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Methods in
Molecular Biology 992

Paul Monagle Editor

Haemostasis
Methods and Protocols
METHODS IN MOLECULAR BIOLOGY™

Series Editor
John M. Walker
School of Life Sciences
University of Hertfordshire
Hatfield, Hertfordshire, AL10 9AB, UK

For further volumes:

http://www.springer.com/series/7651
 Haemostasis

Methods and Protocols

Edited by

Paul Monagle
Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
Editor
Paul Monagle
Department of Paediatrics
University of Melbourne
Parkville, VIC, Australia

ISSN 1064-3745 ISSN 1940-6029 (electronic)

ISBN 978-1-62703-338-1 ISBN 978-1-62703-339-8 (eBook)
DOI 10.1007/978-1-62703-339-8
Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2013932398

© Springer Science+Business Media New York 2013

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction
on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation,
computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this
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Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the
Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions
for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution
under the respective Copyright Law.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
While the advice and information in this book are believed to be true and accurate at the date of publication, neither
the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be
made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed on acid-free paper

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Springer is part of Springer Science+Business Media (www.springer.com)
Preface

The haemostatic system is one the most important physiological systems for maintaining
health and well-being. Disturbances of the haemostatic system, in the broader sense (e.g.,
heart disease, strokes), arguably constitute the single greatest contribution to non-infectious
mortality in the world today. Bleeding and clotting problems are also major causes of
morbidity and mortality in patients with primary underlying diseases such as cancer, whether
secondary to the disease or the therapy. In this context, understanding the laboratory
methods to assess the haemostatic system is vital for the practice of complex clinical medicine.
Perhaps even more importantly, the investigation of the haemostatic system remains a
research priority.
This book provides a basic description of the major components of haemostatic system
in the introductory part. The general principles of haemostatic testing are described in the
second part, and subsequent chapters describe many of the common techniques used to
assess various aspects of the haemostatic system, grouped according to their functional
indications.
The techniques vary from biological clot-based assays to chromogenic assays and immu-
nological measurements of proteins. The obvious link between all these assays is that they
are all in vitro tests that do not really measure the haemostatic system in its functional real-
ity. Thus no test can claim to truly measure the overall functionality of the haemostatic
system. Rather each test provides a result which can, in the light of previous clinical research,
hopefully predict something useful about the patient’s current status or likely outcome.
There remains an urgent need for further research to develop better methods of assess-
ing the haemostatic system in humans, and perhaps through reading this book, which
highlights the benefits and shortcomings of most major tests currently available, a young
scientist will spark an interest that will lead to that discovery.

Parkville, VIC, Australia Paul Monagle

v
Contents

Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

PART I THE HAEMOSTATIC SYSTEM

1 The Coagulation System in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Anthony K.C. Chan and Nethnapha Paredes
2 Platelet Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Matthew D. Linden
3 The Role of the Vessel Wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Nethnapha Paredes and Anthony K.C. Chan

PART II GENERAL PRINCIPLES OF HAEMOSTATIC TESTING

4 Specimen Requirements for the Haemostasis Laboratory. . . . . . . . . . . . . . . . . 49

Linda J. Stang and Lesley G. Mitchell
5 Methods of Coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Gemma Crighton
6 Reference Ranges of Coagulation Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Oliver Speer, Markus Schmugge, Claudia Metzger,
and Manuela Albisetti
7 Lupus Anticoagulant Testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Karen Moffat, Anne Raby, and Mark Crowther

PART III EXAMPLES OF GLOBAL TESTS OF HAEMOSTASIS

8 Activated Partial Thromboplastin Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Vera Ignjatovic
9 Prothrombin Time/International Normalized Ratio . . . . . . . . . . . . . . . . . . . . 121
Vera Ignjatovic
10 Thrombin Clotting Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Vera Ignjatovic
11 Thrombin Generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Leslie R. Berry and Anthony K.C. Chan
12 Activated Clotting Time (ACT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Stephen Horton and Simon Augustin

vii
viii Contents

PART IV EXAMPLES OF TESTS FOR BLEEDING DISORDERS

13 Factor XIII Assays. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Stephen Opat, Jenny Butler, Erica Malan, Elizabeth Duncan,
and Huyen A.M. Tran
14 Fibrinogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Linda J. Stang and Lesley G. Mitchell
15 Platelet Counting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Sylvain Salignac, Véronique Latger-Cannard, Nicole Schlegel,
and Thomas Pierre Lecompte
16 Platelet Morphology Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Véronique Latger-Cannard, Odile Fenneteau, Sylvain Salignac,
Thomas Pierre Lecompte, and Nicole Schlegel
17 Light Transmission Aggregometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Juan Pablo Frontroth
18 Platelet Flow Cytometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Matthew D. Linden

PART V EXAMPLES OF SPECIFIC ASSAYS RELATED TO ANTICOAGULANT

ACTIVITY

19 Anti-factor Xa (Anti-Xa) Assay. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265

Fiona Newall
20 Reptilase Time (RT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Hratsch Karapetian
21 Protamine Titration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Fiona Newall
22 Laboratory Methods for the Assay of Tissue Factor Pathway Inhibitor
in Human Plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Robyn Summerhayes
23 Heparin-Induced Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
Andreas Greinacher, Birgitt Fürll, and Sixten Selleng

PART VI EXAMPLES OF TESTS FOR INHIBITORS OF COAGULATION

24 Nijmegen-Bethesda Assay to Measure Factor VIII Inhibitors. . . . . . . . . . . . . . 321

Elizabeth Duncan, Margaret Collecutt, and Alison Street
25 Kaolin Clotting Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Kottayam Radhakrishnan
26 The Dilute Russell’s Viper Venom Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Kottayam Radhakrishnan
27 Platelet Neutralization Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Kottayam Radhakrishnan
 Contents ix

PART VII EXAMPLES OF TESTS FOR INCREASED RISK OF THROMBOSIS

28 Antithrombin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Mirta Hepner and Vasiliki Karlaftis
29 Protein C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Mirta Hepner and Vasiliki Karlaftis
30 Protein S. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
Mirta Hepner and Vasiliki Karlaftis
31 Testing for Hyperhomocysteinemia in Subjects with a History
of Thromboembolic Events Using HPLC Technique . . . . . . . . . . . . . . . . . . . 383
Jonas Denecke
32 Anticardiolipin Antibody and Anti-beta 2 Glycoprotein I
Antibody Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
Anne Raby, Karen Moffat, and Mark Crowther
33 Testing for Apolipoprotein(a) Phenotype Using Isoelectric
Focusing and Immunoblotting Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
Claus Langer, Bertram Tambyrayah, and Ulrike Nowak-Göttl

PART VIII EXAMPLES OF MEASURES OF FIBRINOLYSIS

34 D-Dimer and Fibrinogen/Fibrin Degradation Products . . . . . . . . . . . . . . . . . 415

Linda J. Stang
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
Contributors

MANUELA ALBISETTI • Division of Haematology, University Children’s Hospital, Zurich,

Switzerland
SIMON AUGUSTIN • Department of Cardiac Surgery, Royal Children’s Hospital,
Melbourne, Australia
LESLIE R. BERRY • Thrombosis and Atherosclerosis Research Institute (TaARI),
McMaster University, Hamilton, ON, Canada
JENNY BUTLER • Haematology Laboratory, Monash Medical Centre, Clayton, VIC,
Australia
ANTHONY K.C. CHAN • Thrombosis and Atherosclerosis Research Institute (TaARI),
McMaster University, Hamilton, ON, Canada
MARGARET COLLECUTT • Alfred Pathology Service, The Alfred Hospital, Melbourne,
Australia
GEMMA CRIGHTON • Department of Haematology, Royal Children’s Hospital,
Melbourne, Australia
MARK CROWTHER • Division of Hematology and Thromboembolism,
McMaster University and St Joseph’s Hospital, Hamilton, ON, Canada
JONAS DENECKE • Department of Paediatrics, University Hospital
Hamburg-Eppendorf, Hamburg-Eppendorf, Germany
ELIZABETH DUNCAN • Division of Haematology, Institute of Medical and Veterinary
Science, Adelaide, SA, Australia
ODILE FENNETEAU • Biological Hematology Department, National French Reference
Center on Inherited Platelet Disorders (CRPP), Robert Debré Hospital, AP-HP and
Paris 7 Denis Diderot University, Paris, France
JUAN PABLO FRONTROTH • Laboratorio de Hemostasia y Trombosis, Hospital de
Pediatría, “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
BIRGITT FÜRLL • Institute for Immunology and Transfusion Medicine,
Ernst-Moritz-Arndt-University, Greifswald, Germany
ANDREAS GREINACHER • Institute for Immunology and Transfusion Medicine,
Ernst-Moritz-Arndt-University, Greifswald, Germany
MIRTA HEPNER • Laboratorio de Hemostasia y Trombosis, Hospital de Pediatría
“Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
STEPHEN HORTON • Department of Cardiac Surgery, Royal Children’s Hospital,
Melbourne, Australia
VERA IGNJATOVIC • Haematology Research Laboratory, Murdoch Childrens Research
Institute, Melbourne, Australia; Department of Paediatrics, The University of
Melbourne, Melbourne, Australia
HRATSCH KARAPETIAN • Division of Paediatric Cardiology, Department of Paediatric and
Adolescent Medicine, Medical University of Vienna, Vienna, Austria
VASILIKI KARLAFTIS • Haematology Research Laboratory, Murdoch Children’s Research
Institute, Melbourne, Australia
CLAUS LANGER • Department of Laboratory Medicine, University Hospital, Munster,
Germany

xi
xii Contributors

VÉRONIQUE LATGER-CANNARD • Hematology Department and Grand East Competence

Center on Inherited Platelet Disorders, CHU Nancy, Nancy, France
THOMAS PIERRE LECOMPTE • Département des Spécialités de Médecine, Service
d’Hématologie, Hôpitaux Universitaires de Genève (HUG), Geneva, Switzerland
MATTHEW D. LINDEN • Centre for Microscopy, Characterisation and Analysis,
University of Western Australia, Crawley, WA, Australia
ERICA MALAN • Haematology Laboratory, Monash Medical Centre, Clayton, VIC, Australia
CLAUDIA METZGER • Division of Haematology, University Children’s Hospital, Zurich,
Switzerland
LESLEY G. MITCHELL • Hematology/Oncology, Department of Pediatrics,
University of Alberta, Edmonton, AB, Canada, T6G 2S2
KAREN MOFFAT • Department of Medicine, McMaster University, Hamilton, ON,
Canada; Hamilton Regional Laboratory Medicine Program, Hamilton,
ON, Canada
FIONA NEWALL • Department of Clinical Haematology, The Royal Children’s Hospital,
Melbourne, Australia; Department of Paediatrics, The University of Melbourne,
Melbourne, Australia; Department of Nursing, The University of Melbourne,
Melbourne, Australia
ULRIKE NOWAK-GÖTTL • Thrombosis and Hemostasis Treatment Center,
University Hospital Schleswig-Holstein, Kiel, Germany
STEPHEN OPAT • Department of Haematology, Monash Medical Centre, Clayton, VIC,
Australia
NETHNAPHA PAREDES • Thrombosis and Atherosclerosis Research Institute (TaARI),
McMaster University, Hamilton, ON, Canada
ANNE RABY • External Quality Assessment, Quality Management
Program – Laboratory Services, Toronto, ON, Canada
KOTTAYAM RADHAKRISHNAN • Department of Clinical Haematology, Royal Children’s
Hospital, Melbourne, Australia
SYLVAIN SALIGNAC • Hematology Department and Grand East Competence Center on
Inherited Platelet Disorders, CHU Nancy, Nancy, France
NICOLE SCHLEGEL • Biological Hematology Department, National French Reference Center
on Inherited Platelet Disorders (CRPP), Robert Debre´ Hospital,
AP-HP and Paris 7 Denis Diderot University, Paris, France
MARKUS SCHMUGGE • Division of Haematology, University Children’s Hospital, Zurich,
Switzerland
SIXTEN SELLENG • Klinik für Anaesthesie und Intensivmedizin, Ernst-Moritz-
Arndt-University, Greifswald, Germany
OLIVER SPEER • Division of Haematology, University Children’s Hospital, Zurich,
Switzerland
LINDA J. STANG • Department of Laboratory Medicine and Pathology,
University of Alberta Hospital, Edmonton, AB, Canada
ALISON STREET • Department of Haematology, The Alfred Hospital, Melbourne,
Australia
ROBYN SUMMERHAYES • Haematology Research Laboratory, Murdoch Children’s
Research Institute, Melbourne, Australia
BERTRAM TAMBYRAYAH • Hemostasis and Thrombosis Unit, University Hospital
Schleswig-Holstein, Kiel, Germany
HUYEN A.M. TRAN • Department of Haematology, Monash Medical Centre, Clayton,
VIC, Australia
 Part I

The Haemostatic System

 Chapter 1

The Coagulation System in Humans

Anthony K.C. Chan and Nethnapha Paredes

Abstract
Complex, interrelated systems exist to maintain the fluidity of the blood in the vascular system while allowing
for the rapid formation of a solid blood clot to prevent hemorrhaging subsequent to blood vessel injury.
These interrelated systems are collectively referred to as haemostasis. The components involved in the
haemostatic mechanism consist of vessel walls, platelets, coagulation factors, inhibitors, and the fibrinolytic
system. In the broadest sense, a series of cascades involving coagulation proteins and enzymes, as well as
cell surfaces (platelets and endothelial cells), work together to generate thrombin, the key enzyme in
coagulation, subsequently leading to the formation of a fibrin clot. However, there also exist direct and
indirect inhibitors of thrombin to ensure that clot formation does not go uncontrolled. Once the fibrin
clot is formed, the fibrinolytic system ensures that the clot is lysed so that it does not become a pathological
complication. Taken together, the systems exist to balance each other and maintain order. The balance of
coagulation and fibrinolysis keeps the haemostatic system functioning efficiently.

Key words Haemostasis, Coagulation, Fibrinolysis, Thrombin generation, Coagulant inhibitors

1 Introduction

The study into the individual components of haemostasis has

revealed that the haemostatic system in infants and children are
profoundly different from adults. The pioneering work of Andrew
et al. in the 1980s established that the haemostatic system in adults
and children are compositionally different (1–4). It is a widely
accepted view that the haemostatic system in the young is an evolv-
ing, dynamic system with the concentration of coagulation pro-
teins varying significantly with age. The young are not “little
adults” in terms of their haemostatic composition and these publi-
cations set the clinical reference ranges for fetuses, premature and
full-term infants, and children (ages 1–16 years). The development
of microassays (5), requiring a smaller volume of blood for testing,
allowed researchers to delineate age-dependent reference ranges
for coagulation parameters for healthy children from preterm
infants to adolescents (1–4).

Paul Monagle (ed.), Haemostasis: Methods and Protocols, Methods in Molecular Biology, vol. 992,
DOI 10.1007/978-1-62703-339-8_1, © Springer Science+Business Media New York 2013

3
4 Anthony K.C. Chan and Nethnapha Paredes

The coagulation system of children provides an innate protection

from thrombosis without an increased risk of bleeding (6). Children
with inherited prothrombotic states, such as factor V Leiden, pro-
thrombin gene mutation, and deficiency of natural inhibitors of the
coagulation system, do not usually develop thrombosis until early
adulthood (6, 7). Also, children undergoing surgery or prolonged
immobilization have a significantly lower incidence of thrombotic
disease when compared to the adult population facing similar throm-
botic challenges (6, 7). However, when children are diagnosed with
thromboembolic disease, it is almost always associated with a higher
rate of morbidity and mortality (8). When an infant has congenital or
acquired haemostatic defects, they are more vulnerable to hemor-
rhagic disorders than older patients or adults (9). However, in the
absence of any disorders, children seem to be protected from throm-
bosis but the mechanism by which this protection is exerted is not
fully understood. The differences in coagulation parameters may be
explained by decreased synthesis, accelerated clearance, and con-
sumption at birth (9).
The haemostatic system of the young is considered physiologic
because it provides protection from hemorrhagic and thrombotic
complications in healthy children (10). The neonatal coagulation
system gradually matures to the adult form and is complete by the
late teenage years (4). Understanding the ontogeny of haemostasis
will provide new insights into the pathophysiology of hemorrhagic
and thrombotic complications for all ages, leading to better
prevention, diagnosis, and treatment of haemostatic diseases. The
following is a general overview of haemostasis with some emphasis
on the developmental aspects of each component of coagulation
and fibrinolysis.

2 Coagulant Proteins

When there is an assault, the coagulation system is activated to

stem the flow of blood. Damage to vessel walls initiates processes
whereby platelets, plasma proteins, and damaged surfaces contrib-
ute to the formation and regulation of haemostatic plugs.
Thrombosis is a complicated process where fibrin clots appear as a
result of reactions within the coagulation cascade, in which forma-
tion of thrombin is the key point in the coagulant process.
The assembly of factor (F) IXa and FVIIIa on phospholipids
surfaces or tissue factor (TF)/FVIIa, in the presence of calcium,
results in the generation of FXa from surface-bound FX (11, 12).
FXa, in turn, converts prothrombin to thrombin in the presence of
FVa, calcium, and a phospholipid surface (the prothrombinase
complex). Physiological activation of coagulation occurs mainly
due to TF/FVIIa activity (13, 14). Once the initial amounts of
thrombin are generated, thrombin causes feedback activation of its
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