Review Article 31

Pathophysiology of Trauma-Induced
Coagulopathy
Herbert Schöchl1 Felix C.F. Schmitt2 Marc Maegele3,4

1 Ludwig Boltzmann Institute for Experimental and Clinical Address for correspondence Herbert Schöchl, MD, Ludwig-
Traumatology Vienna, Paracelsus Medical University, Salzburg, Boltzmann-Institute for Traumatology, the Research Center in
Austria Cooperation with AUVA, Donaueschingenstr. 2, 1020 Vienna, Austria
2 Department of Anaesthesiology, Heidelberg University Hospital, (e-mail: [email protected]).
Heidelberg, Germany
3 Department of Trauma and Orthopaedic Surgery, Cologne-Merheim
Medical Center, University of Witten/Herdecke, Cologne-Merheim
Campus, Cologne, Germany

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4 Institute for Research in Operative Medicine, University of
Witten/Herdecke, Cologne-Merheim Campus, Cologne, Germany

Hamostaseologie 2024;44:31–39.

Abstract Trauma-induced coagulopathy (TIC) is a complex hemostatic disturbance that can

develop early after a major injury. There is no universally accepted definition of TIC.
However, TIC primarily refers to the inability to achieve sufficient hemostasis in
severely injured trauma patients, resulting in diffuse microvascular and life-threaten-
ing bleeding. Endogenous TIC is driven by the combination of hypovolemic shock and
substantial tissue injury, resulting in endothelial damage, glycocalyx shedding,
upregulated fibrinolysis, fibrinogen depletion, altered thrombin generation, and
platelet dysfunction. Exogenous factors such as hypothermia, acidosis, hypokalemia,
and dilution due to crystalloid and colloid fluid administration can further exacerbate
Keywords TIC. Established TIC upon emergency room admission is a prognostic indicator and is
► trauma-induced strongly associated with poor outcomes. It has been shown that patients with TIC are
coagulopathy prone to higher bleeding tendencies, increased requirements for allogeneic blood
► endotheliopathy transfusion, higher complication rates such as multi-organ failure, and an almost
► hyperfibrinolysis fourfold increase in mortality. Thus, early recognition and individualized treatment of
► altered thrombin TIC is a cornerstone of initial trauma care. However, patients who survive the initial
generation insult switch from hypocoagulability to hypercoagulability, also termed “late TIC,”
► platelet dysfunction with a high risk of developing thromboembolic complications.

received © 2024. Thieme. All rights reserved. DOI https://doi.org/

October 22, 2023 Georg Thieme Verlag KG, 10.1055/a-2215-8936.
accepted after revision Rüdigerstraße 14, ISSN 0720-9355.
November 22, 2023 70469 Stuttgart, Germany
32 Pathophysiology of Trauma-Induced Coagulopathy Schöchl et al.

Zusammenfassung Die trauma-induzierte Koagulopathie (TIC) ist eine komplexe hämostatische Störung,
die sich früh nach einer schweren Verletzung entwickeln kann. Bisher gibt es keine
allgemein anerkannte Definition von TIC. TIC bezeichnet in erster Linie die Unfähigkeit,
schwer verletzter Traumapatienten eine suffiziente Blutstillung zu erreichen, was zu
diffusen mikrovaskulären und somit lebensbedrohlichen Blutungen führen kann. Die
TIC ist eine „endogene Gerinnungsstörung“ die durch die Kombination aus hypovolämi-
schem Schock und erheblicher Gewebeschädigung verursacht wird. Dadurch kommt es
zu substanziellen Endothelschäden, Glykokalyxablösungen, einer hochregulierten Fib-
rinolyse, Fibrinogenmangel, veränderter Thrombinbildung und einer Plättchenfunk-
tionsstörung. „Exogene Faktoren“ wie Hypothermie, Azidose, Hypokaliämie und
Verdünnung aufgrund der Verabreichung von Kristalloiden und Kolloiden können
eine TIC weiter verschlimmern. Eine bestehende TIC bei Schockraum-Aufnahme ist

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ein prognostischer Indikator und eng mit einem schlechten Outcome assoziiert. Es hat
Schlüsselwörter sich gezeigt, dass Patienten mit TIC eine höhere Blutungsneigung aufweisen, einen
► traumainduzierte erhöhten Bedarf an allogenen Bluttransfusionen unterliegen, signifikant mehr Kom-
Koagulopathie plikationen wie etwa ein Multiorganversagen zeigen und eine fast vierfach höhere
► Endotheliopathie Mortalität aufweisen als gerinnungkompetente Traumapatienten. Daher ist die Früh-
► Hyperfibrinolyse erkennung und individuelle Behandlung einer bestehenden TIC essenziell in der initialen
► eingeschränkte Versorgung von schwerverletzten Patienten. Trauma Patienten, die das initiale Trauma
Thrombinbildung überleben, wechseln von einer Hypokoagulabilität in einen hyperkoagulablen Zustand,
► Plättchenfunktions- der auch als „späte TIC“ bezeichnet wird. Damit erhöht sich das Risiko für die
störung Entwicklung thromboembolischer Komplikationen.

Current Understanding of the and an almost fourfold increase in mortality compared with
Pathophysiology of Trauma-Induced trauma patients with hemostatic competence.5–7 When
Coagulopathy bleeding and shock-related hypoperfusion is controlled
and patients survive the initial first 24 hours, a transition
Hemorrhage is the second leading cause of death following from an early hypocoagulable to a later hypercoagulable and
trauma, exceeded only by traumatic brain injury.1 If severe prothrombotic state occurs.8 Thus, thromboprophylaxis
blood loss after trauma remains uncontrolled, it leads to should be initiated as soon as possible.9 The purpose of
pronounced hemorrhagic shock, which has been identified this review is to provide current evidence on the potential
as an important driver of trauma-induced coagulopathy drivers and mechanisms resulting in “early” TIC.
(TIC). Historically, coagulopathy after severe trauma was
assumed to be a result of hemodilution due to fluid replace- Definition, Incidence, and Diagnosis of TIC
ment therapy, consumption of coagulation factors at the side So far, no universally accepted definition of TIC has been
of injury, and additional confounders, such as hypothermia established. The term TIC describes an abnormal hemostatic
and acidosis.2 Intensive research over the past 15 years has response following a major injury, which results in an
found that TIC is an endogenous dysregulation of the hemo- inefficient clot formation process, diffuse microvascular
static system, primarily driven by tissue trauma, shock- bleeding, and an increased risk of exsanguination.
related hypoperfusion, endotheliopathy, altered thrombin The diagnosis of TIC still relies on standard coagulation
generation (TG), and platelet dysfunction, which can be tests, such as prothrombin time and international normal-
further complicated by exogenous factors, such as hypother- ized ratio (INR).10–12 However, the correlation between
mia, acidosis, hypocalcemia, and dilution.3 Early TIC is INR and TG is poor. Dunbar and Chandler77 demonstrated
characterized by a hypocoagulative state and the inability that TG parameters in severely injured patients with an
to form sufficient clots, resulting in uncompressible diffuse INR of greater than 1.5—by definition TIC—were upregu-
microvascular bleeding. Studies have revealed that TIC starts lated. Moreover, a single parameter, such as INR, cannot
early after trauma and can be detected in the most severely display the complexity of coagulation abnormalities
injured patients, already at the scene of the accident.4 The related to TIC.
presence of a TIC upon emergency room (ER) admission is More advanced technologies, such as viscoelastic test (VET)
associated with higher blood loss, increased allogeneic blood methods, have discovered more trauma patients with abnor-
product requirements, higher rates of multi-organ failure, mal test results compared with prothrombin time or activated

Hämostaseologie Vol. 44 No. 1/2024 © 2024. Thieme. All rights reserved.

 Pathophysiology of Trauma-Induced Coagulopathy Schöchl et al. 33

partial thromboplastin time.10–17 This partly explains the wide essential role in coagulation and inflammation, serving as a
variation of reported TIC incidences ranging from 25 to 43% of semipermeable barrier between the fluid phase and the
all severely injured patients.6,14 tissue.25 Endotheliopathy of trauma describes a state of
In contrast to VET methods, a general accepted “gold endothelial cell damage and glycocalyx shedding with the
standard” for point-of-care platelet function testing has not release of specific serum biomarkers such as soluble throm-
been established so far.18 Both the applied technologies and bomodulin, syndecan-1, heparan sulfate, chondroitin sulfate,
the composition of platelet agonists used to activate throm- hyaluronic acid, and many more.24,26–28 Endotheliopathy of
bocytes differ considerably between the different platelet trauma is primarily driven by inflammation and shock-
function analyzer.19 Moreover, platelet function analyzers related hypoperfusion with the release of high amounts of
were initially developed to assess the impact of platelet catecholamines (e.g., adrenalin) and vasoactive hormones
inhibitors, such as aspirin or adenosin diphosphate (ADP) such as vasopressin24 (►Fig. 1). In a rat model of hemorrhagic
antagonists, on thrombocytes rather than to detect potential traumatic shock, chemical sympathectomy suppressed the
bleeding related to trauma-induced platelet dysfunction.20 release of inflammatory cytokines, decreased profibrinolytic
Importantly, the laboratory definition of TIC differs from activation, and was associated with less endothelial damage
compared with sham animals.29 In another experimental

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clinically evident coagulopathy with diffuse microvascular
bleeding. Chang et al reanalyzed data from the PROHS study study, Hofmann et al demonstrated an independent associa-
and reported that clinically evident coagulopathy was rare tion between shock severity and the intensity of endotheli-
(4%) compared with laboratory-defined coagulation abnor- opathy and sympathoadrenal activation.27 This aligns with
malities (39%) but was associated with substantially higher the findings in trauma patients, which also showed a strong
mortality (59 vs. 22%).21 association between sympathoadrenal activation and the
release of markers of endothelial cell and glycocalyx dam-
age.30 Both adrenalin concentration and endotheliopathy
Pathophysiology of Trauma-Induced
were identified as independent predictors of poor outcomes
Coagulopathy
in trauma patients.31
Clinical outcomes following traumatic injury depend on the Importantly, a breakdown of the glycocalyx results in
severity of blood loss, the degree of shock on admission, the capillary leakage and a significant loss of intravascular
extent of tissue injury, injury patterns, and the elapsed time volume, which additionally worsens hypovolemia in already
from injury to clinical control of the bleeding source.11,22,23 shocked patients, further intensifying tissue hypoperfusion
Initially, after tissue trauma, TG is upregulated, platelets are and shock severity.8
activated, and clot formation is enhanced to establish rapid Moreover, the release of heparinlike substances, such as
bleeding control. Moreover, the release of antifibrinolytic heparan sulfate or chondroitin sulfate, as a consequence of
molecules from platelet granules protects the established glycocalyx shedding was proposed as a potential additional
clot from premature lysis. Nevertheless, if blood loss remains driver of TIC due to an endogenous autoheparinization
uncontrolled, it results in hypovolemic shock, with devastat- process.32 Whether and to what extent autoheparinization
ing consequences. plays a role as an additional anticoagulant mechanism that
increases bleeding tendency is currently under debate. A
recent study investigating potential autoheparinization with
Shock as a Driver of Trauma-Induced
different VET assays in severely injured trauma patients did
Coagulopathy
not indicate that the release of heparan sulfate plays a
An isolated massive tissue injury without shock induces a significant role in the pathogenesis of TIC.33
prothrombotic phenotype of TIC associated with an in- Taken together, endotheliopathy of trauma is driven by
creased risk of thromboembolic complications.3 In contrast, shock-related release of adrenalin and vasopressin into the
the bleeding type of TIC requires both shock-related hypo- bloodstream, which promotes hypocoagulability, hyperfibri-
perfusion with a corresponding low-flow state and tissue nolysis (HF), increased bleeding risk, transfusion require-
trauma.8 Frith et al demonstrated that the severity of TIC ments, and mortality.
strongly correlated with the combined degree of both injury
and shock.11 A prolongation of the prothrombin time ratio Hyperfibrinolysis
and activated partial thromboplastin time (aPTT) was only HF has been identified as a predominant driver of TIC, which is
detected in shocked patients, defined as an admission base strongly associated with poor outcomes in trauma patients.34–37
deficit of greater than 6 mmol/L. In contrast, when base Two mechanisms have been proposed as potential acti-
deficit remained within normal limits, prothrombin time vators of profibrinolytic pathways after a major injury. Brohi
and aPTT also remained within the reference ranges.11 et al suggested that hypovolemic shock stimulates the en-
dothelial synthesis of thrombomodulin, which binds throm-
Endotheliopathy of Trauma bin. This complex, in turn, activates protein C. Activated
The vascular endothelium and its anticoagulant intraluminal protein C, the main anticoagulant protein of the body,
layer, the glycocalyx, are a huge, often underestimated organ, promotes HF by inhibiting plasminogen activator inhibitor-
with a large surface area of approximately 5,000 m2 and a 1 (PAI-1), which is the most important antagonist of the
weight of approximately 1 kg.24 The endothelium plays an profibrinolytic enzyme tissue plasminogen activator (tPA).38

Hämostaseologie Vol. 44 No. 1/2024 © 2024. Thieme. All rights reserved.

34 Pathophysiology of Trauma-Induced Coagulopathy Schöchl et al.

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Fig. 1 Schematic overview of potential drivers of trauma-induced coagulopathy. t-PA, tissue plasminogen activator; PAI-1, plasminogen
activator inhibitor 1. Activators; inhibitors.

Another hypothesis suggests that hypoxemia, in conjunc- However, not only the percentage of decreased clot
tion with high concentrations of adrenalin, vasopressin, and firmness but also the speed of clot dissolution is linked to
thrombin, powerfully activates endothelial cells. In turn, poor outcomes. Fulminant lysis, defined as a complete
significant amounts of tPA are released from the Weibel– breakdown of the clot within 30 minutes (ROTEM) or the
Palade vesicles into the bloodstream.39 This hypothesis is so-called diamond of death shape of the clot (TEG), is
supported by the finding that HF has also been demonstrated associated with an almost 100% mortality.37,45,46 Thus,
in other nontraumatic low-flow states, such as life-threaten- the pattern of clot lysis seems to be crucial for clinical
ing anaphylactic shock or out-of-hospital cardiac arrest.40,41 outcomes (►Fig. 2). It is essential to note that the absence of
Independent of the suggested mechanism, tPA cleaves lysis signs in VETs does not rule out profibrinolytic activa-
plasminogen to plasmin, which dissolves fibrin and—if avail- tion. Raza et al reported in a cohort of trauma patients that,
able in high amounts—fibrinogen. Thus, upregulated plasmin despite normal maximum lysis (ML) in ROTEM, high plas-
generation promotes premature clot dissolution and min–antiplasmin complexes (>1,500 μg/L) were detected,
hypofibrinogenemia. suggestive of fibrinolytic activation.47 Moreover, currently
With the implementation of VET methods in modern available VET assays are designed to detect systemic lysis
trauma care, HF has been identified as an important contrib- only. Thus, local lysis might take place but remain unnoticed
utor to TIC.35,36,42–44 However, there is no uniform definition by VET methods.
of HF based on VET results. For the ROTEM/ClotPro devices, From an evolutionary point of view, HF counteracts shock-
HF is defined as a breakdown of greater than 15% of the related microvascular stasis, microthrombosis, tissue hypo-
maximum clot firmness. For TEG, a reduction of greater than perfusion, and hypoxemia to maintain blood flow, even at the
3% 30 minutes (LY30) after reaching the maximum ampli- cost of an increased bleeding rate due to the dissolution of
tude of the clot is by definition HF. already established clots48 (►Fig. 3).

Fig. 2 Different lysis patterns measured by rotational viscoelastometry. (a) Fulminant lysis or so-called diamond of death shape. (b)
Intermediate type of clot lysis. (c) Late lysis. (d) Physiologic lysis. (e) Fibrinolytic shutdown.

Hämostaseologie Vol. 44 No. 1/2024 © 2024. Thieme. All rights reserved.

 Pathophysiology of Trauma-Induced Coagulopathy Schöchl et al. 35

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Fig. 3 Hyperfibrinolysis detected by EXTEM (ROTEM) upon (a) emergency room admission. (b) Twenty minutes after admission, no clot
formation in the ROTEM analysis could be detected any more. (c) Plasma (200 µL) collected upon admission and (d) after 20 minutes was spiked
on fibrin plates. Substantial increase in the fibrinolytic area after 20 minutes corresponds to increased lysis observed in EXTEM. 42

Fibrinolytic Shutdown fibrinogen concentrations and higher levels of fibrin degra-

Lysis and HF are strongly inhibited by PAI-1, which starts its dation products than in the patients with physiologic lysis.
upregulation approximately 2 hours after the initial trauma The authors suggested that fibrinolytic shutdown probably
and may result in complete inhibition of clot lysis, a condi- reflects a moderate form of coagulopathy and fibrinolysis
tion known as “fibrinolytic shutdown.”49,50 Numerous stud- rather than hypercoagulopathy.53
ies demonstrated that mortality in patients with fibrinolytic Currently, it remains to be elucidated which is the optimal
shutdown, defined as LY30 < 0.8% in TEG or as ML < 5% in way to identify fibrinolytic shutdown in major trauma
ROTEM, was higher than in patients with physiologic patients, as the measurement of the plasmin–antiplasmin
lysis.51–56 complexes is not feasible in routine clinical practice.58
However, whether VET methods accurately define fibri- In summary, the endothelium reacts uniformly to hypoxic
nolysis phenotypes is still under discussion.47,53,56,57 To stress and sympathoadrenal hyperactivation, with an early
diagnose lysis and HF, D-dimers and plasmin–antiplasmin and robust release of tPA and cleavage of plasminogen to
complexes are potentially more sensitive parameters than plasmin. PAI-1 starts to increase 2 hours after endothelial cell
VETs. Gall et al identified a cohort of trauma patients with activation, resulting in an endogenous inhibition of lysis.59,60
high D-dimer levels and increased blood product consump- This delayed PAI-1 expression promotes a shift toward a
tion and mortality despite low ML in ROTEM.56 Cardenas et al hypofibrinolytic state and may lead to microvascular throm-
analyzed blood samples from trauma patients with TEG and bosis and multi-organ failure.
measured the plasmin–antiplasmin complexes and
D-dimers. A total of 89% of the shutdown patients had Fibrinogen Deficiency
moderate to high fibrinolytic activation by the plasmin– Fibrinogen has a molecular weight of 350 kDa and is synthe-
antiplasmin complexes. Thus, low TEG LY30 does not reflect sized solely in the liver.61 The circulating levels range
hypercoagulability, but a TIC with moderate fibrinolysis and between 2 and 4 g/L in a healthy adult but can be upregulated
fibrinogen consumption associated with poor outcomes.57 20-fold, mediated by infection, inflammation, and IL-6 re-
Similar findings using ROTEM have been reported by David lease.62 Thrombin cleaves fibrinogen to fibrin fibers, cross-
et al, who observed in the ROTEM shutdown group lower linked by activated factor XIII, which increases mechanical

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36 Pathophysiology of Trauma-Induced Coagulopathy Schöchl et al.

strength and resistance to premature fibrinolytic degrada- Hypercoagulability was also reported by Schreiber et al in
tion.63 Moreover, fibrinogen binds with high affinity to 62% of the investigated trauma patients in the first 24 hours
glycoprotein IIb/IIIa receptors expressed on the surface of after injury, with a female predilection.84 Hypercoagulability
activated platelets, thereby facilitating further platelet ag- might be related to tissue factor exposure and the additional
gregation.64 Thus, fibrinogen plays an essential role in both release of procoagulant microparticles and damage-associ-
primary and secondary hemostasis.65 ated molecular patterns.85 Thus, it is highly questionable
In a severely injured bleeding patient, fibrinogen is the whether an initial augmentation of TG should be considered
first coagulation factor to reach critically low levels.4,66 a primary goal of early hemostatic management in major
Moreover, hypofibrinogenemia upon ER admission is asso- traumas.86
ciated with higher bleeding rates, increased allogenic blood In summary, major tissue trauma creates an initial
transfusion requirements, and increased mortality.67–69 A procoagulant environment driven by tissue factor exposure
critical fibrinogen level associated with a tendency toward and the release of procoagulants, resulting in a substantial
increased bleeding is assumed to be less than 1.5 g/L.67,70 upregulation of TG. At a later stage, TG can be altered by
Consequently, current guidelines recommend early fibrino- shock-related activation of the protein C pathway, dilution

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gen substitution, particularly when levels decline below and consumption of the coagulation factors, hypothermia,
1.5 g/L.71 and acidosis.
Hypofibrinogenemia in trauma patients is driven by blood
loss, hemodilution, hyperfibrinogenolysis, and consumption Platelet Dysfunction
due to clot formation at the site of injury.65 Moreover, experi- Platelets play a vital role in initial clot formation. Activated
mental studies demonstrated that hypothermia, which is platelets adhere to the subendothelial collagen of damaged
common in severely injured patients, impairs fibrinogen syn- tissues and provide the surface for the assembly of clotting
thesis, and acidosis accelerates fibrinogen breakdown.72,73 factors to further amplify TG.87 Moreover, platelets are
Schlimp et al observed that fibrinogen levels upon ER admis- involved in inflammation and wound healing by recruiting
sion were strongly associated with shock severity in trauma immune cells from the circulation in a P-selectin-dependent
patients. If base deficit exceeded 6 mmol/L, fibrinogen plasma mechanism.88
concentrations decreased to less than 200 mg/dL in 81% of the There is a growing body of evidence that severe trauma
patients and less than 150 mg/dL in 63% of the patients.74 not only affects plasmatic coagulation factors but also com-
Interestingly, the acute-phase response of fibrinogen is not promises platelet function. Platelet dysfunction occurs early
downregulated by early exogenous fibrinogen substitution after initial tissue injury despite a normal platelet count.15
during initial trauma care.75 Numerous studies have demonstrated that even mildly
Taken together, fibrinogen is the most vital and vulnera- impaired platelet aggregation in response to different plate-
ble coagulation factor, and it reaches critically low levels let agonists, such as thrombin and adenosine diphosphate
earlier than other coagulation proteins. Low fibrinogen upon receptor stimulation, is associated with poor out-
admission is strongly associated with poor outcomes. comes.15,16,89–92 In a retrospective study, Solomon et al
analyzed platelet function in major trauma patients after
Altered Thrombin Generation ER admission. Decreased platelet aggregation assessed by
Thrombin cleaves fibrinogen to fibrin and activates factor XIII Multiplate was associated with increased mortality.90
(FXIII), platelets, endothelial cells, and leucocytes. When Kutcher et al also measured platelet function by Multiplate
bound to thrombomodulin, thrombin activates the protein aggregometry in severely injured patients on admission and
C pathway and becomes an anticoagulant factor.38 Immedi- during their hospital stay. Despite a normal platelet count,
ately after initial tissue trauma, TG is strongly upregulated to platelet dysfunction was observed in 45% of patients on
create sufficient clots for quick termination of blood loss.76,77 admission and in 91% during their hospital stay.15
TG can be altered by several trauma-related mechanisms, The exact mechanism that promotes platelet dysfunction
such as loss and consumption of coagulation factors, dilution, following trauma remains to be elucidated. Verni et al spiked
hypothermia, and acidosis (►Fig. 1).78,79 Studies in severely healthy platelets with plasma collected from trauma patients
injured patients demonstrated that factor V, factor VII, and and detected a significantly diminished response to multiple
factor IX are predisposed to low levels.66,80,81 Nevertheless, platelet agonists. The authors suggested that soluble plasma
experimental and clinical studies have demonstrated that TG species may downregulate various platelet activation path-
remains unaffected.80,82 ways.91 Another hypothesis suggested that platelets are
Cardenas et al reported that trauma patients upon ER captured by leukocytes, which was linked to impaired plate-
admission had significantly higher TG parameters than let function detected by Multiplate.17 Vulliamy et al observed
uninjured subjects.76 Only 17% of the patients demonstrated a ballooning of platelets induced by histone H4, a damage-
a peak TG of less than 250 nM. However, these patients associated molecular pattern, which is released in massive
required more allogeneic blood products, had a fourfold quantities after severe injury.93
increased risk of massive transfusion, and a threefold Taken together, platelet dysfunction occurs early after
increased risk of mortality.76 Coleman et al also observed severe trauma independently of platelet count. This initial
high-volume blood transfusion in trauma patients with inhibition of platelet function has been linked to adverse
compromised TG.83 outcomes. Interestingly, recent studies in major trauma

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 Pathophysiology of Trauma-Induced Coagulopathy Schöchl et al. 37

patients could not demonstrate a clear clinical benefit of 5 MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early
early estimation of platelet dysfunction by Multiplate or TEG coagulopathy predicts mortality in trauma. J Trauma 2003;55
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German Trauma Society (DGU) Early coagulopathy in multiple
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disorder that starts early after the initial injury. Many patients. Injury 2007;38(03):298–304
8 Moore EE, Moore HB, Kornblith LZ, et al. Trauma-induced coagul-
different potential drivers, of which shock-related hypoper-
opathy. Nat Rev Dis Primers 2021;7(01):30
fusion seems to be the most critical, have been identified.
9 Rappold JF, Sheppard FR, Carmichael Ii SP, et al. Venous thrombo-
Advanced understanding of the pathophysiology of TIC, in embolism prophylaxis in the trauma intensive care unit: an
alliance with innovative coagulation monitors, which allow American Association for the Surgery of Trauma Critical Care
individualized guidance of hemostatic therapy, has the Committee Clinical Consensus Document. Trauma Surg Acute
potential to improve a patient’s outcome. Care Open 2021;6(01):e000643
10 Baksaas-Aasen K, Gall LS, Stensballe J, et al. Viscoelastic haemo-

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Funding static assay augmented protocols for major trauma haemorrhage
(ITACTIC): a randomized, controlled trial. Intensive Care Med
None.
2021;47(01):49–59
11 Frith D, Goslings JC, Gaarder C, et al. Definition and drivers of acute
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HS: Consulting fees: Octapharm, Alexion; Payment or tions. J Thromb Haemost 2010;8(09):1919–1925
honoraria for lectures, presentations, speakers bureaus, 12 Bouzat P, Charbit J, Abback PS, et al; PROCOAG Study Group.
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bin complex concentrate in patients with trauma at risk of
Bristol Mayers Squipp, Haemonetics.
massive transfusion: the PROCOAG randomized clinical trial.
FCFS: Consulting fees: CSL Behring, Roche Diabetes; Pay- JAMA 2023;329(16):1367–1375
ment or honoraria for lectures, presentations, speakers 13 Davenport R, Manson J, De’Ath H, et al. Functional definition and
bureaus, manuscript writing or educational events: CSL characterization of acute traumatic coagulopathy. Crit Care Med
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MM: Grants or contracts from any entity: Astra Zeneca, 14 Khan S, Brohi K, Chana M, et al; International Trauma Research
Network (INTRN) Hemostatic resuscitation is neither hemostatic
Baxter, Bayer, Biotest, CSL Behring, LFB Biomedicaments,
nor resuscitative in trauma hemorrhage. J Trauma Acute Care Surg
IL-Werfen, TEM International, Octapharma, Portola; Con- 2014;76(03):561–567, discussion 567–568
sulting fees: Astra Zeneca, Baxter, Bayer, Biotest, CSL 15 Kutcher ME, Redick BJ, McCreery RC, et al. Characterization of
Behring, LFB Biomedicaments, IL-Werfen, TEM Interna- platelet dysfunction after trauma. J Trauma Acute Care Surg 2012;
tional, Octapharma, Portola; Payment or honoraria for 73(01):13–19
16 Vulliamy P, Montague SJ, Gillespie S, et al. Loss of GPVI and GPIbα
lectures, presentations, speakers bureaus, manuscript
contributes to trauma-induced platelet dysfunction in severely
writing or educational events: Astra Zeneca, Baxter,
injured patients. Blood Adv 2020;4(12):2623–2630
Bayer, Biotest, CSL Behring, LFB Biomedicaments, IL-Wer- 17 Zipperle J, Altenburger K, Ponschab M, et al. Potential role of
fen, TEM International, Octapharma, Portola; Support for platelet-leukocyte aggregation in trauma-induced coagulopathy:
attending meetings and/or travel: Astra Zeneca, CSL Behr- ex vivo findings. J Trauma Acute Care Surg 2017;82(05):921–926
ing, LFB Biomedicaments, IL-Werfen, TEM International, 18 Zipperle J, Schmitt FCF, Schöchl H. Point-of-care, goal-directed
management of bleeding in trauma patients. Curr Opin Crit Care
Octapharma; Participation on a Data Safety Monitoring
2023;29(06):702–712
Board or Advisory Board: Astra Zeneca, Baxter, Bayer, 19 Connelly CR, Yonge JD, McCully SP, et al. Assessment of three
Biotest, CSL Behring, LFB Biomedicaments, IL-Werfen, point-of-care platelet function assays in adult trauma patients.
TEM International, Octapharma, Portola. J Surg Res 2017;212:260–269
20 Schriner JB, George MJ, Cardenas JC, et al. Platelet function in
trauma: is current technology in function testing missing the
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