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Anaesthesia 2015, 70 (Suppl. 1), 96101 doi:10.1111/anae.


Review Article
The pathogenesis of traumatic coagulopathy
A. Cap1 and B. J. Hunt2

1 Lieutenant Colonel, Medical Corps, US Army and Associate Professor of Medicine, Uniformed Services University,
Blood Research Program, US Army Institute of Surgical Research, Sam Houston, Texas, USA
2 Professor of Thrombosis and Haemostasis, Departments of Haematology, Pathology and Lupus, Guys & St Thomas
NHS Foundation Trust, London, UK

Over the last 10 years, the management of major haemorrhage in trauma patients has changed radically. This is
mainly due to the recognition that many patients who are bleeding when they come in to the emergency department
have an established coagulopathy before the haemodilution effects of uid resuscitation. This has led to the use of
new terminology: acute traumatic coagulopathy, acute coagulopathy of trauma shock or trauma-induced coagulopa-
thy. The recognition of acute traumatic coagulopathy is important, because we now understand that its presence is a
prognostic indicator, as it is associated with poor clinical outcome. This has driven a change in clinical management,
so that the previous approach of maintaining an adequate circulating volume and oxygen carrying capacity before, as
a secondary event, dealing with coagulopathy, has changed to haemostatic resuscitation as early as possible. While
there is as yet no universally accepted assay or denition, many experts use prolongation of the prothrombin time to
indicate that there is, indeed, a coagulopathy. Hypoxia, acidosis and hypothermia and hormonal, immunological and
cytokine production, alongside consumption and blood loss, and the dilutional effects of resuscitation may occur to
varying extents depending on the type of tissue damaged, the type and extent of injury, predisposing to, or amplify-
ing, activation of coagulation, platelets, brinolysis. These are discussed in detail within the article.
Correspondence to: B. Hunt; Email: beverley.hunt@gstt.nhs.ukAccepted: 19 September 2014

Introduction matic coagulopathy [36]. This has led to the use of

Trauma remains a major cause of global morbidity new terminology: acute traumatic coagulopathy (ATC);
and mortality, accounting for over 10% of deaths, with acute coagulopathy of trauma shock or trauma-
the majority due directly or indirectly to bleeding [1, induced coagulopathy. In this review, we will use the
2]. Over the last 10 years, the management of major term ATC. The recognition of ATC is very important
haemorrhage in trauma patients has changed radically. because we now understand that its presence is a prog-
This is mainly due to the recognition that many nostic indicator, as it is associated with poor clinical
patients who are bleeding when they come to the outcome [7]. This has driven change in clinical
emergency department have an established coagulopa- management, so that the previous approach of main-
thy before the dilutional effects of uid resuscitation. taining an adequate circulating volume and oxygen
Traumatic coagulopathy has been demonstrated in carrying capacity before, as a secondary event, dealing
patients who received little or no intravenous uid with coagulopathy, has changed to haemostatic resusci-
therapy, negating the long-held belief that iatrogenic tation as early as possible. However, the type of hae-
haemodilution is the main causative factor in trau- mostatic resuscitation varies, with the USA giving

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Cap and Hunt | Pathogenesis of traumatic coagulopathy Anaesthesia 2015, 70 (Suppl. 1), 96101

fresh frozen plasma, while there is a different approach (non-overt DIC) or 5 (overt DIC) or abnormalities
in Europe, led by Austria, where brinogen concen- in clotting amplitude and clot lysis in whole blood vi-
trates are used and supported by other factor products. sco-elastic tests [5]. While there is as yet no universally
The divergence in clinical practice reects our limited accepted assay or denition, many experts use prolon-
understanding of ATC and comparisons between gation of the PT to indicate that there is, indeed, a
approaches need to be addressed in clinical trials. coagulopathy. Ironically, the abnormal test results that
The range of bleeding injuries is wide, and one have heightened our awareness of ATC may have
has to question whether injuries from civilian, com- contributed to well-intentioned but physiologically
pared with military, trauma result in similar haemo- misguided therapeutic strategies.
static changes. Military casualties commonly suffer
blast injury (primary blast wave, thermal and chemical Phases of ATC
burns, penetrating fragment wounds, and blunt There are different temporal phases in the evolution
trauma) from high-energy munitions as well as pene- of ATC. The rst phase is an immediate activation of
trating trauma from high velocity gunshot wounds. multiple haemostatic pathways, including brinolysis,
The different mechanisms of injury and increased in association with tissue injury. The second phase is
energy transfer that occur after military trauma may due to resuscitation-related factors, for example the
or may not result in different pathophysiological use of colloids and red cells will dilute haemostatic
responses when compared with a civilian after a road factors; and post-resuscitation, there is an acute phase
trafc accident or stab wound. Understanding the response leading to a prothrombotic state, predispos-
admission coagulopathy prole of a military or civilian ing to later venous thromboembolism. In some
patient will help to inform future transfusion resuscita- patients, especially if resuscitated late or inadequately
tion protocols and may help to develop potential med- so that there is continuing tissue hypoxia, DIC may
ical therapies that will be of benet. This article ensue.
summarises the authors current understanding of the
pathogenesis of ATC. Immediate effects of tissue injury
The following may occur to varying extent depending
Clinical definition on the type of tissue damaged, the type and extent of
The concept of ATC stems from the recognition that a injury, predisposing to, or amplifying, ATC:
prolonged prothrombin time (aPTT) and/or activated
(1) Consumption and loss. Coagulation factors and
partial thromboplastin time (PT) at hospital admission,
platelets are consumed during the formation of
before resuscitation, is associated with a three to four-
extravascular clots and thrombus (thrombus is a
fold higher mortality rate and is independently associ-
clot formed within a vessel wall), as well as exter-
ated with increased transfusion requirements, organ
nal loss from the intravascular compartment dur-
injury, sepsis and critical care length of stay [4]. In
ing bleeding. A reduction in circulating red cells
two large observational studies, one quarter of trauma
has a major effect on primary haemostasis through
patients had prolongation of PT and/or aPTT on
reduction in axial blood ow. Red cells usually
admission, which was independently associated with
ow through the centre of an artery or arteriole,
bleeding and death [7]. The development of ATC
and platelets and plasma are pushed to the vessel
occurs as a function of the extent of tissue damage
wall, so that when a vessel is severed the necessary
and duration of shock.
haemostatic factors are close by; this is disrupted
The tests used to describe ATC have varied
once the haematocrit falls below about 30% [8],
between studies, and have included standard plasma-
such that there is an inverse correlation between
based tests resulting in denitions based on abnormal:
the haematocrit and in vitro bleeding time [9].
aPTT; PT; thrombin time (TT); international norma-
(2) Dilution. The reversal of Starling forces and con-
lised ratio (INR); platelet count; brinogen level; dis-
sequent shifts of interstitial uid into the vascular
seminated intravascular coagulation (DIC) score of 14

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Anaesthesia 2015, 70 (Suppl. 1), 96101 Cap and Hunt | Pathogenesis of traumatic coagulopathy

compartment results in autodilution of haemo- (5) Immune activation. Tissue damage and shock are
static factors. This is aggravated by replacement associated with platelet release of soluble CD40-
of lost whole blood with crystalloid, colloid and ligand, a potent immune activator that itself can
red cell transfusion. Even so-called balanced cause further ECA and platelet activation, and is
transfusion strategies, such as 1:1:1, that attempt known to be necessary in order to stabilise thrombi
to deliver the functionality of whole blood with [29]. Immune stimulation, including complement
red cells, plasma and platelets in equal ratios, activation, is associated with release of damage-
deliver a dilute nal product due to the presence associated molecular patterns (DAMPs), such as
of anticoagulants and red cell additive solutions. mitochondrial DAMPs and histone-complexed
The nal 1:1:1 product has a haematocrit of 29%, DNA [30, 31]. Immune activation can aggravate
a platelet count of about 80 9 109.l 1 and coagu- tissue damage through mechanisms including pro-
lation factors diluted to 65% of normal. Ulti- teolytic degradation and oxidative stress, thus
mately, the resultant dilutional coagulopathy is amplifying haemostatic activation.
proportional to the volume of uid administered,
both in vitro and in vivo [10, 11]. Pathophysiology
(3) Hormonal and cytokine changes follow tissue Current available evidence suggests that ATC is due to
injury. The levels of cytokines and hormones such massive stimulation of thrombin generation, brinogen
as epinephrine and vasopressin rise, hormone and and platelet consumption, and brinolysis by damaged
thrombin production leads to endothelial cell acti- tissues. Tissue damage exposes tissue factor (TF),
vation (ECA). Tissue plasminogen activator (t-PA) which is present on all cells within the body that are
and WeibelPalade body contents are released not normally in contact with the blood, and also the
from the endothelium after stimulation by vaso- sub-endothelial matrix. Tissue factor drives localised
pressin. WeibelPalade bodies anneal with the thrombin and brin generation. Collagen within the
endothelial wall releasing von Willebrand factor sub-endothelial matrix binds to platelet glycoprotein
and exposing P-selectin present on their inner wall, VI and vWF to glycoprotein Ib, causing platelet activa-
onto the surface of the endothelial cell, enhancing tion. Activated platelets adhere to damaged tissues and
platelet recruitment. Cytokines, such as TNF and serve as catalysts for amplication of thrombin genera-
IL-1 as well as thrombin and continued hypoxia, tion. These processes are reected in the ndings of
cause ECA and lead to a slow change in endothelial observational clinical studies that show reduced clot-
cell phenotype from antithrombotic to prothrom- ting factor and physiological anticoagulant levels [21
botic which, in inadequately resuscitated patients, 23], high thrombin generating capacity [3, 4, 21, 24
leads to DIC. Endothelial cell activation down-reg- 26] and reduced platelet counts [27, 28] Overall, these
ulates thrombomodulin and brinolysis, (PAI-1 data indicate a consumptive coagulopathy. The most
levels increase) causing cleavage of glycosamino- depleted coagulation factors are brinogen and factor
glycans and sloughing of the glycocalyx from the V [22, 28], which are likely consumed in part by acti-
cell surface, limiting activation of antithrombin; vated Protein C or free plasmin [29, 30], although the
increases in platelet activating factor production relative importance of these proteases in reducing fac-
increase endothelial permeability and, in vitro, up- tor levels remains unknown.
regulates the expression of tissue factor [12, 13]. Thrombin is the key effector molecule in haemo-
(4) Hypoxia, acidosis and hypothermia. This triad stasis; its generation not only converts brinogen to
predisposes to bleeding by impairing the function brin but, like a cytokine, it also activates platelets,
of platelets and coagulation proteases while leucocytes and endothelium. Thrombin is also a major
increasing brinolysis [14]. Hypoxia exacerbates stimulator of endothelial t-PA secretion, an effect pre-
ECA, and coagulopathic changes are most pro- viously known as secondary brinolysis (as brinolytic
nounced once the pH is < 7.1 [15] and core tem- activation is secondary to coagulation activation).
perature is < 33 C [16]. Stimulation of t-PA release from the endothelium by

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Cap and Hunt | Pathogenesis of traumatic coagulopathy Anaesthesia 2015, 70 (Suppl. 1), 96101

other factors such as hypoxia, epinephrine and vaso- generation of brin degradation products such as D-
pressin, is known as primary brinolysis. High t-PA dimers [3, 4, 39, 4446] are characteristic of bleeding
levels have been reported in coagulopathic trauma trauma patients. Furthermore, free plasmin can break
patients [4, 26]. In addition, when bound to the endo- down coagulation factors, and the extent of this effect
thelial receptor, thrombomodulin, thrombin activates has not been fully evaluated in traumatic coagulopathy
Protein C. [47].
It has been proposed that activated protein C The pathophysiology of ATC evolves after the
(aPC) is a major effector of ATC through cleavage of immediate haemostatic effects triggered by tissue
factors Va and VIIIa. In addition, by binding PAI-1 injury. Endothelial cell activation, stimulated by
and de-repressing t-PA, it may activate brinolysis [3, thrombin and various cytokines, as well as hypoxia
5, 29]. This mechanism is plausible but problematic and hypoperfusion [48], generates a prothrombotic
due to the kinetics of the reactions. Platelets and environment. Hypoperfusion plays a critical role in the
plasma Factor Va are resistant to aPC cleavage at con- pathogenesis of ATC as demonstrated in numerous
centrations of aPC seen in ATC or even therapeutic clinical studies [3, 6, 4251], animal models [6, 50]
use of recombinant human aPC in sepsis [31]. As a and in vitro experiments [22, 51]. These data indicate
normal platelet count of 200 9 109 l 1 overcame aPC that as shock severity increases, the PT and INR rise
anticoagulant effects even at very high concentrations [4, 5, 7, 52] and coagulation factor levels fall [6, 48].
of aPC, and there was no detectable effect on brinoly- The most compelling of these studies, that included
sis with or without platelets [31], it is difcult to envis- 3646 patients, demonstrated that ATC (INR > 1.2)
age how aPC could drive the phenotype described as occurred only when signicant hypoperfusion (base
ATC. Furthermore, though factor V is depleted and decit > 6 mmol.l 1) was combined with severe injury
PC converted to aPC in ATC, it has been amply dem- (Injury severity score > 15) [6].
onstrated that thrombin generation potential is dra- As ATC evolves over time, the prothrombotic
matically elevated in trauma patients; this is surely effects of endothelial cell activation eventually predom-
inconsistent with the notion that aPC is inhibiting inate, particularly if hypoxia and acidosis are not alle-
thrombin generation by inactivating factor V [32]. viated. Many factors contribute, but release of
Also, it must be noted that PAI-1 is a potent inhibitor phosphatidylserine positive microvesicles from the
of aPC in the presence of vitronectin [33]. It is unli- endothelium exacerbates the prothrombotic environ-
kely that inactivation of aPC by vitronectin/PAI-1 ment [53]. A net production of PAI-1 over t-PA fur-
would lead to PAI-1 depletion and acceleration of ther leads to shutdown of brinolysis [4, 25, 45]. This
brinolysis, as PAI-1 circulates at about ten times may explain why antibrinolytic treatment at this stage
higher levels than aPC [34, 35]. It seems more likely may worsen outcome [40].
that the enormously increased release of t-PA due to Platelets form the scaffold of clots during primary
epinephrine, vasopressin and thrombin signalling haemostasis, and serve as the catalysts of coagulation in
drives the brinolytic phenotype of ATC. the current cell-based model of coagulation. Platelets are
The CRASH-2 trial underscored the central role of relatively unresponsive to collagen, ADP and arachi-
brinolysis in ATC by demonstrating a one-third donic acid after trauma [54, 55]. The pathophysiology
reduction in death due to haemorrhage in trauma underlying this dysfunction, which remains obscure,
patients given tranexamic acid (TXA), which inhibits probably explains improved outcomes associated with
activation of plasminogen to plasmin [36, 37]. Other platelet transfusion despite adequate platelet counts [56,
clinical studies have reported that brinolytic activa- 57]. Lower platelet counts on hospital admission predict
tion is correlated with transfusions [38] and mortality trauma mortality, even when within the normal range
[3842]. The plasminantiplasmin complex (PAP) is [58, 59]. Furthermore, outcomes may be determined by
perhaps the most sensitive indicator of brinolytic the quality of transfused platelets [60].
activation, and its levels are increased in approximately Cellular microvesicles also contribute to normal
60% of trauma patients [43]. Plasmin activation and haemostasis. Tissue factor initiates clot formation

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Anaesthesia 2015, 70 (Suppl. 1), 96101 Cap and Hunt | Pathogenesis of traumatic coagulopathy

when P-selectin glycoprotein ligand 1 (PSGL-1)/TF- tor-based coagulopathies, and they are not predictors
bearing microvesicles from monocytes interact with P- of bleeding in these circumstances [72]. Moreover,
selectin on platelets attached to injured tissue [61]. they do not take into consideration the contribution of
This procoagulant microvesicle production increases in platelets to haemostasis, the role of brinolysis, throm-
trauma [62] and accelerates prothrombotic change bin generation, or the interactions between coagulation
[63]. enzymes and cellular phospholipid surfaces. Further-
In some ways, the initial changes of ATC are simi- more, these are not point-of-care assays and turn-
lar to DIC [40, 64]. However, in most trauma patients, around times often negate the value of the results [5].
there is no evidence of inappropriate disseminated clot Therefore, plasma-based coagulation assays are rarely
formation on histological examination [65], so early helpful in the immediate management of ATC, but
ATC is not DIC. they do have an important role in monitoring ongoing
bleeding, to guide the use of appropriate blood prod-
The importance of rapidly identifying ucts.
Severely injured patients are more likely to suffer from Thromboelastography and thromboelastometry
haemorrhagic shock, require massive transfusions, and Increasingly, TEG (Hemonetics Corporation, Brain-
are at high risk of death due to bleeding. Acute trau- tree, MA, USA) and ROTEM (TEM International
matic coagulopathy is the key pathophysiological GmbH, Munich, Germany) are being used to guide
derangement, driven by tissue damage, which results trauma resuscitation [38, 41]. Minimally injured
in TF exposure, shock and hypoxia, and must be miti- patients tend to have normal proles, whereas moder-
gated to successfully resuscitate the patient [66, 67]. ately or severely injured patients typically exhibit TEG
changes [38, 46]. Thromboelastograpy and ROTEM
Predicting coagulopathy can play a role in the diagnosis of severe brinolysis,
Scoring systems have been developed for adult and but are insensitive to more limited brinolytic activity
paediatric trauma populations that predict which [73]. Marked brinolysis detected by TEG or ROTEM
patients will develop severe haemorrhage and require is associated with a poor prognosis. Schochl et al. [41]
massive resuscitation. Algorithms based on these and others have dened hyperbrinolysis as a reduc-
scores shift clinical management from a reactive to a tion in maximal amplitude (MA) of 15% on ROTEM
proactive stance [6671]. Unfortunately, none of these testing. However, this denition conicts with the clas-
scoring systems identify all patients at risk of ATC sic understanding of hyperbrinolysis, which describes
and death due to bleeding. Therefore, it should be a kinetic reversal whereby brinolytic activity is greater
assumed that any patient considered at risk of exsan- than brin formation, and clot strength is compro-
guination is at risk of ATC and death [70]. mised [74]. Thrombolastographic hyperbrinolysis
should perhaps be used to describe increased lysis only
Current methods for ATC diagnosis and in relation to TEG visco-elastic measurements.
their pitfalls There is no commonly accepted visco-elastic de-
Standard coagulation tests nition of ATC, although the candidates include:
These include PT-based tests (PT, INR), aPTT and increases in clotting time and clot formation time; and
Clauss brinogen. The PT/INR is considered an ade- loss of clot amplitude (CA) and maximal clot ampli-
quate screen for multiple coagulation factor decien- tude [40, 50, 75]. One group used ROTEM to dene
cies, and was thus adopted as a marker of ATC [28]. an EXTEM CA5 (CA at 5 min) value of < 36 mm as
Every laboratory can provide PT, aPTT and brinogen diagnostic of ATC [5]. Another group suggests that
results, and they are useful in guiding transfusion and TEG or ROTEM A10 correlates well with platelet
predicting mortality [51]. count and brinogen level and predicts transfusion
Originally, these tests were designed to evaluate requirements. Advocates for visco-elastic monitoring
clotting factor deciencies, not acquired multiple fac- suggest that the capacity to distinguish specic haemo-

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Cap and Hunt | Pathogenesis of traumatic coagulopathy Anaesthesia 2015, 70 (Suppl. 1), 96101

static abnormalities provides a means of individualis- of ATC [90]. The evolution of divergent clinical prac-
ing coagulation and transfusion management [37, 41]. tices underscores the need for a better understanding
However, there are no ROTEM and TEG algorithms of the pathophysiology of ATC and for more clinical
validated by randomised trials. Another important lim- research looking at the full risks and benets of
itation is that, like other standard coagulation tests, improved haemostatic management. For example,
TEG and ROTEM are typically performed at 37 C, there are no studies looking at the effect of modern
and results underestimate coagulation disturbances in treatment on the rate of post-trauma venous thrombo-
hypothermic patients. embolism, which is a major cause of morbidity and
mortality. It is recognised that the use of prothrombin
The evolving importance of ATC in complex concentrate may induce later prothrombotic
trauma resuscitation changes [91], and potentially this may affect the rate
The recognition of ATC has driven dramatic change of posttrauma thromboembolism.
in trauma management. Until the military experience
in Iraq and Afghanistan was published over the last Conclusion
10 years, resuscitation was started with red cell con- Over the last decade, the incidence and implications of
centrates, and scant attention was paid to coagulopathy ATC have become clearer to the trauma community.
until much later. Retrospective data from the USA and Further clinical studies are required to increase our
UK military and leading civilian institutions described understanding of the pathophysiology of traumatic co-
improved outcomes in those treated with fresh whole agulopathy and inform the direction of studies to
blood [7678] or fresh frozen plasma (FFP), cryopre- improve haemostatic management and outcomes.
cipitate and platelets in combination with red cells and
tranexamic acid, with extremely limited use of colloid Acknowledgements
or crystalloid infusions [7682], a practice known as The opinions or assertions contained herein are the
haemostatic resuscitation [83]. It is possible that cur- private views of the authors and are not to be con-
rent transfusion strategies can be optimised to further strued as ofcial or as reecting the views of the US
improve survival after ATC [84]; the results of rando- Department of the Army or the US Department of
mised controlled trials will guide further developments Defence.
[85]. In North America, the challenge of managing
ATC has generated renewed interest in whole blood Competing interests
for trauma resuscitation [8689]. On the other hand, No external funding and no competing interests
in some European countries, brinogen and other fac- declared.
tor concentrates have replaced FFP in the management

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Anaesthesia 2015, 70 (Suppl. 1), e32e34 Cap and Hunt | Pathogenesis of traumatic coagulopathy

References tissue and endothelial damage, coagulopathy and mortality.

1. WHO. World Health Organisation. Global Health Indicators, Journal of Thrombosis and Haemostasis 2012; 10: 20716.
2011. 19. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial
Part2.pdf (accessed 17/09/2014). DAMPs cause inflammatory responses to injury. Nature 2010;
2. Eastridge BJ, Mabry RL, Seguin P, et al. Death on the battle- 464: 1047.
field (2001-2011): implications for the future of combat casu- 20. Johansson PI, Srensen AM, Perner A, et al. Blood levels of
alty care. Journal of Trauma and Acute Care Surgery 2012; histone-complexed DNA fragments are associated with coag-
73: S4317. ulopathy, inflammation and endothelial damage early after
3. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pit- trauma. Journal of Emergencies, Trauma and Shock 2013; 6:
tet J-F. Acute traumatic coagulopathy: initiated by hypoperfu- 1715.
sion: modulated through the protein C pathway? Annals of 21. Floccard B, Rugeri L, Faure A, et al. Early coagulopathy in
Surgery 2007; 245: 8128. trauma patients: an on-scene and hospital admission study.
4. Brohi K, Cohen MJ, Ganter MT, et al. Acute coagulopathy of Injury 2012; 43: 2632.
trauma: hypoperfusion induces systemic anticoagulation and 22. Jansen JO, Scarpelini S, Pinto R, Tien HC, Callum J, Rizoli SB.
hyperfibrinolysis. Journal of Trauma 2008; 64: 12117. Hypoperfusion in severely injured trauma patients is associ-
5. Davenport R, Manson J, DeAth H, et al. Functional definition ated with reduced coagulation factor activity. Journal of
and characterization of acute traumatic coagulopathy. Critical Trauma 2011; 71: S43540.
Care Medicine 2011; 39: 26528. 23. Shaz BH, Winkler AM, James AB, Hillyer CD, MacLeod JB. Path-
6. Frith D, Goslings JC, Gaarder C, et al. Definition and drivers of ophysiology of early trauma-induced coagulopathy: emerging
acute traumatic coagulopathy: clinical and experimental inves- evidence for hemodilution and coagulation factor depletion.
tigations. Journal of Thrombosis and Haemostasis 2010; 8: Journal of Trauma 2011; 70: 14017.
191925. 24. Dunbar NM, Chandler WL. Thrombin generation in trauma
7. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopa- patients. Transfusion 2009; 49: 265260.
thy. Journal of Trauma 2003; 54: 112730. 25. Chandler W. Procoagulant activity in trauma patients. Ameri-
8. Valeri CR, Khuri S, Ragno G. Nonsurgical bleeding diathesis in can Journal of Clinical Pathology 2010; 134: 906.
anemic thrombocytopenic patients: role of temperature, red 26. Hayakawa M, Sawamura A, Gando S, et al. Disseminated
blood cells, platelets, and plasm-clotting proteins. Transfusion intravascular coagulation at an early phase of trauma is asso-
2007; 47: S20648. ciated with consumption coagulopathy and excessive fibrino-
9. Eugster M, Reinhart WH. The influence of the haematocrit on lysis both by plasmin and neutrophil elastase. Surgery 2011;
primary haemostasis in vitro. Thrombosis and Haemostasis 149: 22130.
2005; 94: 12138. 27. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M.
10. Bolliger D, Szlam F, Molinaro RJ, Rahe-Meyer N, Levy JH, Early coagulopathy predicts mortality in trauma. Journal of
Tanaka KA. Finding the optimal concentration range for Trauma 2003; 55: 3944.
fibrinogen replacement after severe haemodilution: an in 28. Yuan S, Ferrell C, Chandler WL. Comparing the prothrombin
vitro model. British Journal of Anaesthesia 2009; 102: 7939. time INR versus the APTT to evaluate the coagulopathy of
11. Maegele M, Lefering R, Yucel N, et al. Early coagulopathy in acute trauma. Thrombosis Research 2007; 120: 2937.
multiple injury: an analysis from the German Trauma Registry 29. Cohen MJ, Call M, Nelson M, et al. Critical role of activated
on 8724 patients. Injury 2007; 38: 298304. Protein C in early coagulopathy and later organ failure, infec-
12. Hunt BJ, Jurd KM. Endothelial cell activation. British Medical tion and death in trauma patients. Annals of Surgery 2012;
Journal 1998; 316: 13289. 255: 37985.
13. Johansson PI, Sorensen AM, Perner A, et al. Disseminated 30. Omar MN, Mann KG. Inactivation of factor Va by plasmin.
intravascular coagulation or acute coagulopathy of trauma Journal of Biological Chemistry 1987; 262: 97595.
shock early after trauma? A prospective observational study. 31. Campbell JE, Meledeo MA, Cap AP. Comparative response of
Critical Care 2011; 15: R272. platelet fV and plasma fV to activated protein C and relevance
14. Dirkmann D1, Radu rlinger K, Peters J. Recom-
-Berlemann J, Go to a model of acute traumatic coagulopathy. PLoS ONE 2014;
binant tissue-type plasminogen activator-evoked hyperfibrin- 9: e99181.
olysis is enhanced by acidosis and inhibited by hypothermia 32. Rezaie AR. Vitronectin functions as a cofactor for rapid inhibi-
but still can be blocked by tranexamic acid. Journal of Trauma tion of activated protein C by plasminogen activator inhibitor-
and Acute Care Surgery 2013; 74: 4828. 1. Implications for the mechanism of profibrinolytic action of
15. Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, activated protein C. Journal of Biological Chemistry 2001;
Holcomb JB. Independent contributions of hypothermia and 276: 1556770.
acidosis to coagulopathy in swine. Journal of Trauma 2005; 33. Cardenas JC, Rahbar E, Pommerening MJ, et al. Measuring
58: 10029. thrombin generation as a tool for predicting hemostatic
16. Wolberg AS, Meng ZH, Monroe DM 3rd, Hoffman M. A system- potential and transfusion requirements following trauma.
atic evaluation of the effect of temperature on coagulation Journal of Trauma and Acute Care Surgery DOI: 10.1097/
enzyme activity and platelet function. Journal of Trauma TA.0000000000000348.
2004; 56: 12218. 34. Lijnen HR. Pleiotropic functions of plasminogen activator inhibi-
17. Andre P, Srinivasa P, Denis CV, et al. CD40L stabalizes arterial tor-1. Journal of Thrombosis and Haemostasis 2005; 3: 3545.
thrombi by a beta3 integrin-dependent mechanism. Nature 35. Griffin JH, Fernandez JA, Gale AJ, Mosnier LO. Activated pro-
Medicine 2002; 8: 24752. tein C. Journal of Thrombosis and Haemostasis 2007; 5:
18. Johansson PI, Windelv NA, Rasmussen LS, Srensen AM, Os- S7380.
trowski SR. High sCD40L levels early after trauma are associ- 36. CRASH-2 trial collaborators. Effects of tranexamic acid on death,
ated with enhanced shock, sympathoadrenal activation, vascular occlusive events, and blood transfusion in trauma

e32 2014 The Association of Anaesthetists of Great Britain and Ireland

Cap and Hunt | Pathogenesis of traumatic coagulopathy Anaesthesia 2015, 70 (Suppl. 1), e32e34

patients with significant haemorrhage (CRASH-2): a rando- 54. Castellino FJ, Chapman MP, Donahue DL, et al. Traumatic brain
mised, placebo-controlled trial. Lancet 2010; 376: 2332. injury causes platelet adenosine diphosphate and arachidonic
37. CRASH-2 collaborators. The importance of early treatment acid receptor inhibition independent of hemorrhagic shock in
with tranexamic acid in bleeding trauma patients: an explor- humans and rats. Journal of Trauma and Acute Care Surgery
atory analysis of the CRASH-2 randomised controlled trial. 2014; 76: 116976.
Lancet 2011; 377: 1096101. 55. Kutcher ME, Redick BJ, McCreery RC, et al. Characterization of
38. Kashuk JL, Moore EE, Sawyer M, et al. Primary fibrinolysis is platelet dysfunction after trauma. Journal of Trauma and
integral in the pathogenesis of the acute coagulopathy of Acute Care Surgery 2012; 73: 139.
trauma. Annals of Surgery 2010; 252: 43442. 56. Perkins JG, Cap AP, Spinella PC, et al. An evaluation of the
39. Levrat A, Gros A, Rugeri L, Floccard B, Negrier C, David J-S. impact of apheresis platelets used in the setting of massively
Evaluation of rotation thrombelastography for the diagnosis transfused trauma patients. Journal of Trauma 2009; 66: S77
of hyperfibrinolysis in trauma patients. British Journal of 84.
Anaesthesia 2008; 100: 7927. 57. Zink KA, Sambasivan CN, Holcomb JB, Chisholm G, Schreiber
40. Sawamura A, Hayakawa M, Gando S, et al. Disseminated MA. A high ratio of plasma and platelets to packed red blood
intravascular coagulation with a fibrinolytic phenotype at an cells in the first 6 hours of massive transfusion improves out-
early phase of trauma predicts mortality. Thrombosis Research comes in a large multicenter study. American Journal of Sur-
2009; 124: 60813. gery 2009; 197: 56570.
41. Schochl H, Frietsch T, Pavelka M, Jambor C. Hyperfibrinolysis 58. Brown LM, Call MSMargaret Knudson MCohen MJ. Trauma Out-
after major trauma: differential diagnosis of lysis patterns comes Group. A normal platelet count may not be enough:
and prognostic value of thrombelastometry. Journal of Trauma the impact of admission platelet count on mortality and
2009; 67: 12531. transfusion in severely injured trauma patients. Journal of
42. Schochl H, Nieaber U, Hofer G, et al. Goal-directed coagulation Trauma 2011; 71: S33742.
management of major trauma pateints using thromboelas- 59. Stansbury LG, Hess AS, Thompson K, Kramer B, Scalea TM,
tometry (ROTEM)-guided administration of fibrinogen concen- Hess JR. The clinical significance of platelet counts in the first
trate and prothrombin complex concentrate. Critical Care 24 hours after severe injury. Transfusion 2013; 53: 7839.
2010; 14: R55. 60. Inaba K, Branco BC, Rhee P, et al. Impact of the duration of
43. Hunt BJ, Raza I, Brohi K. The incidence and magnitude of platelet storage in critically ill trauma patients. Journal of
fibrinolytic activation in trauma patients: a reply to a rebut- Trauma 2011; 71: 176673.
tal. Journal of Thrombosis and Haemostasis 2013; 11: 61. Falati S, Liu Q, Gross P, et al. Accumulation of tissue factor
14378. into developing thrombi in vivo is dependent upon micropar-
44. Kushimoto S, Gando S, Saitoh D, et al. Clinical course and out- ticle P-selectin glycoprotein ligand 1 and platelet P-selectin.
come of disseminated intravascular coagulation diagnosed by Journal of Experimental Medicine 2003; 197: 158598.
Japanese Association for Acute Medicine criteria. Comparison 62. Morel N, Morel O, Petit L, et al. Generation of procoagulant
between sepsis and trauma. Thrombosis and Hemostasis microparticles in cerebrospinal fluid and peripheral blood after
2008; 100: 1099105. traumatic brain injury. Journal of Trauma 2008; 64: 698704.
45. Chen JP, Rowe DW, Enderson BL. Contrasting post-traumatic 63. Park MS, Owen BA, Ballinger BA, et al. Quantification of hy-
serial changes for D-dimer amd PAI-1 in critically injured percoagulable state after blunt trauma: microparticle and
patients. Thrombosis Research 1998; 94: 17585. thrombin generation are increased relative to injury sever-
46. Rugeri L, Levrat A, David JS, et al. Diagnosis of early coagulation ity, while standard markers are not. Surgery 2012; 151:
abnormalities in trauma patients by rotation thrombelastogra- 8316.
phy. Journal of Hemostasis and Thrombosis 2007; 5: 28995. 64. Gando S, Sawamura A, Hayakawa M. Trauma, shock and dis-
47. Nogami K, Shima M, Matsumoto T, Nishiya K, Tanaka I, Yo- seminated intravascular coagulation: lessons from the classical
shioka A. Mechanism of plasmin-catalyzed inactivation of Fac- literature. Annals of Surgery 2011; 254: 109.
tor VIII. Journal of Biological Chemistry 2007; 282: 528795. 65. Rizoli S, Nascimento B, Key N, et al. Disseminated Intravascu-
48. Faller DV. Endothelial cell responses to hypoxic stress. Clinical lar Coagulopathy in the first 24 hours after trauma: the asso-
and Experimental Pharmacology and Physiology 1999; 26: ciation between ISTH score and anatomopathologic evidence.
7484. Journal of Trauma 2011; 71: S4417.
49. Niles SE, McLaughlin DF, Perkins JG, et al. Increased mortality 66. Maegele M1, Lefering R, Wafaisade A, et al. Revalidation and
associated with the early coagulopathy of trauma in combat update of the TASH-Score: a scoring system to predict the
casualties. Journal of Trauma 2008; 64: 145965. probability for massive transfusion as a surrogate for life-
50. Darlington DN, Craig T, Gonzales MD, Schwacha MG, Cap AP, threatening haemorrhage after severe injury. Vox Sanguinis
Dubick MA. Acute coagulopathy of trauma in the rat. Shock 2011; 100: 2318.
2013; 39: 4406. 67. Cancio LC, Wade CE, West SA, Holcomb JB. Prediction of mor-
51. Pinksy DJ, Yan SF, Lawson C, et al. Hypoxia and modification tality and of the need for massive transfusion in casualties
of the endothelium: implications for regulation of vascular arriving at combat support hospitals in Iraq. Journal of Trauma
homeostatic properties. Seminars in Cellular Biology 1995; 6: 2008; 64: S516.
28394. 68. Ruchholtz S, Pehle B, Lewan U, et al. The emergency room
52. Komissarov AA, Andreasen PA, Declerck PJ, Kamikubo Y, Zhou transfusion score (ETS): prediction of blood transfusion
A, Gruber A. Redirection of the reaction between activated requirement in initial resuscitation after severe trauma. Trans-
protein C and a serpin to the substrate pathway. Thrombosis fusion Medicine 2006; 16: 4956.
Research 2008; 122: 397404. 69. Schreiber MA, Perkins J, Kiraly L, Underwood S, Wade C, Hol-
53. Chironi GN1, Boulanger CM, Simon A, Dignat-George F, Freys- comb JB. Early predictors of massive transfusion in combat
sinet JM, Tedgui A. Endothelial microparticles in diseases. Cell casualties. Journal of the American College of Surgery 2007;
and Tissue Research 2009; 335: 14351. 205: 5415.

2014 The Association of Anaesthetists of Great Britain and Ireland e33

Anaesthesia 2015, 70 (Suppl. 1), e32e34 Cap and Hunt | Pathogenesis of traumatic coagulopathy

70. Yucel N, Lefering R, Maegele M, et al. Trauma associated 82. Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ. Ras-
severe hemorrhage (TASH)-score: probability of mass transfu- mussen TE Association of cryoprecipitate and tranexamic acid
sion as surrogate for life threatening hemorrhage after multi- with improved survival following wartime injury: findings
ple trauma. Journal of Trauma 2006; 60: 122837. from the MATTERs II Study. Journal of the American Medical
71. Reed MJ, Lone N, Walsh TS. Resuscitation of the trauma Association Surgery 2013; 148: 21825.
patient: tell me a trigger for early haemostatic resuscitation 83. Johansson PI, Stensballe J. Hemostatic resuscitation for massive
please!. Critical Care 2011; 15: 126. bleeding: the paradigm of plasma and platelets a review of
72. Dzik WH. Predicting hemorrhage using preoperative coagula- the current literature. Transfusion 2010; 50: 70110.
tion screening assays. Current Hematology Reports 2004; 3: 84. Khan S, Brohi K, Chana M, et al. International Trauma
32430. Research Network (INTRN). Hemostatic resuscitation is neither
73. Raza I, Davenport R, Rourke C, et al. The incidence and mag- hemostatic nor resuscitative in trauma hemorrhage. Journal
nitude of fibrinolytic activation in trauma patients. Journal of of Trauma and Acute Care Surgery 2014; 76: 5617; discus-
Thrombosis and Haemostasis 2013; 11: 30714. sion 567-8.
74. Hunt BJ, Segal H. Hyperfibrinolysis. Journal of Clinical Pathol- 85. Holcomb JB, Pati S. Optimal trauma resuscitation with plasma
ogy 1996; 49: 958. as the primary resuscitative fluid: the surgeons perspective.
75. Carroll RC, Craft RM, Langdon RJ, et al. Early evaluation of American Society of Hematology Education Program 2013;
acute traumatic coagulopathy by thromboelastography. Trans- 2013: 6569.
lational Research 2009; 154: 349. 86. Spinella PC, Reddy HL, Jaffe JS, Cap AP, Goodrich RP. Fresh
76. Spinella PC, Holcomb JB. Resuscitation and transfusion princi- whole blood use for hemorrhagic shock: preserving benefit
ples for traumatic hemorrhagic shock. Blood Reviews 2009; while avoiding complications. Anesthesia and Analgesia
23: 23140. 2012; 115: 7518.
77. Perkins JG, Cap AP, Spinella PC, et al. 31st Combat Support 87. Cotton BA1, Podbielski J, Camp E, et al. Early Whole Blood
Hospital Research Group. Comparison of platelet transfusion Investigators. A randomized controlled pilot trial of modified
as fresh whole blood versus apheresis platelets for massively whole blood versus component therapy in severely injured
transfused combat trauma patients. Transfusion 2011; 51: patients requiring large volume transfusions. Annals of Sur-
24252. gery 2013; 258: 52732.
78. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood 88. Murdock AD, Berse us O, Hervig T, Strandenes G, Lunde TH.
products transfused affects the mortality in patients receiving Whole blood: the future of traumatic hemorrhagic shock
massive transfusions at a combat support hospital. Journal of resuscitation. Shock 2014; 41: 629.
Trauma 2007; 63: 80513. 89. Cap AP. The school of hard knocks: what weve learned and
79. Pidcoke HF, Aden JK, Mora AG, et al. Ten-year analysis of relearned about transfusion in a decade of global conflict.
transfusion in Operation Iraqi Freedom and Operation Endur- Transfusion Medicine 2014; 24: 1357.
ing Freedom: increased plasma and platelet use correlates 90. Coagulation management in trauma-related massive bleeding
with improved survival. Journal of Trauma and Acute Care Recommendations of the Task Force for Coagulation (AGPG)
Surgery 2012; 73: S44552. of the Austrian Society of Anesthesiology, Resuscitation and
80. Spahn DR, Bouillon B, Cerny V, et al. Management of bleeding Intensive Care Medicine (OGARI). Anasthesiologie und Inten-
and coagulopathy following major trauma: an updated Euro- sivmedizin Notfallmed Schmerzther 2010; 45: 55261.
pean guideline. Critical Care 2013; 17: R76. 91. Schochl H, Voelckel W, Maegele M, Kirchmair L, Schlimp CJ.
81. Rourke C, Curry N, Khan S, et al. Fibrinogen levels during Endogenous thrombin potential following hemostatic therapy
trauma hemorrhage, response to replacement therapy, and with 4-factor prothrombin complex concentrate: a 7-day
association with patient outcomes. Journal of Thrombosis and observational study of trauma patients. Critical Care 2014; 18:
Haemostasis 2012; 10: 134251. R147.

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