative ventilation time, stay in ICU, composite adverse events
(acute renal failure, sepsis, thrombotic complications, and allergic reactions) (8 %
versus 38 %; p < 0.001), and six-month mortality (4 % versus 20 %; p = 0.013).
Since this single-center study was not set up to look at mortality and safety, the
results will have to be confirmed by adequately powered multicenter RCTs and
huge prospective observational studies.

24.6.2.4 Cost-Effectiveness of Goal-Directed Therapy Guided by

Point-of-Care Testing in a German University Hospital
The impact of the implementation of goal-directed hemostatic therapy guided by
POC testing on the acquisition costs of allogeneic blood products and coagulation
factor concentrates has been analyzed for Essen University Hospital, Germany.
Costs pre-implementation (in 2004) were compared to costs post-implementation
(in 2007). Costs for hemostatic management of patients with hemophilia were not
included. Between these dates, costs for coagulation factor concentrates (fibrino-
gen, PCC, antithrombin, and factor XIII concentrate) increased by EUR 810,609. At
the same time, costs for allogeneic blood products (PRBCs, FFP, and pooled platelet
concentrates) decreased by EUR 1,874,682, resulting in a total cost saving of EUR
1,064,073 per year for Essen University Hospital. Costs for ROTEM® analyses
(disposables and reagents) amounted to EUR 24,000 per year (2.3 % of the cost
saving) (Görlinger et al. 2008; Görlinger et al. 2011b). Therefore, the cost-
effectiveness of implementing goal-directed therapy guided by POC testing can be
assumed to be very high. It is worth noting that activity-based costs, as well as
secondary costs induced by transfusion-associated adverse events and prolonged
length of stay in the ICU, were not considered in this cost analysis (Table 24.3).
Table 24.3 Studies analyzing cost savings and impact of length of stay (LOS) in an ICU by point-of-care testing and goal-directed hemostatic therapy
434

Clinical setting, Study type, number of Costs for POC ICU LOS Mean reason for cost
Author (year) country patients POC device Cost saving diagnostics (calculated costs) saving
Spiess et al. Cardiac surgery, Before-and-after; 1,079 TEG Cost saving not NA NA Decreased transfusion
(1995) USA patients specified requirement
Spalding et al. Cardiac surgery, Before-and-after; 1,422 ROTEM €51,000 per €1,580 per Decreased PRBC,
(2007) Germany patients month (−44 %) month (3.1 % of platelets, PCC, FXIII,
cost saving and rFVIIa
Görlinger et al. University Before-and-after (2007 ROTEM €1,064,073 per €24,000 (2.3 % NA Decrease FFP and
(2008) Hospital, versus 2004); about year of cost saving) PRBC transfusion
Germany 50,000
Goerlinger Visceral surgery Before-and-after (2009 ROTEM €270,167 per €16,500 (6.1 % NA Decrease FFP, PRBC,
et al. (2010) and LTX, versus 1999); about year (−36 %) of cost saving) and platelet
Germany 4,800 patients incl. 240 transfusion
LTX
Görlinger et al. Visceral surgery Before-and-after ROTEM €1,765,280 in €165,000 (9.3 % NA Decrease FFP, PRBC,
(2010) and LTX, (1999–2009); 21,814 10 years of cost saving) and platelet
Germany patients incl. 1,105 LTX transfusion
Görlinger et al. Cardiac surgery, Before-and-after (2009 ROTEM and €50,000 per NA NA Decrease FFP and
(2011a, b) Germany versus 2005); 3,865 Multiplate year (−6.5 %) PRBC transfusion
patients
Hanke et al. Type A aortic Before-and-after; 10 ROTEM €2,757 per case NA −5.8 days Decreased FFP and
(2012) dissection, patients (×2,980 PRBC transfusion
Germany €a = €17,284)
Weber et al. Complex cardiac RCT; 100 patients ROTEM and €79,034 (€1,580 €6,520 (€130.40 −3 h (median) Decreased FFP,
(2012) surgery, Germany multiplate per patient) per patient) PRBC, platelets, and
rFVIIa
Esler et al. Cardiac suregry, Before-and-after; 2,176 ROTEM and AU$ 928,998 NA NA Decreased FFP,
(2013) Australia patients Multiplate (€608,385) per PRBC and platelet
year (−48.3%) transfusion (−39.2%)
See Dasta et al. (2005)
K. Görlinger and S.A. Kozek-Langenecker

NA not analyzed
a
Costs per ICU day
24 Economic Aspects and Organization 435

24.7 Organization of Perioperative Bleeding Management

All hospitals dealing with bleeding patients should have a task force on managing
severe bleeding, with the mission of continually developing and implementing stan-
dard operating procedures (SOPs) or algorithms adapted to their local patient popu-
lation’s needs and the diagnostic and therapeutic options available. The successful
implementation of such SOPs can only be accomplished in a multi-specialty setting.
Input and representation from departments such as anesthesiology, intensive care
medicine, hemostaseology and hematology, transfusion medicine, laboratory medi-
cine, trauma and emergency medicine, surgery, and obstetrics are necessary to suc-
cessfully formulate and implement such protocols. Once a severe bleeding
management protocol has been agreed upon, education of the entire nursing and
physician staff is equally essential to its success. Once implemented, this process
may lead to improved clinical outcomes and decreased overall blood use, with
extremely little waste of vital blood products (Görlinger and Schlenke 2012; Levy
et al. 2010; Markova et al. 2012; Milligan et al. 2011; Nunez et al. 2010).
Perioperative bleeding management can be understood as a part of “patient blood
management,” focusing on the stabilization of perioperative hemostasis and a reduc-
tion of perioperative blood loss and transfusion requirements (Gombotz 2012;
Goodnough and Shander 2012; Shander et al. 2012). Leadership in perioperative
bleeding management depends on the kind of strategy hospitals use. In hospitals
using formula-driven transfusion protocols with transfusion packages, clinical
scores to predict the need for massive transfusion are essential to activate massive
transfusion protocols (Maegele et al. 2012). A transfusion medicine department
would have a central position here (Johansson 2007). In contrast, hospitals using
laboratory- or POC-driven protocols focus on early detection and differentiation
between coagulopathies and subsequent goal-directed therapy. Here, POC testing
not only facilitates timely detection of hemostatic disorders and goal-directed ther-
apy, but it can also be used to improve staff education and interdisciplinary com-
munication by visualization of hemostasis as a didactic tool. In hospitals using this
concept, anesthetists, intensivists, hematologists, and laboratory scientists are in
central positions for the management of severe perioperative bleeding (Görlinger
2012; Kozek-Langenecker 2010; Lier et al. 2013). The optimal location for the POC
device – either in the emergency room, operating room or ICU, or in the central
laboratory – is dependent on the local situation, regional structure, staff education,
and the hospital’s requirements. If the POC device is located in the central labora-
tory, then a quick, effective system to transport blood samples and an electronic
connection to get results back to the operating room are crucial. If the POC device
is used in a mobile way, moving between the operating room and the ICU, then
extensive staff education and training is necessary, as well as strict quality control
management (Perry et al. 2010; Spannagl et al. 2010). If this can be done, turn-
around times for POC testing and the “time-to-treat” for a bleeding patient can be
minimized (Haas et al. 2012b). However, any local concept should be based on an
interdisciplinary consensus and should aim for the optimal treatment of the bleeding
patient concerned. In order to support physicians in hospitals in their
436 K. Görlinger and S.A. Kozek-Langenecker

decision-making, the European Society of Anaesthesiology’s “Task Force on Severe

Bleeding Management” has developed evidence-based guidelines on the manage-
ment of severe perioperative bleeding which were first presented at its autumn meet-
ing in Prague, in November 2012. They have been published in the European
Journal of Anaesthesiology (Kozek-Langenecker et al. 2013).

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Wang SC, Shieh JF, Chang KY, Chu YC, Liu CS, Loong CC, Chan KH, Mandell S, Tsou MY (2010)
Thromboelastography-guided transfusion decreases intraoperative blood transfusion during ortho-
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Warmuth M, Mad P, Wild C (2012) Systematic review of the efficacy and safety of fibrinogen
concentrate substitution in adults. Acta Anaesthesiol Scand 56(5):539–548
Watson GA, Sperry JL, Rosengart MR, Minei JP, Harbrecht BG, Moore EE, Cuschieri J, Maier RV,
Billiar TR, Peitzman AB, Inflammation and Host Response to Injury Investigators (2009)
Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and
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Waydhas C, Görlinger K (2009) Coagulation management in multiple trauma. Unfallchirurg
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Index

A antifibrinolytic agents, 356

Abciximab, 247 autologous retransfusion, 357–359
Acenocoumarol, 123 goal-directed transfusions, 355
Acidosis, 253–254 hypotensive epidural anesthesia, 356
Acquired coagulation factor deficiencies normovolemic hemodilution, 356–357
FV, 99 platelet gel and fibrin sealant, 357
FVIII, 98 preoperative autologous blood
FXIII, 99 donation, 353
Acquired platelet dysfunction, 93–94 preoperative intravenous iron therapy,
Activated partial thromboplastin time 353–354
(aPTT), 14–16 temperature, 355
Activated recombinant coagulation transfusion triggers, 353
factor VII, 323 Aminocaproic acid, 210, 252
Acute traumatic coagulopathy Amplification, 7
acidemia, 317 Anemia
acute coagulopathy of trauma shock, 314 definition, 225, 227
acute traumatic coagulopathy, 314 risk, 225, 227
endogenous acute coagulopathy, 314 screening and treatment, 227–228
endothelial activation, 312 Antiaggregant agents, 244–248
hemodilution, 315–316 Antiaggregant therapy, double, 246–247
hyperfibrinolysis, 313 Anticoagulants
hypothermia, 316–317 antiplatelet agents, 366–368
inflammation, 317 anti-Xa agents, 371–372
plasminogen activator inhibitor, 313 direct thrombin inhibitors, 371–372
protein C, 312 low molecular weight heparin,
shock, 315 369–370
tissue plasminogen activator, 313 thrombolytics, 372
tissue trauma, 314–315 unfractionated heparin, 367–369
trauma-induced coagulopathy, 314 vitamin K antagonists, 370–371
Afibrinogenemia, 76 Antidepressant drugs, 101
Albumin Antifibrinolytics
clinical studies, 137 administration and dosage, 213
effects on coagulation factors, 136 ε-aminocaproic acid, 427
effects on platelets, 137 aprotinin, 427
viscoelastic findings, 136–137 description, 210–211
Allogenic blood transfusions, alternatives to in nonsurgical bleeding, 211–212
adaptation of perioperative medication, side effects and contraindications, 215
354–355 in surgical bleeding, 212–213
administration of erythropoiesis-stimulating tranexamic acid, 427
agents (ESA), 354 in trauma, 212

C.E. Marcucci, P. Schoettker (eds.), Perioperative Hemostasis, 447

DOI 10.1007/978-3-642-55004-1, © Springer-Verlag Berlin Heidelberg 2015
448 Index

Antiphospholipid antibody syndrome, 105 protein C, 249

Antiplatelet therapy, 110–113, 246 pumps and circuits, 251
aspirin, 110 secondary hemostasis, 247–248
BMS, 112 shed blood, 249–250
cangrelor, 112 Cascade model, 7
classification, 110 Cell-based model of hemostasis, 7–9
clopidogrel, 110 Cell salvage, 428–429
DES, 112 Chronic liver disease, 94–96
dual AP therapy, 112 management, 95–96
dual therapy, 115 Clopidogrel, 246
duration, 113 Clotting factor assays, 18
hemorrhagic risk, 114–115 Coagulation cascade model, 15
intraoperative management, 118 Coagulation factors, 6
pharmacokinetics, 111 Coagulation test(ing), 14–19, 121
pharmacology, 110 Coagulation tests in liver dysfunction
prasugrel, 111 routine coagulation testing, 269
preoperative management, 116, 117 thrombin generation assays, 270
ticagrelor, 112 viscoelastic tests, 270–271
withdrawal of, 113–114 Coagulopathy in liver cirrhosis, 267–269
Antithrombin deficiency, 11 Colloid solutions, 136–143
Apixaban, 124 Combined deficiency
Aspirin, 246 factors V and VIII, 81–82
vitamin K-dependent clotting factors,
82–83
B Costs of bleeding complications, 422–426
Balanced fluids Costs of blood, 421
clinical studies, 135 Costs of ischemic and thromboembolic
effects on coagulation factors, 135 events, 426
Bare-metal stent (BMS), 109 CPB. See Cardiopulmonary bypass (CPB)
Bernard-Soulier disease Critically ill patients
laboratory findings, 85 activated protein C, 379
prevalence, 86 causes of thrombocytopenia, 379–382
treatment, 85 coagulation and inflammation in critically
Bleeding management, liver dysfunction/liver ill patients, 378–379
transplantation, 271–273 incidence, 377–378
Bleeding time, 20, 68 prolonged global coagulation times,
Blood transfusion 382–383
complications, 223 protein C receptor, 379
costs protein S, 379
activity-based cost, 422 Cryoprecipitate
primary/acquisition costs, 422 description, 155–156
secondary costs, 422 dosage, 156–157
indications, 156–157
therapeutic effect, 156–157
C Crystalloids, 134
Cardiopulmonary bypass (CPB) Crystalloid solutions
anticoagulation, 251 effect on coagulation factors, 134
antithrombin III, 249 normal saline, 134
blood conservation, 250 viscoelastic findings, 1–135
clotting disorders, 247–250
fibrinolysis, 249, 252
hemodilution, 250 D
heparin, 251 Dabigatran, 123
mini circuits, 252 Desmopressin
primary hemostasis, 247 in acquired bleeding disorders, 208–209
Index 449

administration and dosage, 209–210 Factor XII deficiency, 84

description, 205–206 Factor XIII concentrate
in inherited bleeding disorders, 207–208 description, 183
side effects and contraindications, 210 dosing, 186
in surgery, 209 efficacy and safety, 184–185
Dextran indications, 183
clinical studies, 139 monitoring, 184
effects on coagulation factors, 138 Factor XIII deficiency
effects on platelets, 138–139 laboratory findings, 85
viscoelastic findings, 138 treatment, 85
Dilution coagulopathy, 144–145 Fibrinogen, 17
d-Dimer assay, 19 measurement, 17
Disseminated intravascular coagulation Fibrinogen concentrate
antifibrinolytic agents, 98 description, 178–180
diagnosis, 97 dosing, 182
management, 97–98 efficacy and safety, 181–182
target blood component levels, 97 indications, 180
Drug-eluting stents (DESs), 109 monitoring, 180–181
Dysfibrinogenemia, 77 Fibrinogen deficiency
laboratory findings, 77
treatment of, 77
E Fibrinolytic system
Eptifibatide, 247 plasmin 9
Extrinsic pathway, 7 plasmin inhibitor 9
plasminogen 9
plasminogen activator inhibitor
F (PAI) 9
Factor II (prothrombin) deficiency thrombin-activatable fibrinolysis inhibitor
laboratory findings, 81 (TAFI) 9
prevalence, 80 First-line therapy with fibrinogen and
treatment, 81 prothrombin complex concentrate
Factor V deficiency activated recombinant factor VII
incidence, 81 (rFVIIa), 278
laboratory findings, 81 antifibrinolytic drugs, 276
treatment, 82 cryoprecipitate, 276
Factor V Leiden, 10 fibrinogen concentrate, 276
Factor VII deficiency fresh frozen plasma (FFP), 277
laboratory findings, 82 platelet concentrate, 277
prevalence, 82 prothrombin complex concentrate
treatment, 82 (PCC), 277
Factor VIII deficiency Fondaparinux
laboratory findings, 78 effects of anticoagulants, 121
prevalence, 78 monitoring, 119, 122
severity of, 78 reversal, 122
treatment of, 78 Formula-driven transfusion protocols, 430
Factor IX deficiency FFP to PRBC ratio, 430
laboratory findings, 79 Fresh frozen plasma (FFP), 229
prevalence, 79
treatment of, 79
Factor X deficiency G
laboratory findings, 83 Gelatin, 139–140
treatment, 83 clinical studies, 140
Factor XI deficiency effect on coagulation factors, 139
laboratory findings, 84 effects on platelets, 140
treatment, 84 viscoelastic studies, 139–140
450 Index

Glanzmann’s thrombasthenia, 85 Heparins, 119–122, 256

laboratory findings, 85 effects of anticoagulants, 121
prevalence, 85 monitoring, 119–122
treatment, 85 reversal, 122
Goal-directed therapy, point-of-care testing Hydroxyethyl starch (HES), 140
(cardiovascular surgery) Hypertonic–hyperoncotic solutions, 143–144
algorithms based on routine laboratory effects on coagulation factors, 143–144
testing, 432 effects on platelets, 144
POC algorithm, 432 viscoelastic tests, 144
GP IIb/IIIa inhibitors, 251 Hypertonic 7.2–7.5 % saline, 143
Hypofibrinogenemia, 76
Hypothermia, 253–254
H
Hemophilia A, 77–78
laboratory findings, 78 I
prevalence, 77 Impedance aggregometry, 54, 246
severity of, 78 Implementation of transfusion and coagulation
treatment of, 78 management protocols, 429–434
Hemophilia B, 78–80 transfusion-associated costs, 429
laboratory findings, 79 Initiation, 7
prevalence, 79 Intensive care patients, 377–387
treatment of, 79 antifibrinolytic agents, 385
Hemostasis in neurosurgical patients, future fresh/frozen plasma, 385
management of management, 384–387
from bleeding to clotting, 345 platelet transfusion, 384–385
early goal-directed therapy, 344–345 pro-hemostatic, 385
secondary brain injury, 345 prothrombin complex concentrates, 385
Hemostatic changes in neurosurgical patients recombinant factor VIIa (rFVIIa), 386
classic biological tests, 340 soluble thrombomodulin represents, 386
clinical evaluation, 399–340 Intrinsic pathway, 6
point-of-care assessment of hemostasis,
340–342
Hemostatic resuscitation L
antifibrinolytic drugs, 321 Light transmission aggregometry, 67
calcium, 322 Light transmission platelet aggregometry,
fibrinogen, 321–322 20–21
fresh frozen plasma, 320 Liver dysfunction, bleeding management in
packed red blood cells, 319–320 patients with, 270–273
platelet concentrates, 320–321 Liver transplantation, bleeding management
prothrombin complex concentrate, 322 in patients with, 270–273
Heparin-induced thrombocytopenia, 92–93 Low-molecular-weight heparins (LMWH),
argatroban, 93 119, 244
danaparoid, 93
4Ts scoring system, 93
laboratory testing, 92 M
treatment, 92 Malignancies, 101–102
Heparin-induced thrombocytopenia (HIT) diagnosis, 102
bivalirudin, 259 management, 102
cardiac surgery, 259–260 Management of hemostasis in neurosurgery
diagnosis, 257–258 complex concentrate, 343
4Ts score, 258 deferoxamine, 344
pathophysiology, 257 fibrinogen, 343
prostacyclin, 260 fresh frozen plasma, 343
tirofiban, 260 platelets, 342–343
treatment, 258–259 prothrombin, 343
Index 451

recombinant activated factor VII, 344 hemostatic management of PPH, 305

tranexamic acid, 343 modifications to coagulation during
Mixing studies, 17–18 pregnancy, 302
Monitoring of antithrombotic treatment, 21–23 principal causes of PPH, 301–302
fondaparinux and danaparoid, 22 transfusion strategy, 306–308
heparin, 21 Opioid abuse, 100
low molecular weight heparin Oral anticoagulants (OAC), 245
(LMWH), 22 Orthopedic surgery, 351–359
novel direct oral anticoagulants
(NOACs), 23
unfractionated heparin (UFH), 22 P
vitamin K antagonist treatment, 22 Patient blood management, 225, 227
Monoclonal gammopathies, 103–104 Pediatric hemostasis, 285
diagnosis, 103–104 Perioperative bleeding management, 435, 436
mechanism, 103 Perioperative coagulation management
Multiple electrode aggregometry analyzer intraoperative fluid management, 288
(Multiplate®), 54–57 intraoperative laboratory findings and
clinical use in perioperative care, 57 therapy, 289–294
limitations and pitfalls, 57 preoperative considerations, 287–288
normal values and result interpretation, 56 Perioperative coagulation testing in children
working mechanism, 54–56 intraoperative coagulation testing, 286–287
Myeloproliferative neoplasms, 104–105 preoperative screening of hemostasis,
hemorrhagic complications, 104 285–286
thrombotic complications, 104 standard plasmatic coagulation testing, 286
treatment, 104–105 thromboelastometry, 286–287
Pharmacological prophylaxis
apixaban, 409
N aspirin, 405
Neurosurgery, 331–345 dabigatran, 407–408
Neurosurgical patients danaparoid, 405
activation of coagulation processes, 331 direct thrombin Inhibitors, 406–408
antiepileptic drugs, 334 evidence-based guidelines, perioperative
antiplatelet agents, 336 thromboprophylaxis, 410–413
bleeding, 333–334 fondaparinux, 404–405
desmopressin, 335 heparin and derivatives, 401–405
hydroxyethyl starch, 335 hirudin analogues, 406–407
hypertonic saline, 335 low-molecular-weight heparin, 403–404
mannitol, 335 oral anti-factor Xa agents, 408–409
neurosurgical techniques, 339 rivaroxaban, 408–409
new oral anticoagulants, 338 unfractionated heparin, 401–403
release of thromboplastins, 331–332 vitamin K antagonists, 399
role of thrombin and iron, 332 Phenprocoumon, 123
thrombolytics, 339 Plasma, 151–155
thrombosis, 333 ABO compatibility, 153
vitamin K antagonists, 336–338 cryoprecipitate reduced, 155–157
Novel oral anticoagulants, 123–126, 245 description, 151–153
pharmacology, 123–124 dose and therapeutic effect, 154–155
reversal, 124–125 fresh frozen, 151
frozen within 24 h, 151
indications, 153–154
O liquid, 152
Obstetrics methylene blue (MB)-treated, 153
coagulopathies in PPH, 302 pathogen-reduced, 152
hemorrhages during placental solvent/detergent-treated, 152
expulsion, 300 thawed, 152
452 Index

Platelet concentrates, 157–159, 229 efficacy and safety, 196

description, 157–158 indications, 195
dose, 158–159 monitoring, 196
indication, 158–159 Regional anesthesia
pathogen-inactivated, photochemically antiplatelet agents, 366–368
treated, 159 anti-Xa agents, 371–372
platelet additive solutions (PAS), 159 direct thrombin inhibitors, 371–372
therapeutic effect, 158–159 low molecular weight heparin,
Platelet count, 20 369–370
Platelet function analyzer (PFA), 20, 68 thrombolytics, 372
Platelet function analyzer (PFA)-100/200®, unfractionated heparin, 368–369
47–49 vitamin K antagonists, 370–371
clinical use in perioperative care, 49 The Reptilase test, 18
limitations and pitfalls, 49 Resuscitation strategies, formula driven versus
normal values and interpretation, 48–49 goal directed/laboratory driven,
working mechanism, 47–48 323–324
Platelet function tests, 45–60, 254 Rivaroxaban, 124
Platelets, 4 ROTEM®, 229, 254
Plateletworks®, 49–51
clinical use in perioperative care, 50
limitations and pitfalls, 51 S
normal values and result interpretation, 50 Secondary hemostasis, 5–7
working mechanism, 49–50 Starches, 140–143
Point-of-care testing-driven transfusion and clinical studies, 142–143
coagulation management protocols effect on coagulation factors, 143–144
goal-directed therapy, 431 effects on platelets, 144
in liver transplantation, 431 viscoelastic studies, 144
in severe trauma, 431 Strategies for perioperative
transfusion and coagulation management thromboprophylaxis
algorithms, 431 anesthetic technique and early
Prasugrel hydrochloride, 246 ambulation, 397
Primary hemostasis, 4–5, 19–21, 67–68 continuous passive motion, 397
assessment of, 67 elasticated compressive stockings, 397
testing, 19–20 intermittent pneumatic compression
Propagation, 7 devices, 397
Prophylactic hemostatic interventions, mechanical prophylaxis, 397–398
426–428 multimodal thromboprophylaxis
Protamine, 256 approach, 396
Protein C/S system, 10 non-pharmacological approach, 396
thrombomodulin (TM), 10
Prothrombin complex concentrates, 189–195
description, 190 T
dosing, 194 TEG®, 229, 254
efficacy and safety, 194 Thrombin generation test, 19
indications, 190–191 Thrombin time, 18
monitoring, 192–194 Thrombocytopenia
Prothrombin time (PT), 16–17 acquired, 89–92
Pseudothrombocytopenia, 67 causes, 91
P2Y12 receptor antagonists, 246 drug-induced, 90
HIV, 90
Thromboelastography platelet mapping®
R clinical use in perioperative care, 49
Recombinant activated factor VII limitations and pitfalls, 49
description, 195 normal values and result interpretation, 48
dosing, 196 working mechanism, 47–48
Index 453

Thrombolytic drugs, 101 deep vein thrombosis, 392

Thrombophilia testing, 19 prevalence, 392–393
Thromboprophylaxis, 391–413 pulmonary embolism (PE), 392
Thrombotic microangiopathies, 105 symptomatic VTE, 393
Ticagrelor, 246 time course and cost implications,
Tirofiban, 247 393–394
Tranexamic acid, 210, 252 Venous thrombi, 392
Transfusion Venous thromboprophylaxis, 278–279
acute hemolytic reaction, 161 VerifyNow®
adverse effects, 223–225 clinical use in perioperative care, 54
allergic reactions/anaphylaxis, 162 limitations and pitfalls, 54
bacterial contamination, 160–161 normal values and result interpretation,
febrile nonhemolytic reaction, 161–162 53–54
transmitted infections, 160 working mechanism, 51–53
Transfusion-associated circulatory overload Viscoelastic tests
(TACO) activators, 29
diagnosis and management, 166 fibrinogen deficiency, 34, 38
metabolic complications and hypothermia, heparin influence, 38, 40
166–167 hypercoagulable states, 30
pathophysiology, 165–166 hyperfibrinolysis, 37, 39
Transfusion-related acute lung injury (TRALI) influence of specific coagulation factors,
diagnosis and management, 163–164 38–39
pathophysiology, 165–166 normal patient, 34, 36
prevention, 164–165 platelet deficiency, 34, 37
Transfusion triggers, 230, 232, 252–253 reference ranges, 33
Trauma, 311–324 ROTEM®, 26
Trauma-induced coagulopathy, 318–320 ROTEM®-derived parameters, 32
acidemaia, 317 technical characteristics, 27
acute coagulopathy of trauma shock, 314 technology, 27
acute traumatic coagulopathy, 314 TEG®-derived parameters, 31–32
damage control resuscitation, 318–319 TEG® hemostasis analyzer, 26
diagnosis, 317–318 tests and agents, 28–30
endogenous acute coagulopathy, 314 thromboelastography, 26
endothelial activation, 312 thromboelastometry, 26
hemodilution, 315–316 Vitamin K
hyperfibrinolysis, 313 clinical uses, 214–215
hypothermia, 316–317 deficiency, 94
inflammation, 317 description, 214
management, 318–319 side effects and contraindications, 215
plasminogen activator inhibitor, 314 Vitamin K antagonists (VKAs),
protein C, 312 123, 244
shock, 315 von Willebrand disease (vWD)
tissue plasminogen activator, 314 classification, 73
tissue trauma, 314–315 diagnosis of, 21
trauma-induced coagulopathy, 314 laboratory findings, 74
prevalence, 73
treatment of, 76
U Type 1, 74
Unfractionated heparin (UFH), 119, 244 Type 2, 74
Type 2A, 74
Type 2B, 74–75
V Type 2M, 75
Vena Cava filters, 126–127 Type 2N (vWF Normandy), 75
Venous thromboembolism Type 3, 75
assessment of VTE risk factors, 394–396 von Willebrand factor, 77
454 Index

von Willebrand factor (vWF), 4 von Willebrand syndrome, acquired,

Von Willebrand factor/factor VIII concentrates 99–100
description, 186–187 vWD. See von Willebrand disease (vWD)
dosing, 189
efficacy and safety, 188–189
indications, 187–188 W
monitoring, 188 Warfarin, 123