TRAUMA-INDUCED COAGULOPATHY: A CLINICAL AND SCIENTIFIC PERSPECTIVE

Mechanisms of trauma-induced coagulopathy

Nathan J. White1

1Division of Emergency Medicine, University of Washington, Seattle, WA

The identification and management of coagulopathy is a critical component of caring for the severely injured patient.
Notions of the mechanisms of coagulopathy in trauma patients have been supplanted by new insights resulting from
close examination of the biochemical and cellular changes associated with acute tissue injury and hemorrhagic shock.
Acute intrinsic coagulopathy arising in severely injured trauma patients is now termed trauma-induced coagulopathy
(TIC) and is an emergent property of tissue injury combined with hypoperfusion. Mechanisms contributing to TIC
include anticoagulation, consumption, platelet dysfunction, and hyperfibrinolysis. This review discusses current
understanding of TIC mechanisms and their relative contributions to coagulopathy in the face of increasingly severe
injury and highlights how they interact to produce coagulation system dysfunction.

Introduction resuscitative treatment.2,3 From these data, the thrombin-thrombo-

Hemorrhagic shock from blood loss is a critical cause of mortality in
severely injured patients. Contributing to blood loss is an intrinsic
dysregulation of the blood coagulation system now named trauma-
induced coagulopathy (TIC). TIC arises in the presence of both
tissue hypoperfusion from blood loss and severe anatomical tissue
injury and, when present, is strongly and positively associated with
mortality. The physiological environment in which TIC arises is a
complex mixture of inflammation, anticoagulation, and cellular
dysfunction of mixed etiology. The coagulation system balance also
changes rapidly during injury and resuscitation so that the TIC
phenotype can evolve quickly over time from primarily an anticoagu-
lant to a procoagulant state within hours to days if the patient
survives. Given the complexity and rapidly changing nature of
traumatic injury and TIC, underlying mechanisms have not been
fully elucidated. However, several key processes, including dysfunc-
tion of natural anticoagulant mechanisms, platelet dysfunction,
fibrinogen consumption, and hyperfibrinolysis, have been identified
as primary components of TIC. In addition, specific effects of blood
dilution from resuscitation fluids, environmental hypothermia, and
acidosis can modulate clot formation, adding more layers of
complexity to TIC. This review focuses on the initial intrinsic TIC
phenotype found almost immediately after severe injury with tissue
hypoperfusion. This phenotype arises quickly after injury with
blood loss and is relatively independent of secondary influences.
The individual underlying contributors and their interaction to
produce TIC are highlighted, in addition to some of the key
controversies in mechanism and current knowledge gaps.
Anticoagulation
Anticoagulation is a primary component of TIC. TIC was initially
described as an increased international normalized ratio (INR) by
Brohi et al in severely injured trauma patients measured on arrival at
the emergency department.1 Activated partial thromboplastin times
(aPTT) were also elevated in patients with severe injury and there
was tissue hypoperfusion as measured by the base deficit, although
changes in this assay lagged behind changes in INR. The investiga-
tors presumed that elevations in INR and aPTT were independent of
dilution by fluid resuscitation or environmental influences due to the
limited resuscitation fluids received by these patients before sam-
pling.1 Later, several studies corroborated this assumption by
showing TIC to be present at the scene of injury before onset of
modulin-protein C anticoagulant system was implicated as a
potential primary mechanism of anticoagulation.4,5 Brohi et al found
increased circulating thrombomodulin that correlated with de-
creased plasma protein C levels and attributed the decrease in
protein C to its activation (activated protein C [aPC]) by thrombin
bound to thrombomodulin.5 Interestingly, this anticoagulant pattern
was only present in those patients demonstrating both severe
anatomical injury and tissue hypoperfusion.5 Subsequent studies
have confirmed an increase in aPC concentration in similar trauma
patients.6,7 The anticoagulant properties of aPC are derived by its
degradation of activated factors V and VIII, producing reduced
concentrations and activities. Supporting this mechanism, Rizoli et
al found that, among 110 trauma patients, factor V deficiency was
always present as a component of critical factor deficiency.8
Experimental murine studies have confirmed that the anticoagulant
property of aPC can mediate increased aPTT in the setting of
combined injury and hemorrhagic shock.9 Investigators found that
blocking of the anticoagulant function of aPC by monoclonal
antibody reversed the trauma-induced elevation of aPTT in this
murine model but had no impact on survival. Interestingly, blockade
of the anticoagulant and endothelial interactions of aPC in the same
model led to rapid mortality with massive intravascular thrombosis,
suggesting a protective role for aPC in regulating endothelial
interactions during traumatic shock in addition to its anticoagulant
effects.9
Other anticoagulant mechanisms may contribute to the pathomecha-
nism of TIC. Endogenous autoheparinization, possibly related to
shedding of the endothelial glycocalyx, has been suggested by the
ability to reverse anticoagulation in the presence of heparinase in
whole blood from TIC patients.10 There is also disagreement
regarding the contribution of disseminated intravascular coagula-
tion (DIC) to the anticoagulated state of TIC. Gando et al contend
that TIC is primarily a reflection of coagulation activation and
fibrinolysis that they describe as DIC with fibrinolytic phenotype.11
Measuring fibrinopeptides liberated either by thrombin or from
degradation by plasmin, they have shown a relatively greater
increase of plasmin relative to thrombin activation during the initial
encounter with trauma patients. These investigators propose that
activation of plasmin fully accounts for the initially anticoagulated
state and that there is no need to separate TIC from DIC with

660 American Society of Hematology

hyperfibrinolysis.11 They also point out that increased concentration
of degradation products from cross-linked fibrin (D-dimer) argues
for diffuse fibrin generation from thrombin generation. They also
argue that increasing the concentration of soluble thrombomodulin
in plasma does not necessarily conclude that it is responsible for
anticoagulation because solubilized thrombomodulin demonstrates
decreased activity versus thrombomodulin bound to endothelium.12
Nevertheless, it is clear that anticoagulation, either directly from the
thrombin-thrombomodulin-aPC system or through thrombin activa-
tion and factor consumption, is an important component of TIC that
deserves further focused study to fully understand.
Platelet dysfunction
There is a rapidly growing body of support for a prominent role of
platelet dysfunction in the pathophysiology of TIC. Historically,
platelet-specific transfusion and hemostatic management were based
on critical thresholds in platelet counts and less so on platelet
function. In trauma, platelet count does strongly influence hemosta-
sis and a low or decreasing platelet count in trauma patients does
predict greater mortality.13 However, platelet counts are typically
within the normal range during early TIC, indicating that their
consumption or dilution is not a major contributor to the early TIC
mechanism.13
Moderate or even mildly decreased platelet aggregation is strongly
associated with mortality. Kutcher et al used impedance aggregom-
etry to characterize platelet dysfunction in trauma patients on arrival
at the emergency department.14 They found that of 101 patients,
almost half (45.5%) showed decreased platelet aggregation in
response to ADP, thrombin receptor-activating peptide, arachidonic
acid (AA), and/or collagen. There was an astonishing 10-fold
increase in mortality in patients having any one of these platelet
aggregation deficits, and admission AA and collagen responsive-
ness were sensitive and specific predictors of mortality. Solomon et
al showed similar results in 163 trauma patients of which 20
(12.3%) died15 and, again, even relatively minor defects in platelet
aggregation detected by multiple electrode aggregometry were
associated with mortality. They also found the platelet contribution
to clot firmness measured using rotational thromboelastometry
(ROTEM) to be significantly decreased in nonsurvivors. Using
thrombelastography modified to detect platelet-specific effects
(Platelet Mapping; Haemonetics) Wohlauer et al also found a
pronounced inhibition of clot strength when activated with ADP and
AA in 51 trauma patients sampled within 30 minutes of injury.16
These studies highlight the importance of intact platelet aggregation
and contraction in the response to hemorrhage; however, they do not
suggest a specific mechanism of action for platelet dysfunction.
Some clues may be found in the relative increased tendency for
ADP and collagen-induced platelet dysfunction. ADP-induced
platelet aggregation is mediated by a subgroup of nucleotide-
activated platelet receptors designated as P2T. Members of this
subgroup produce calcium influx (P2X),17 inhibition of adenylyl
cyclase (P2TAC),18 and mobilization of intracellular calcium stores
through inositol phosphate production (P2TPLC),18 thus mediating
shape change, aggregation, and granule secretion. Activation of the
collagen surface receptor primarily produces calcium influx through
reversal of the Na⫹/Ca⫹ exchanger. Therefore, common mecha-
nisms of decreased platelet aggregation in trauma may include
inhibition of multiple receptors, altered calcium influx in response
to activation, or possibly even energetic defects arising downstream
from receptor activation. Further focused study is required to
elucidate the culprit molecular pathways.
Hematology 2013
Fibrinogen consumption and fibrinolysis
After its activation by thrombin, fibrinogen spontaneously polymer-
izes from its individual monomers to form an insoluble polymeric
fibrin mesh to stop blood loss at sites of vascular injury. This
process, along with platelet-induced clot contraction, is the primary
component of secondary hemostasis. There is strong evidence that
consumption of fibrinogen and fibrinolysis by the action of plasmin
are key mechanistic components of TIC. Rourke et al found that low
hospital admission fibrinogen concentration was independently
associated with severity of anatomical injury, shock, and volumes of
fluids administered. Admission fibrinogen concentrations correlated
with measurements of clot firmness (ROTEM) and were noted to be
independent predictors of both early and late mortality in this cohort
of 517 trauma patients.19 Fibrinogen was also rapidly depleted in the
plasma in animal models of traumatic hemorrhagic shock. Martini et
al demonstrated in a swine model that increased rates of loss were
greater than liver production during hemorrhage and resuscitation.20
Others have demonstrated rapid decrease in functional fibrinogen
concentration and clot strength during hemorrhage and before fluid
resuscitation.21
Fibrin clot formation is naturally counterbalanced by enzymatic clot
breakdown or fibrinolysis. During fibrinolysis, tissue plasminogen
activator (tPA) and the precursor plasminogen undergo high-affinity
binding to fibrin, where tPA activates plasminogen to plasmin.
Plasmin then cuts fibrin fibers at specific lysine residues. As a result,
the scaffold of the formed clot is rapidly degraded and the clot is
eventually destroyed. An increase in fibrinolysis, known as hyperfi-
brinolysis, is a known consequence of trauma with hemorrhagic
shock. It was described as a critical mechanism of action of TIC by
Brohi et al, who detected increased levels of tPA and the clot
breakdown product D-dimer.5 Raza et al then measured the plasmin-
antiplasmin complex concentration as a marker of plasmin genera-
tion and overt clot lysis by ROTEM in 303 trauma patients. They
found that overt lysis was rare (⬍ 5%), whereas moderate fibrino-
lytic activation, defined at plasmin-antiplasmin complex ⬎ 2⫻ the
control levels was common, having been present in 57% of patients
in this cohort. In addition, those with fibrinolytic activation demon-
strated higher mortality (12% vs 1%, P ⬍ .001) and had more
complications.22 Increased tPA antigen concentration and reduced
fibrinogen concentration has also been found in trauma patients
meeting the criteria for early DIC.23,24 When using viscoelastic
methods of measurement, overt hyperfibrinolysis is associated with
an exceedingly high (60%-100%) mortality rate in trauma patients
with rapid primary clot lysis and is often associated with a
perimortem state.25,26 Mortality is also directly and positively
associated with degree of fibrinolysis, as demonstrated by Schochl
et al, who found that mortality increased with the speed of clot
breakdown.27
The mechanism of hyperfibrinolysis in trauma is attributed to
activated protein C-mediated inactivation of plasminogen activator
inhibitor-1 (PAI-1), leaving tPA unchecked. Brohi et al have
provided evidence for this mechanism by demonstrating that
activation of protein C by thrombin-thrombomodulin is associated
with reduced PAI-1 concentration and elevated D-dimer.5 They
conclude that this association is mediated by an inhibitory action of
aPC on PAI-1, which has also been demonstrated in vitro.28
However, Urano et al used the euglobin lysis time assay to show that
recombinant aPC inhibited cleavage and inactivation of PAI-1,
concluding that aPC appears to normalize hyperfibrinolysis by
inhibiting thrombin-dependent PAI-1 degradation.29 Therefore, aPC
may alternatively enhance fibrinolysis by its thrombin-reducing
661
effects rather than by a direct inhibitory effect on PAI-1. Destruc-
tion of PAI-1 via neutrophil elastase may also enhance fibrinolysis
in trauma. In a smaller series of 57 trauma patients, Hayakawa et al
found that those meeting the criteria for early DIC also displayed
increased neutrophil elastase concentrations and neutrophil elastase-
specific fibrin degradation products in addition to markers of
plasmin activation and tPA release on day 1 of treatment.30 In
addition to direct cleavage of fibrin and fibrinogen, neutrophil
elastase can also degrade and inactivate PAI-1,31 so it may act
similarly to the aPC system by altering PAI-1 availability during
traumatic shock. Obviously, these data raise more questions than
answers and further specific study of the mechanisms involved in
hyperfibrinolysis during trauma are needed to reach definitive
conclusions.
Combining injury and shock to produce TIC
Observational clinical data have demonstrated that TIC is most
common in severely injured trauma patients who are subjected to a
high degree of both anatomical tissue injury and hypoperfusion
from hemorrhagic shock. A multicenter retrospective study of over
3646 trauma patients confirmed that the severity of TIC is strongly
associated with combined severe injury and shock.32 A synergistic
effect of materials released from tissue injury with inflammation
and anticoagulant factors induced by endothelial injury and tissue
hypoxia likely mediate this relationship to produce TIC.
There is evidence that circulating intracellular contents such as
histones, known to be released from injured tissue, are associated
with TIC. Kutcher et al examined plasma histone concentration in
132 trauma patients on hospital arrival, finding a high degree of
circulating histone burden in patients with higher anatomical injury
severity.33 Increased histone concentration was present in patients
with abnormal coagulation tests, increased markers of fibrinolysis,
and elevated aPC. Rapid measurement of extracellular DNA levels
in the plasma of trauma patients also revealed a significant elevation
within 20 minutes of injury.34 In a small study of 37 multiple trauma
patients, patterns of elevated histones and extracellular DNA
derived from activated neutrophils followed leukocyte counts, IL-6
levels, and myeloperoxidase levels and were associated with
subsequent sepsis, multiple organ failure, and death.35 These early
investigations suggest that circulating material from direct tissue
trauma and leukocyte activation may be primary candidates to
explain the critical role of anatomical injury severity in the
development of TIC.
Neurohormonal and endothelial activation in response to acute
blood loss may also be involved in the development of TIC.
Johansson et al examined 75 victims of trauma and found that
neurohormonal response in the form of increased circulating
adrenaline concentration was significantly elevated in nonsurvivors
and was independently associated with mortality, coagulation
dysfunction, and markers of tissue and endothelial damage.36 This
relationship may be mediated by products of endothelial or platelet
activation, such as soluble vascular endothelial growth factor
receptor 1 or soluble CD40 ligand, both of which have been shown
to be predictive of shock, coagulopathy, and mortality in trauma
patients.37,38
Although specific mechanisms of shock-induced endothelial activa-
tion and dysfunction have not yet been elucidated, there is emerging
evidence that disruption of the endothelial glycocalyx barrier
(indicated by syndecan-1 release) plays an important role in the
endothelial response to traumatic shock. Haywood-Watson et al
662
found elevated plasma syndecan-1 concentration in severely injured
trauma patients in hemorrhagic shock.39 They also found that 3
proinflammatory cytokines, IFN-␥, IL-1␤, and fractalkine, were
negatively associated with plasma syndecan-1 levels, presumably
by their binding and activation of endothelium. These investigators
then showed that endothelial barrier function was reduced in
association with shedding of syndecan-1 and that this process was
inhibited by application of fresh frozen plasma in vitro. Glycocalyx
shedding and associated loss of endothelial barrier function also
presumably promotes leukocyte recruitment and activation, libera-
tion of injurious reactive oxygen species, and endothelial cell
damage, as demonstrated by the damaging effect of incubating
leukocytes captured from trauma patients on endothelial progenitor
cells in vitro.40
Summary
Clearly, TIC arises from a complex interplay among coagulation,
inflammation, and cellular dysfunction (platelets, leukocytes, endo-
thelium). Recent evidence points toward several interconnected
mechanisms, including anticoagulation by the thrombin-thrombo-
modulin protein C system, platelet dysfunction, and hyperfibrinoly-
sis. New evidence regarding the prominent role of inflammation and
endothelial activation/dysfunction as orchestrators of TIC continues
to add to our understanding of this important and complex
pathology. Although our understanding of this disease has improved
immensely in recent years, there remain many questions yet to be
answered.
Disclosures
Conflict-of-interest disclosure: The author is on the board of
directors or an advisory committee for Stasys Medical Corporation;
has received research funding from the National Institutes of Health,
the Department of Defense, the Wallace H. Coulter Foundation, and
the Washington State Life Sciences Discovery Fund; has consulted
for Stasys Medical Corporation; holds patents with or receives
royalties from Stasys Medical Corporation; and has equity owner-
ship in Stasys Medical Corporation. Off-label drug use: None
disclosed.
Correspondence
Nathan J. White, Harborview Medical Center, Emergency Dept,
Box 359702, 325 9th Ave, Seattle, WA 98104; Phone: 206-744-
8465; Fax: 206-744-4095; e-mail: whiten4@uw.edu.
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