REVIEW

URRENT
C
OPINION

The pathophysiology of trauma-induced

coagulopathy
Daniel Frith and Karim Brohi

Purpose of review
Transfusion paradigms and protocols have evolved at a rapid pace in the last few years to ameliorate the
adverse effects of trauma-induced coagulopathy (TIC). This has occurred despite fragmented and
inadequate knowledge of the underlying pathophysiology that they are supposed to treat. This review will
collate and assimilate the most recent data about TIC in order to present our state-of-the-art understanding
of this condition.
Recent findings
TIC was conventionally construed simply as depletion, dysfunction or dilution of procoagulant factors.
However, contemporary understanding recognizes it as an imbalance of the dynamic equilibrium between
procoagulant factors, anticoagulant factors, platelets, endothelium and fibrinolysis. The endogenous
component of TIC (acute traumatic coagulopathy) is not merely a consumptive coagulopathy, but is
characterized by isolated factor V inhibition, dysfibrinogenaemia, systemic anticoagulation, impaired
platelet function and hyperfibrinolysis. Acute traumatic coagulopathy then becomes exacerbated by
hypothermia, acidosis and resuscitation with hypocoagulable fluids.
Summary
Further improvement in the outcome from trauma-haemorrhage is possible with more refined and tailored
haemostatic resuscitation. Achieving this will depend upon a better understanding of the haemostatic
defects that develop after injury.
Keywords
coagulopathy, fibrinolysis, protein C, transfusion, trauma

INTRODUCTION
Trauma-induced coagulopathy (TIC) has long been
known to coexist with severe haemorrhage. However, our understanding of the mechanisms and
clinical importance of coagulopathy changed significantly after the identification of an endogenous
acute traumatic coagulopathy (ATC) nearly a decade ago [1,2]. Presence of this haemostatic impairment early after injury is an independent predictor
for increased organ injury, infection and death [3 ].
Although not yet proven in a human study, these
outcomes are probably mediated in part by
increased blood loss and greater exposure to transfusion products. Better prevention and treatment of
ATC should theoretically deliver improved outcomes for our trauma patients.
Other mediators of haemostatic impairment
such as hypothermia, acidosis and haemodilution
exacerbate the early ATC and contribute collectively
to TIC. Transfusion paradigms and protocols have
evolved at a rapid pace in the last few years to
&&

ameliorate the adverse effects of this entity. The

introduction of damage control resuscitation with
formula-guided administration of high volumes of
plasma, platelets and other haemostatic agents has
been associated with reduced mortality [4 ]. It is
generally assumed that these products deliver
improved haemostatic competence and this translates into better haemorrhage control. This remains
unproven and the mechanism by which it is delivered is unclear. For example, high ratios of plasma
are advocated based upon the assumption that augmentation of the whole coagulation network is
&

Trauma Sciences, Blizard Institute, Barts & The London School of

Medicine & Dentistry, Queen Mary University of London, London, UK
Correspondence to Professor Karim Brohi, Trauma Sciences, Blizard
Institute, Newark St, London, E1 2AT, UK. Tel: +44 207 3777695;
fax: +44 207 3777044; e-mail: k.brohi@qmul.ac.uk
Curr Opin Crit Care 2012, 18:631636
DOI:10.1097/MCC.0b013e3283599ab9

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Trauma

KEY POINTS

procoagulant factors, anticoagulant factors, platelets,

endothelium and fibrinolysis.

Trauma-induced coagulopathy is an imbalance of the

dynamic equilibrium between procoagulant factors,
anticoagulant factors, platelets, endothelium
and fibrinolysis.

PROCOAGULANT IMPAIRMENT

The endogenous component of trauma-induced

coagulopathy (acute traumatic coagulopathy) is not
merely a consumptive coagulopathy, but is
characterized by isolated factor V inhibition,
dysfibrinogenaemia, systemic anticoagulation, impaired
platelet function and hyperfibrinolysis.

Protein C is activated in acute traumatic coagulopathy
and, as a functional anticoagulant, can be expected to
influence the haemostatic competence of victims of
severe trauma.

Acute traumatic coagulopathy is exacerbated by
hypothermia, acidosis and resuscitation with
hypocoagulable fluids, which contribute collectively to
establish trauma-induced coagulopathy.

required early after severe injury. However, evidence

is emerging to suggest that although some coagulation factors are statistically reduced with ATC,
most components of secondary haemostasis are
sufficient in themselves to produce a normal clotting time [5]. The endogenous thrombin potential, a
global measure of function of the procoagulant
system up to fibrinogen cleavage, has been reported
as normal or even enhanced in patients with ATC
[6,7]. It is not clear, therefore, that, if plasma is
beneficial, it acts by increasing procoagulant factor
levels.
The current knowledge gap of the underlying
pathophysiology of TIC is a key barrier to producing
more effective and tailored resuscitation strategies.
Multiple hypotheses have been proffered to explain
how and why haemostasis becomes impaired at the
time of its greatest need. However, at present the
evidence is fragmented, sometimes contradicting
and insufficient in scope to formulate a cohesive
narrative of the haemostatic response to injury and
haemorrhagic shock. This review will collate and
assimilate the most recent data about TIC in order
to present our state-of-the-art understanding of this
condition.

MECHANISMS OF TRAUMA-INDUCED
COAGULOPATHY
TIC was conventionally construed simply as depletion, dysfunction or dilution of procoagulant factors.
However, contemporary understanding recognizes it
as an imbalance of the dynamic equilibrium between
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ATC develops rapidly and has been identified within

minutes of injury. Blood samples taken from 45
trauma patients at the accident scene have shown
that 56% already had abnormal coagulation only
25 min after injury [8 ]. Similarly, a variety of
abnormal thromboelastography (TEG) measurements have been found in the blood of 161 trauma
patients taken prehospital [9]. In a recent study, a
panel of eight coagulation factors (II, V, VII, VIII, IX,
X, XI and XII) were analysed from 110 adult trauma
patients attending the emergency department (ED)
with an Injury Severity Score (ISS) of greater than 15
[10 ]. Twenty-two were found to have a critical
clotting factor deficiency (activity level <30% of
normal) that could be expected to impair haemostasis in vivo. There was no pan-consumption of
coagulation factors. Factor V was deficient in all
of the 22 cases, but only five patients had a critical
deficiency of any of the other factors. The authors
speculated that this isolated critical deficit of factor
V could be caused by activated protein C (aPC) and
might contribute to the pathophysiology of ATC.
Fibrinogen concentrations are known to decline
rapidly after injury and then rebound to supraphysiological levels in subsequent days [11,12]. In a
prospective observational study, Johansson et al.
[13] divided 80 patients into coagulopathic [INR
>1.2 or activated partial thromboplastin time
(aPTT) >35] and noncoagulopathic cohorts. Those
with ATC had significantly lower fibrinogen concentration (1.53 vs. 2.54 g/l, P < 0.001). Rourke et al.
[14 ] characterized the fibrinogen profile of 517
trauma patients in response to damage control
resuscitation. The proportions of patients with
admission fibrinogen levels below 1.5, 1.0 and
0.8 g/l were 14, 5 and 3%, respectively and low
fibrinogen was found to be an independent predictor of mortality at both 24 h and 28 days (P < 0.001).
Patients who received fibrinogen supplementation
(cryoprecipitate) during resuscitation maintained
their admission fibrinogen level (1.60 g/l) throughout the first eight units of packed red blood cell
(PRBC) transfusion (1.54 g/l) with a small, nonsignificant reduction by the 12th unit (1.31 g/l). In comparison, fibrinogen levels rapidly decreased in
patients receiving no transfusion source of fibrinogen supplementation to 0.5 g/dl by eight PRBC
units. Ex-vivo spiking of coagulopathic blood
samples with fibrinogen concentrate (a 12 g dose
equivalent) or high dose cryoprecipitate (four
pools/20 units, equivalent to 7.8 g of fibrinogen)
&&

&&

&&

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Pathophysiology of trauma-induced coagulopathy Frith and Brohi

was capable of completely correcting the 36%

reduction of EXTEM and FIBTEM CA5 seen on
admission in these patients. This is important
because, if reproducible in vivo, early fibrinogen
replacement with cryoprecipitate or concentrate
could be a logistically more efficient method to
combat ATC than high volumes of plasma. Prospective randomized controlled trials are warranted.

SYSTEMIC ANTICOAGULATION
We have previously proposed that systemic anticoagulation via activation of protein C may be a
functional mediator of ATC [15]. Data from our
murine model of trauma and haemorrhaghic shock
support this hypothesis [16]. Depletion of protein C
at the injury scene and on admission to hospital has
been associated with prolongations of both the
prothrombin time (PT) and aPTT [8 ]. Interestingly,
this also correlated with a specific reduction of
circulating factor V activity, a target substrate of
aPC. Johansson et al. [13] were the first group to
record an increase in aPC concentrations after
injury. However, only 12 patients in this study were
coagulopathic and it did not differentiate between
those with and without ATC.
Resolution of the relationship between aPC and
ATC has been improved by a prospective observational study of 203 major trauma patients performed
at San Francisco General Hospital [3 ]. Patients with
a combination of tissue hypoperfusion and severe
traumatic injury showed a strong activation of the
protein C pathway with significant increase in
circulating aPC and reciprocal reduction in residual
protein C. This was associated with a coagulopathy
characterized by inactivation of the coagulation
factors V and VIII and a derepression of the fibrinolysis with high plasma levels of plasminogen
activator and high D-dimers. There is now a significant body of evidence developing to demonstrate
that protein C is activated in ATC and, as a functional anticoagulant, can be expected to influence
the haemostatic competence of victims of severe
trauma. What remains unclear is the magnitude
of this anticoagulant effect in vivo and its dominance
relative to other known and unknown mediators
of coagulopathy.
&&

&&

room and observed hyperfibrinolysis in 23, an incidence of 6.8%. In 14 cases, hyperfibrinolysis was
considered fulminant with a complete breakdown
of the clot observed within 60 min. A reduction of
clot firmness between 16 and 35% was observed in
another nine patients. The mortality rate in patients
with fulminant hyperfibrinolysis was 85.7%,
compared with 11.1% in low-grade fibrinolysis.
Patients with hyperfibrinolyis had higher ISS, lower
Glasgow Coma Score (GCS), lower systolic blood
pressure and higher lactates than patients without
hyperfibrinolysis.
In a study of 118 patients meeting criteria for the
highest tier of trauma team activation, Ives et al. [18]
diagnosed hyperfibrinolysis in 13 (11%) using a TEG
definition of at least 15% estimated percentage lysis.
Nine of these patients died (81.8) and in a stepwise
logistic regression model, consisting of 12 significant univariate variables, hyperfibrinolysis and
massive transfusion (>10 PRBC in 24 h) were the
only significant predictors of early (24 h) mortality
(predicting 53 and 69% of deaths, respectively).
Compared with patients without hyperfibrinolysis,
patients with hyperfibrinolysis had a greater need
for massive transfusion [76.9 vs. 8.7%; adjusted odds
ratio 19.1; 95% confidence interval (CI) 3.6
101.3; P < 0.001] and had a greater early mortality
(69.2 vs. 1.9%; adjusted odds ratio 55.8; 95% CI
7.2432.3; P < 0.001) and in-hospital mortality
(92.3 vs. 9.5%; adjusted odds ratio 55.5; 95% CI
4.8649.7; P 0.001).
Although we have an international randomized
controlled trial to direct the use of tranexamic acid
in trauma, the inclusion criteria for this study were
broad and quite possibly included a large number for
whom it delivered no haemostatic benefit [19]. Over
half of the study cohort did not receive any blood
transfusion and for those who did, the study drug
had minimal impact upon the volume they
received. There is scope for refinement in the selection criteria of recipients of this therapeutic. At
present, TEG appears to have poor sensitivity for
detecting subtle fibrinolysis that might still contribute to ATC and be modified by antifibrinolytics.
Better assessment tools are needed to direct tailored
management of fibrinolysis after trauma.

PLATELET DYSFUNCTION
HYPERFIBRINOLYSIS
Fibrinolysis is also clearly a functional component
of ATC. Some recent prospective clinical studies
have better defined the incidence and clinical
importance of this entity. Tauber et al. [17 ] performed RoTEM analysis on 334 major trauma
patients (ISS >15) upon admission to the emergency
&

Platelet counts are mildly reduced by trauma and

this appears to associate with poor outcomes. For
example, Brown et al. [20 ] performed a retrospective cohort study of 389 massively transfused
trauma patients and reported that, in a logistic
regression model controlling for ISS, GCS and
admission base deficit, the odds of death at 24 h

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Trauma

decreased by 12% for every 50  109/l increase in

platelet count. However, in most contemporary
studies, they do not decline to levels that may be
expected to contribute significantly to coagulopathy [13,21]. Nevertheless, one or two reports have
identified that a high ratio of platelets to PRBCs is
associated with improved outcomes [22 ]. This may
lead us to conclude that the primary platelet impairment provoked by injury and/or haemorrhagic
shock is functional. A single study of 163 trauma
patients has recently reported a minor, but significant, difference in platelet aggregometry parameters
(ADP test and thrombin receptor activating peptide
test) between survivors and nonsurvivors [23 ].
Wohlauer et al. [24] added to this by studying
the platelet function of 51 trauma patients prior
to significant resuscitation using point of care
TEG-based platelet function analysis (TEG platelet
mapping). In trauma patients, the median ADP
inhibition of platelet function was 86.1% [interquartile range (IQR) 38.697.7%] compared with
4.2% (IQR 018.2%) in healthy volunteers. After
trauma, the impairment of platelet function in
response to arachidonic acid was 44.9% (IQR
26.659.3%) compared with 0.5% (IQR 03.02%)
in volunteers (Wilcoxon nonparametric test,
P < 0.0001 for both tests). These are useful data
but the clinical implications remain unclear. Further
studies are urgently required in order to develop a
rounded understanding of the contribution that
platelet dysfunction makes to ATC.
&

&

ENDOTHELIAL ACTIVATION
Vascular endothelium is an active participant in the
pathophysiology of ATC. Large capillary beds host
thrombomodulin and endothelial protein C receptors anchored through their luminal surface that
capture thrombin and accelerate protein C activation 1000-fold [25]. In addition to inactivating
coagulation factors Va and VIIIa, aPC also consumes
plasminogen activator inhibitor-1 (PAI-1), the
major antagonist of tissue-type plasminogen activator inhibitor-1 (t-PA). Consequently, traumatic
haemorrhage with tissue hypoperfusion leads to
overwhelming release of t-PA from vascular endothelial cells and subsequent hyperfibrinolysis [26].
However, aPC is potentially not the only endothelial
anticoagulant system influencing ATC. By measuring the difference between KaolinTEG and HeparinaseTEG in samples taken from 77 trauma patients on
ED arrival, a recent study found that four of these
patients (5.2%) had evidence of a high degree of
autoheparinization, which appeared mechanistically linked to endothelial glycocalyx degradation
[27 ]. This group had higher ISS [median IQR, 31
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(2637) vs. 17 (1026)], lower haemoglobin level

(median, 5.8 vs. 8.4 mmol/l) and received more
transfusions during the first 1 h (median, 5 vs. 0)
and 24 h (median, 10 vs. 0; all P < 0.05).
Using almost the same patient cohort, another
group have published fascinating data demonstrating an association between tissue hypoperfusion,
neurohormonal activation and markers of endothelial disruption [28 ,29 ]. Circulating adrenaline
levels were elevated in patients with higher ISS,
higher lactate and lower systolic blood pressure.
This correlated positively and independently with
the incidence of ATC as well as levels of syndecan-1,
histone-complexed DNA, high-mobility group
box 1, soluble thrombomodulin, t-PA and D-dimers.
In a follow-up study, these authors offer some
preliminary evidence that sCD40L may play a pathophysiological role in this process [30 ]. Endothelial
glycocalyx degradation is capable of triggering
thrombin generation, protein C activation and
hyperfibrinolysis. This is important because it
indicates another potential mechanism by which
tissue injury and shock mediate systemic anticoagulation early after injury.
&

&

&

HYPOTHERMIA, ACIDOSIS AND

HAEMODILUTION
Other mediators of TIC develop over time from
injury as a consequence of haemorrhage, hypoperfusion, exposure and resuscitation with hypocoagulable resuscitation products. However, hypothermia
and acidosis probably do not produce a clinically
relevant effect until body temperatures are under
338C and/or pH is below 7.2 [31]. High volumes
(>3 l) of crystalloid or colloid fluid administered
prehospital are independently associated with a
worse ED coagulation profile [32]. Matched pair
analysis was performed on two groups of 1351
trauma patients that had been divided into low
volume prehospital resuscitation (1500 ml crystalloid or colloid) or high volume (2000 ml). The high
volume group had significantly worse coagulation
profile, required more blood products and had
higher incidence of organ failure, although overall
mortality was similar [33]. These iatrogenic factors
are at least partially preventable after injury and
damage control resuscitation should be practised
to minimize their effects [34].

ACTIVATION OF HAEMOSTASIS AFTER

INJURY
Traumatic tissue damage leads to activation of
coagulation by exposure of the subendothelial
matrix with subsequent interaction between factor
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Pathophysiology of trauma-induced coagulopathy Frith and Brohi

VII and endothelial tissue factor (TF). The volume of

tissue injury should, therefore, determine the degree
of coagulation factor consumption and it would
remain localized to the site of injury. However, in
both clinical and laboratory studies, tissue injury
alone does not lead to coagulopathy [35]. Systemic
hypoperfusion is necessary to produce ATC.
Haemorrhagic shock is known to activate a
systemic inflammatory response [36] and induces
TF presentation on a variety of vascular constituents
[37]. This is a potential mechanism by which activation of coagulation could become delocalized
after tissue injury and explain the substantial influence of hypoperfusion on ATC. However, whether
systemic activation of coagulation occurs after
trauma and whether this is synonymous with our
established understanding of disseminated intravascular coagulation (DIC) is an issue of some
scientific contention. In a recent study of 423
trauma patients, 11% could be diagnosed with
overt DIC by the International Society for Thrombosis and Hemostasis scoring system [38 ]. As might
be expected, these patients had higher mortality,
worse bleeding and received more transfusions.
However, histopathologic examination of 40 organs
for microvascular thrombi, intravascular fibrin
deposition or associated ischaemia (by pathologists
blinded to clinical or laboratory data) failed to detect
evidence of DIC in any specimens [38 ]. Proponents
of the DIC hypothesis might argue that this is
unsurprising as trauma patients are unique in that
they exhibit a fibrinolytic phenotype and all
thrombi formed are rapidly and completely lysed
by plasmin or neutrophil elastase [39 ]. Either way,
although some patients with ATC meet diagnostic
criteria for overt DIC, this scoring system should
probably not be used for trauma as it is heavily
influenced by the D-dimer result, a fibrin degradation product that is almost universally elevated
after tissue injury.
&&

&&

&

CONCLUSION
ATC is an endogenous impairment of all components
of haemostasis that develops rapidly in response to
tissue injury and haemorrhagic shock. Rather than
being merely a consumptive coagulopathy, ATC is
characterized by isolated factor V inhibition, dysfibrinogenaemia, systemic anticoagulation, impaired
platelet function and hyperfibrinolysis. It is exacerbated by hypothermia, acidosis and resuscitation
with hypocoagulable fluids, which contribute collectively to establish TIC. Further improvement in
the outcome from trauma-haemorrhage is possible
with more refined and tailored haemostatic resuscitation. Achieving this will depend upon a better

understanding of the haemostatic defects that

develop after injury.
Acknowledgements
K.B. has received unrestricted reagent/equipment grants
from ROTEM.
Conflicts of interest
There are no conflicts of interest.

REFERENCES AND RECOMMENDED

READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
Additional references related to this topic can also be found in the Current
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&&
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&&
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&&
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&
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&
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Interesting study showing that poor outcomes are dose-dependently associated with
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&
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&&
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&
adrenaline levels at admission predict increased mortality after trauma.
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&
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pathy in the first 24 h after trauma: the association between ISTH score
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A prospective study evaluating the possible involvement of DIC in the pathophysiology of ATC.
39. Hayakawa M, Sawamura A, Gando S, et al. Disseminated intravascular
&
coagulation at an early phase of trauma is associated with consumption
coagulopathy and excessive fibrinolysis both by plasmin and neutrophil
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A good study examining the response of fibrinolytic components of haemostasis to
injury.
&

Volume 18
Number 6
December 2012

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