E NARRATIVE REVIEW ARTICLE

Pathophysiological Response to Trauma-Induced

Coagulopathy: A Comprehensive Review
Patricia Duque, MD, PhD,* Lidia Mora, MD,† Jerrold H. Levy, MD, FAHA, FCCM,‡ and
Herbert Schöchl, MD, PhD§║

Hypercoagulability can occur after severe tissue injury, that is likely related to tissue factor expo-
sure and impaired endothelial release of tissue plasminogen activator (tPA). In contrast, when
shock and hypoperfusion occur, activation of the protein C pathway and endothelial tPA release
induce a shift from a procoagulant to a hypocoagulable and hyperfibrinolytic state with a high
risk of bleeding. Both thrombotic and bleeding phenotypes are associated with increased mor-
tality and are influenced by the extent and severity of tissue injury and degree of hemorrhagic
shock. Response to trauma is a complex, dynamic process in which risk can shift from bleed-
ing to thrombosis depending on the injury pattern, hemostatic treatment, individual responses,
genetic predisposition, and comorbidities. Based on this body of knowledge, we will review and
consider future directions for the management of severely injured trauma patients.  (Anesth
Analg XXX;XXX:00–00)

GLOSSARY
AA = arachidonic acid; ADP = adenosine diphosphate; AIS = Abbreviated Injury Scale; AT I =
antithrombin I; DAMPs = damage-associated molecular patterns; DNA = deoxyribonucleic acid;
HTS = hemorrhagic traumatic shock; ICU = intensive care unit; ISS = injury severity score; LY30 =
percent of clot lysis assessed by TEG at 30 minutes after achievement of maximum clot strength;
ML = maximum lysis; OR = odds ratio; PAI-1 = plasminogen activator inhibitor-1; PAP = plasmin-
antiplasmin; PROPPR trial = Pragmatic Randomized Optimal Platelet and Plasma Ratio trial; ROC =
receiver operating characteristic; ROTEM = rotational thromboelastometry; SHINE = shock-induced
endotheliopathy; TEG = thromboelastography; TIC = trauma-induced coagulopathy; TNF-α = tumor
necrosis factor-alpha; tPA = tissue plasminogen activator; TRAP-6 = thrombin receptor activating
peptide-6; TXA = tranexamic acid; VHAs = viscoelastic hemostatic assays

INTRODUCTION TO COAGULATION BALANCE TIC could be renamed coagulopathic response to trauma

IN SEVERE TRAUMA: A DESCRIPTION OF
PHENOTYPES
Traumatic injuries are the fourth leading cause of mortal-
ity worldwide with approximately 50% of deaths due
to exsanguination within 6 hours following trauma.1
Exsanguination remains a significant cause of preventable
mortality in trauma patients. Trauma-induced coagulopa-
thy (TIC) is present in 25%–35% of severely injured patients
on hospital admission and is associated with a higher inci-
dence of bleeding, transfusion requirement, and multior-
gan failure. Trauma patients with TIC have nearly a 4-fold
higher mortality than those with comparable injury severity
scores (ISS) but no TIC.2
From the *Anesthesiology and Critical Care Department, Gregorio Marañon
Hospital, Madrid, Spain; †Anesthesiology and Critical Care Department, Vall
d´Hebron, Hospital, Barcelona, Spain; ‡Departments of Anesthesiology and
Critical Care, Duke University School of Medicine, Durham, North Carolina;
§Department of Anesthesiology and Intensive Care Medicine, AUVA
Trauma Centre Salzburg, Academic Teaching Hospital of the Paracelsus
Medical University, Salzburg, Austria; and ║Ludwig Boltzmann Institute for
Experimental and Clinical Traumatology, Vienna, Austria.
Accepted for publication September 10, 2019.
Funding: None.
Conflicts of Interest: See Disclosures at the end of the article.
Reprints will not be available from the authors.
Address correspondence to Patricia Duque, MD, PhD, Department of Anes-
thesiology and Intensive Care Medicine, Gregorio Marañon Hospital, Dr Es-
querdo 46, 28007, Madrid, Spain. Address e-mail to patriduque@gmail.com.
Copyright © 2019 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000004478
because derangement of the coagulation system is not a
uniform phenotype. Following traumatic injury, sympa-
thoadrenal activation, upregulated inflammatory/immune
reactions, and coagulopathy lead to endothelial activation
and injury (Figure  1). Proinflammatory mediators acti-
vate the coagulation system and are associated with a rise
in plasma concentrations of chemokines and subsequent
mobilization of granulocytes and monocytes.3 Clot forma-
tion and lysis is critical to maintaining microvasculature
blood flow and tissue perfusion which is altered by severe
traumatic injury.
TIC phenotypes range from prothrombotic profiles to
bleeding disorders. Both thrombotic and bleeding pheno-
types are associated with increased mortality4 and are influ-
enced by the extent and severity of tissue injury and degree
of hemorrhagic shock. As we highlight in this review, blunt
trauma without shock is associated with thrombotic phe-
notypes, while severe trauma with shock is associated
with bleeding phenotypes (Figure  2A, B) and early rever-
sal of shock and preservation of microcirculation are key to
improving survival.
PATHOPHYSIOLOGY
TIC is a downstream effect of multiple mechanisms such
as endothelial damage, impaired thrombin generation,
hypofibrinogenemia, profibrinolytic activation, and plate-
let dysfunction. Together, different pathophysiological
mechanisms appear to produce specific TIC phenotypes,

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 EE Narrative Review Article
Figure 1. Coagulopathic response to trauma. Physiological response to minor trauma based on endothelial activation becomes a pathological
response when facing massive trauma that leads to endothelial damage.
and whether or not these are influenced by genetic precon-
ditioning or injury patterns remains to be elucidated. We
review the individual aspects as follows.
Endothelial Damage
Hypoperfusion and oxygen debt are triggers for endotheli-
opathy. As the endothelium regulates inflammation, coagu-
lation, oxygen delivery, vascular reactivity, and lymphatic
vascular integrity, its restoration is crucial. Endothelial
injury and activation occur after even minor to moderate
trauma that stimulates procoagulant release in response
to inflammatory and neuroendocrine stress. Shock-related
hypoperfusion due to severe or massive injuries causes
extensive endothelial damage and glycocalyx shedding of
heparans and thrombomodulin that provoke endogenous
anticoagulation.5 A consequence of endothelial barrier func-
tion loss is an increase in capillary permeability that results
in edema formation and multiorgan failure. These events
exacerbate shock and sustain sympathoadrenal hyperacti-
vation resulting in a vicious circle.6
Minor trauma in which the endothelium is likely intact
does not cause hemostatic imbalance, while moderate
trauma is associated with a hypercoagulable state designed
to prevent bleeding. Using a calibrated automated throm-
bogram, a thrombotic tendency was recently reported in 40
moderately injured trauma patients (mean ISS = 10.3) and
compared with 20 normal subjects.7 Severe injuries associ-
ated with shock (hemorrhagic traumatic shock [HTS]), by
contrast, cause hypocoagulability, a state that is often fatal
in massive trauma. In addition, hypercoagulability has been
associated with decreased morbidity and mortality com-
pared with early hypocoagulability.8
Almost a decade ago, Johansson and Ostrowski9
hypothesized that progressive hypocoagulability is an
evolutionary response in which the fluid phase (cells and
plasma) becomes progressively more hypocoagulable in
an attempt to counterbalance the more hypercoagulable
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solid phase (endothelium) observed with increasing injury
severity. The ultimate goal is to induce local hemostasis
and preserve oxygen delivery to the tissues to maintain
microcirculatory perfusion. The goal of the hypocoagu-
lable fluid phase is to keep the microvessels open in an
increasingly prothrombotic endothelium. Higher plasma
viscosity was recently associated with worsened micro-
circulatory flow dynamics after traumatic hemorrhagic
shock.10,11 This evolutionary hypothesis implies a direct
relationship between hemostatic derangement and sym-
pathetic activation secondary to shock, which are both
regulated by the degree of endothelial damage that occurs
with increasing injury severity. In 2017, Johansson et al12
introduced the term shock-induced endotheliopathy
(SHINE) to describe a unifying mechanism in which high
circulating catecholamine levels, secondary to shock of
whatever origin, are associated with endotheliopathy and
poor outcome. The theory is supported by various clinical
and experimental studies. Xu et al,13 using an experimental
model of acute traumatic coagulopathy in rats with chemi-
cal sympathectomy, found that sympathetic denervation
was associated with less inflammatory response, less
endothelial damage, and less fibrinolysis. In this study,
plasma levels of catecholamines, syndecan-1 (a marker of
glycocalyx shedding), interleukin-6, tissue plasminogen
activator (tPA), and tumor necrosis factor-alpha (TNF-α)
were all inhibited by sympathectomy. Hofmann et al,14 in
turn, using a rat model of hemorrhagic shock evaluating
volume-controlled versus laboratory-guided manage-
ment, demonstrated an independent association between
base deficit and both endothelial damage and sympatho-
adrenal activation. Endothelial damage manifests during
hemorrhagic shock regardless of resuscitation or reperfu-
sion. The authors concluded that reproducible endotheli-
opathy requires a certain degree of shock and might occur
without reperfusion.
ANESTHESIA & ANALGESIA
 Hemostatic Response to Trauma

Figure 2. Coagulopathic response to trauma. Novel concepts. A, Coagulopathic response to trauma with associated shock: bleeding
phenotype. Shock and hypoperfusion in patients with severe trauma can induce hypocoagulability and hyperfibrinolysis that might lead
to life-threatening bleeding. B, Coagulopathic response to trauma without associated shock: thrombotic phenotype. Severe tissue injury
is shortly followed by a hypercoagulable state probably related to tissue factor exposure and impaired endothelial release of tissue
plasminogen activator.

In a prospective observational study of trauma patients,
Johansson et al15 had previously observed that syndecan-1
levels were associated with the severity of shock, inflamma-
tion, and coagulopathy, indicating a relationship between
shock and endothelial damage. Moreover, patients with
higher circulating syndecan-1 levels had higher mortal-
ity than would be expected based on their ISS. Thus, the
main determinants for poor outcome were the degree of
shock and endothelial damage, not the severity of tissue
injury. Their results have been replicated in isolated trau-
matic brain injury. Di Battista et al16 reported that increased
levels of markers of endothelial damage, inflammation,
and coagulopathy on admission and at 24 hours postin-
jury in patients with traumatic brain injury were associated
with poor 6-month outcome measured by the Extended
Glasgow Outcome Scale. These biomarkers correlated with
neuroadrenergic response assessed by circulating catechol-
amines. Ostrowski et al17 recently reported an association
between both sympathoadrenal activation and endothe-
lial damage and hypocoagulability, hyperfibrinolysis, and
higher mortality in a cohort of 404 trauma patients (median
ISS = 17; range, 9–26; 73% blunt trauma).

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 EE Narrative Review Article
To summarize, the severity of shock is an important
determinant for endotheliopathy hypocoagulability, hyper-
fibrinolysis, and inflammation.
Thrombin Generation Disorder
In normal hemostasis, thrombin is generated primarily at the
site of tissue injury and is modulated by circulating antico-
agulants (eg, antithrombin, protein C, protein S, tissue factor
pathway inhibitor) that prevent systemic thrombin genera-
tion and as a result, thrombosis. However, procoagulant fac-
tors are released into the circulation shortly after severe tissue
injury, and any additional impairment of endogenous antico-
agulant activity may pose a risk of thrombosis. As a result,
thrombin generation may extend beyond the site of injury,18
and penetrating trauma could be associated with lower levels
of procoagulant activity compared to blunt trauma due to a
decreased extent of tissue injury.
There are many reports of increased thrombin genera-
tion shortly after trauma. Schreiber et al19 found hyperco-
agulability to be more prevalent in the first 24 hours after
injury and in female patients. Dunbar and Chandler20
reported excessive thrombin generation due to circulat-
ing procoagulant activity and a loss of coagulation inhibi-
tors in trauma patients (81% blunt trauma) compared
with healthy subjects (n = 25). Trauma patients had high
thrombin generation and increased native and tissue fac-
tor–stimulated thrombin generation compared with the
control group. This hypercoagulable state might be related
to tissue factor exposure, with circulating procoagulants
playing an additional role. Microparticles (derived from
activated cells such as platelets, endothelial cells, leuko-
cytes, and erythrocytes), endothelial-derived extracellu-
lar vesicles,21 and damage-associated molecular patterns
(DAMPs), such as extracellular deoxyribonucleic acid
(DNA) and DNA-binding proteins released by organs fol-
lowing tissue injury, are important factors in procoagulant
responses.18
Hypercoagulability usually occurs usually within 48
hours of blunt trauma,22 and it is associated with increased
mortality.23 As a result, increasing thrombin generation
should no longer be considered a routine goal in trauma
patients.24 Accordingly, care must be taken when planning
procoagulant interventions in this setting.25
Hypoperfusion in shock induces activation of the pro-
tein C pathway, leading to a hypocoagulable state and
induces endothelial expression of thrombomodulin.26
Thrombomodulin, in turn, forms a complex with thrombin
that releases activated protein C to modulate thrombin gen-
eration. Increased levels of soluble thrombomodulin and
decreased levels of protein C have been associated with
increased mortality (odds ratio [OR] =2.5 and 6.2, respec-
tively).27 This finding is further supported by reports that
hypocoagulability does not occur in the absence of hypo-
perfusion, regardless of tissue injury severity.28 Brohi et al27
proposed that hypocoagulability in the context of hypo-
perfusion occurs to protect microvessels from thrombosis
in states of low flow and to maintain tissue perfusion. This
concept is consistent with the previous reports9 and is sup-
ported by experimental data showing that elimination of
protein C in hemorrhagic shock in mice is lethal due to dif-
fuse microvascular thrombosis.29
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Further, activated protein C functions as an anticoagu-
lant by inhibiting FVa and FVIIIa, leading to a hypocoagu-
lable state and consumes plasminogen activator inhibitor-1
(PAI-1). However, because PAI-1 circulates at levels 10
times higher than activated protein C,30,31 it is question-
able whether this interaction results in PAI-1 depletion and
accelerates fibrinolysis.32 Hyperfibrinolysis secondary to
endothelial tPA overexpression in response to hypoperfu-
sion seems more plausible as an underlying mechanism.
Subsequent protein C depletion may lead to late hyper-
coagulability. Moreover, protein C has important anti-
inflammatory and anticoagulant properties and low levels
have been reported in septic patients.33 Protein C depletion
may occur and decreased levels of protein C could explain,
at least in part, the increased risk of late thrombosis and sub-
sequent organ failure described in severe trauma patients
who were initially in a hypocoagulable state due to previ-
ous protein C activation.34
To summarize, severe tissue injury is followed by a
hypercoagulable state that is likely related to tissue factor
exposure and the release of procoagulants into the systemic
circulation, posing severe blunt trauma patients at risk for
systemic thrombosis. However, when shock and hypoper-
fusion occur, activation of the protein C pathway and endo-
thelial release of tPA result in a shift to a hypocoagulable
and hyperfibrinolytic state.
Hypofibrinogenemia
Fibrinogen plays a critical role in maintaining hemostasis as
it is converted to fibrin to form a stable clot with activated
platelets and further stabilized by FXIII-mediated fibrin
cross-linking.35 Fibrinogen is the first coagulation factor to
reach critically low levels in traumatic hemorrhagic shock.
Low fibrinogen levels in trauma are related to multiple fac-
tors, including blood loss, consumption of clotting factors
and platelets, decreased fibrinogen synthesis due to hypo-
thermia, increased fibrinogen breakdown due to acidemia,
dilution by fluids, and fibrinolysis. Hypofibrinogenemia is
an independent risk factor for increased mortality in trauma
patients requiring massive transfusion.36,37
Low circulating fibrinogen levels are associated with
poor outcomes.38 In a cohort of 1133 severely injured
patients, 19.2% had hypofibrinogenemia (as defined by
fibrinogen concentration <2 g/L), with higher mortality
in those with fibrinogen levels >2.29 g/L.39 Low fibrino-
gen is also strongly associated with shock severity.40 In this
study, 81% of the patients with a base excess of less than
−6 mmol/L had low fibrinogen levels (<200 mg/dL) while
63% had critical levels (<150 mg/dL). The respective per-
centages of patients with a base excess of less than −10
mmol/L were 89% and 78%. In a study of critically injured
patients, Kornblith et al41 also reported low fibrinogen lev-
els to be associated with higher mortality as determined by
clot strength measured by thromboelastography (TEG). For
each 1% increase in clot strength contribution, there was
a 12.9% decrease in the risk of mortality at discharge (P <
.001). Fibrinogen levels and its contribution to clot strength
are important for maintaining hemostatic stability and pre-
venting further bleeding.42,43
Fibrinogen is also an important biomarker of acute inflam-
mation. In 10 major trauma patients without coagulopathy
ANESTHESIA & ANALGESIA
 Hemostatic Response to Trauma
on admission, increased fibrinogen and reduced percentage
clot lysis was found compared with healthy volunteers.44
Thus, in the absence of coagulopathy, spontaneous hyperfi-
brinogenemia may indicate worsening inflammation44 and
increased thrombosis risk.
In summary, fibrinogen is a key element in primary and
secondary hemostasis. Low fibrinogen is strongly associ-
ated with poor outcome in major trauma.
Fibrinolytic Dysfunction: Hyperfibrinolysis and
Fibrinolytic Shutdown
Hyperfibrinolysis is associated with increased mortality.45
Using rotational thromboelastometry (ROTEM), 3 patterns
of hyperfibrinolysis were defined in severely injured patients
(mean ISS = 47). The patterns were fulminant (breakdown
of clot within 30 minutes), intermediate (30–60 minutes),
and late (>60 minutes). They were respectively associated
with mortality rates of 100%, 91%, and 73%. Overall mortal-
ity exceeded that predicted by ISS scores (which reflect the
severity of tissue injury). With TEG, Cotton et al46 demon-
strated a 2-fold increase in mortality for percent of clot lysis
assessed by TEG at 30 minutes (LY30) >3%.
Severe shock and major tissue trauma are significant
factors for hyperfibrinolysis. The underlying mechanisms
of trauma-associated hyperfibrinolysis, however, are still
poorly understood. Until recently, hyperfibrinolysis in
trauma was thought to be secondary to PAI-1 inhibition
driven by protein C activation,26 although as discussed ear-
lier, this theory has been questioned.32 In 2016, Chapman et
al47 reported that trauma-associated hyperfibrinolysis was a
result of plasma tPA elevation. PAI-1, the physiologic inhibi-
tor, has a high affinity for tPA, and tPA would be expected to
be rapidly cleared. This mechanism of inhibition, however,
is overcome by massive elevated tPA levels in traumatic
hemorrhagic shock. Thus, excessive tPA release is necessary
for overt hyperfibrinolysis to occur.
In a prospective study including 180 trauma patients
with a mean ISS = 29, mean base deficit −9 mEq/L, and 79%
blunt trauma, Moore et al48 characterized patients based
on their systemic fibrinolysis reported as: hyperfibrinoly-
sis (LY30 > 3%, n = 33), physiologic lysis (LY30 0.8%–3%,
n = 32), and fibrinolysis shutdown (LY30 < 0.8%, n = 115).
There were no differences in ISS or injury patterns among
the groups. The majority of patients (64%) had fibrinolytic
shutdown, and mortality was highest (44%) in the hyper-
fibrinolysis group primarily related to exsanguination.
Patients with fibrinolytic shutdown had the second-highest
mortality rate (17%), and death occurred later primarily due
to multiorgan dysfunction thought to be related to fibrin
deposition in the microcirculation. The mortality rate in the
physiological fibrinolysis group was 3%. The same team
demonstrated fibrinolytic shutdown in a larger population
of severe trauma patients (n = 2540, median ISS = 25, 83%
blunt injury) and again it was associated with increased mor-
tality due to septic/thrombotic/organ failure.49 Fibrinolytic
shutdown has also been identified as a prognostic marker of
poor outcome in pediatric trauma patients.50
Gall et al51 described the same 3 fibrinolysis phenotypes
in 914 patients based on maximum lysis (ML) rates assessed
by ROTEM. Hyperfibrinolysis was defined as ML > 15%,
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physiologic fibrinolysis as ML 5%–15%, and fibrinolytic
shutdown as ML < 5%. The authors also found mortality
to follow a U-shaped distribution. Taylor et al52 used the
same stratification criteria as Moore et al48 in a subpopula-
tion of severely injured trauma patients with major bleeding
(n = 547) from the Pragmatic Randomized Optimal Platelet
and Plasma Ratio (PROPPR) trial. Patients with hyperfibri-
nolysis experienced the highest 24-hour (35%) and 30-day
(54%) mortality and had lower Glasgow Coma Scale scores
on admission and greater laboratory evidence of shock.
No significant differences were observed between patients
with fibrinolytic shutdown and physiologic fibrinolysis for
24-hour (9% vs 5%) or 30-day mortality (17% vs 13%).
Meizoso et al22 further divided fibrinolytic shutdown
(43% from a sample of 181 severely injured trauma patients)
into persistent shutdown (continuing for 1 week after
admission) and transient shutdown (resolving within a
week). Those with persistent shutdown had a 4-fold higher
mortality (21% vs 5%; P < .05) and 8.5-fold higher risk of
late mortality independently of age, sex, ISS, admission
hemodynamics, or mechanism of injury. In this study, plate-
let transfusion during the first week was associated with a
higher risk of persistent fibrinolytic shutdown, with each
additional unit of platelets increasing the risk 2.8-fold.
Platelets contain a large quantity of PAI-1 and α2 antiplas-
min. In a clinical study, Vulliamy et al53 demonstrated that
platelet transfusion decreases fibrinolysis due to the release
of PAI-1.54
Platelet transfusion has also shown an adverse effect in
nontrauma settings.55 Among severely injured, bleeding
patients, while early administration of plasma, platelets,
and red blood cells in a 1:1:1 ratio compared with a 1:1:2
ratio was not associated with reduced mortality at 24 hours
or at 30 days,56 early platelet administration itself did result
in improved hemostasis and survival.57 Using a viscoelas-
tic hemostatic assay (VHA)–guided transfusion protocol,
Gonzalez et al58 demonstrated better survival with less
early platelet and plasma transfusion. With the current evi-
dence, early goal-directed transfusion protocols avoiding
late platelet transfusion is likely a good strategy to follow in
bleeding shocked trauma patients.
Hyperfibrinolysis is attributed to the release of tPA.47
To understand fibrinolytic shutdown mechanisms, Moore
et al59 measured fibrinolysis sensitivity to exogenous
tPA and demonstrated that shutdown can occur without
upregulation of fibrinolysis inhibitors such as PAI-1 and
α2-antiplasmin. They also suggested a possible role for
impaired tPA generation after injury. These results again
suggest that endothelial dysfunction is the mechanism of
impaired fibrinolysis in trauma, where it can cause either
extensive tPA release in shock, resulting in hyperfibrinolysis,
or impaired tPA release, resulting in fibrinolytic shutdown.
In summary, fibrinolytic shutdown after trauma is a
common phenotype and is associated with a higher mor-
tality than physiologic fibrinolysis.59,60 An experimental
model of isolated blast injury showed that extensive tis-
sue injury was associated with an early hypercoagulable
state.61 Hyperfibrinolysis is a less common phenotype that
occurs in the context of shock and hypoperfusion62 and
is associated with the highest mortality, primarily due to
 EE Narrative Review Article
exsanguination.48,49,51 Tissue hypoxia and ischemia of any
origin trigger tPA release from endothelial Weibel-Palade
bodies as an important cause of fibrinolysis.63 Increased
fibrinolysis has been found to predict poor outcome in car-
diac arrest with presumed cardiac etiology64 in a nontrauma
setting.
Value of VHA to Detect Different Phenotypes of
Lysis
Given these fibrinolytic phenotypes, several authors suggest
that tranexamic acid (TXA) should only be administered in
patients with severe shock.47,65–67 Empirical administration of
TXA in the prehospital setting with withholding of further
doses until confirmation of fibrinolysis by VHAs has been
proposed as a strategy for avoiding administration of TXA
to patients with possible fibrinolytic shutdown. However,
VHAs are only capable of diagnosing the severest forms of
hyperfibrinolysis (2.5%–7% of all trauma patients),68 and
occult hyperfibrinolysis may be more common than initially
thought. Raza et al69 confirmed this in severely injured trauma
patients in which 57% of patients had evidence of fibrinolytic
activation, measured by plasmin-antiplasmin (PAP) complex
levels, that was not detected by a VHA. These patients had
higher morbidity and mortality rates than those without
fibrinolytic activation. Gall et al51 reported that high D-dimer
levels were associated with poor outcomes independently
of the fibrinolysis phenotype detected by VHA. In addition,
they found levels of S100A10 (a plasminogen receptor) to be
associated with D-dimer levels, injury severity, traumatic
brain injury, and increased mortality, even in patients with
low ML, that is, patients with hyperfibrinolysis not detected
by a VHA. S100A10 is widely expressed in body tissues,
especially in the brain, and is upregulated when hypoperfu-
sion occurs. The authors concluded that a subpopulation of
severely injured patients in shock could present with hyper-
fibrinolysis undetectable by VHA.
Furthermore, VHA does not always detect hyperfibri-
nolysis with great sensitivity nor fibrinolytic shutdown.
Recently, PAP complex levels have been reported as a spe-
cific marker of fibrinolytic activity, capable of identifying
fibrinolytic shutdown and a hypercoagulability tendency
while low TEG Ly30 was associated with shock and mod-
erated fibrinolysis.70 VHA, as a global coagulation assay,
likely reflects a mechanistic combination of fibrinolysis,
fibrinogen, and platelet dysfunction and low clot lysis index
should no longer be considered a reliable marker of fibri-
nolytic shutdown. Unfortunately, PAP complex levels are
not currently available in clinical practice. However, indica-
tions for TXA administration based on VHAs may need to
be reevaluated.
In summary, severe trauma and hypoperfusion acti-
vate profibrinolytic pathways. Upregulated lysis is associ-
ated with poor outcome. Fibrinolytic shutdown detected
by VHAs should be assumed to represent a compensated
coagulopathy, which results in higher mortality than physi-
ologic lysis.
Platelet Dysfunction
Although activated platelets are essential for forming a sta-
ble clot, platelet dysfunction and its implications for trauma
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patient outcomes have only been recently characterized.
Wohlauer et al71 reported that platelet dysfunction was pres-
ent in patients with severe blunt trauma (mean ISS = 19) on
hospital admission. They noted a substantial inhibition of
platelet reactivity to adenosine diphosphate (ADP) (86.1%
in trauma patients vs 4.2% in healthy volunteers) and less
dramatic but significant, inhibition of reactivity to arachi-
donic acid (AA) (44.9% vs 0.5%). This platelet dysfunc-
tion, measured by TEG PlateletMapping, existed despite a
normal platelet count (median 232 ± 13.2 × 103/µL). ADP-
mediated platelet function was also associated with the
degree of shock and tissue injury.
Li et al,72 using microfluid technology, also observed
platelet dysfunction in a subpopulation of trauma patients
(14/20) on arrival at a level 1 trauma center. The dysfunc-
tion was characterized by delayed platelet recruitment to
collagen and attenuated secondary aggregation. All of the
patients had a normal platelet count.
Using impedance aggregometry, Kutcher et al73 pro-
spectively studied platelet function in 91 trauma patients
(mean ISS = 23). Platelet dysfunction was observed in 45.5%
on hospital arrival and in 91.1% during intensive care unit
(ICU) admission. Platelet count on admission was normal
(274.4 ± 85.4 × 103/μL) and none of the patients had a count
below 140 × 103/μL. Patients with early dysfunction had
nearly 10-fold higher 24-hour mortality (20% vs 2.1%).
Hypoperfusion as measured by base deficit was found to be
an independent predictor of admission platelet hypofunc-
tion. Decreased platelet responses to all agonists (AA, ADP,
thrombin receptor activating peptide-6 [TRAP] and colla-
gen) were present. Platelet response to TRAP and collagen
recovered within 24–48 hours of trauma, but remained low
up to day 4 in the case of AA and ADP. Based on receiver
operating characteristic (ROC) curves, AA (area under the
curve [AUC] 0.769) and collagen (AUC 0.717) responses
were robust predictors of in-hospital mortality. An associa-
tion between platelet dysfunction and higher mortality has
been repeatedly reported.74,75
Similarly to the protein C pathway, tissue injury and
hypoperfusion have been suggested to cause platelet hyper-
activation with a massive release of granules due to wide-
spread ADP expression, rendering platelets unresponsive to
subsequent stimulation; a phenomenon known as platelet
exhaustion characterized as circulating platelets without
granules.73,74,76 Other investigators, however, have postu-
lated that ADP pathway impairment may be due to reduced
platelet granule release rather than platelet exhaustion.77
Impaired platelet responsiveness might also be explained
by the concomitant inflammatory responses that occur fol-
lowing severe trauma, as activated platelets can be cap-
tured and immobilized by monocytes, resulting in platelet
dysfunction.78
Brain injury is a predictor of platelet dysfunction on
admission.73,75,79,80 Ramsey et al,76 using light transmission
aggregometry with ADP and TRAP as agonists, reported
a stepwise association between head injury severity and
platelet dysfunction. They reported an inversely propor-
tional association between TRAP-mediated platelet aggre-
gation and head and neck Abbreviated Injury Scale (AIS)
scores and a positive correlation between TRAP- and ADP-
mediated aggregation and Glasgow Coma Scale scores.
ANESTHESIA & ANALGESIA
 Hemostatic Response to Trauma

In summary, recent data suggest that early platelet dys-
function is prevalent after severe trauma and associated
with increased mortality.
CLINICAL IMPLICATIONS
With growing understanding of the complex nature of TIC,
it can be inferred that a patient presenting with severe tis-
sue injury without shock is at high risk of perioperative
thrombosis and that management should focus on prevent-
ing thrombosis, even in cases of slight bleeding without
hemodynamic decompensation. A severely injured trauma
patient with shock and hypoperfusion, by contrast, is at
risk of hypocoagulability and hyperfibrinolysis, which are
associated with high mortality and require urgent treatment
with early hemostatic goal-directed resuscitation. The abil-
ity of patients to compensate varies considerably in situ-
ations of shock and targeted therapy based on shock end
points, such as base deficit changes, could mirror specific
endothelial damage.14
Following trauma, the normal progression from bleed-
ing to thrombosis changes over time and recovery. From
the evidence presented, different patient phenotypes may
be determined by the presence or absence of shock and
hypoperfusion on admission, but clinical evolution changes
based on the injury pattern. For example, blunt trauma
might favor thrombosis due to the large extent of tissue
injury18 while traumatic brain injury is reported to be asso-
ciated with delayed clot formation.81 Replacement with
hypertonic saline may predispose to hypocoagulation82
while over resuscitation with plasma might be associated
with sustained fibrinolytic shutdown as noted in pediatric
trauma patients.83 Platelet transfusions may favor fibrino-
lytic shutdown and stored red blood cells transfusion may
have a negative impact on microcirculation rheology by
increasing red blood cell endothelial adherence.84 Individual
factors such as response to treatment, sex (severely injured
females seem to be more hypercoagulable than males85 as
well as pediatric population50), genetic predisposition, and
comorbidities86 (Figure  3) also influence the coagulation
profile.
In the future, treatment of severely injured trauma
patients may be based on phenotypic presentation. We
suggest that specific treatment strategies for TIC, like TXA
administration, should be individualized based on shock
end points such as base deficit, as shock and/or tissue injury
are factors that influence either a thrombotic or a bleeding
phenotype. Clinicians should consider early goal-directed
therapy based on diagnostic testing, including viscoelastic
assays. They should also be aware of the multiple factors
that may alter trauma phenotypes, including preexisting
antiplatelet or anticoagulant therapy, sex, injury pattern,
and hemostatic resuscitation.
CONCLUSIONS
Based on current evidence, tissue injury triggers an adaptive
response characterized by increased thrombin generation,
acute inflammation, fibrinolytic shutdown, and platelet
activation all designed to increase clot formation and pre-
vent exsanguination. In patients with severe or massive
tissue injury, this response is pathological, overwhelming

Figure 3. Therapeutic approach. Patients presenting with severe tissue injury without shock are at high risk of thrombosis and every effort
should be made to prevent this serious condition. However, shock and hypoperfusion in patients with severe trauma can induce hypocoagu-
lability and hyperfibrinolysis. This state is associated with very high mortality and needs to be treated urgently with early hemostatic goal-
directed resuscitation. Response to trauma is a complex, dynamic process in which risk can shift from bleeding to thrombosis depending on
the injury pattern, treatment administered, individual responses, and comorbidities.

XXX XXX • Volume XXX • Number XXX www.anesthesia-analgesia.org

7
Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
 EE Narrative Review Article
normal physiologic mechanisms, and induces a throm-
botic phenotype associated with increased mortality. Shock
and hypoperfusion induce a state of low flow. To keep the
microcirculation patent and maintain tissue perfusion,
shock-induced sympathoadrenal activation triggers hypo-
coagulability, hyperfibrinolysis, and platelet hyperactiva-
tion, ultimately leading to platelet dysfunction due to the
respective endothelial overexpression of activated protein
C, tPA, and ADP resulting in a bleeding phenotype. When
shock is prolonged, oxygen debt becomes potentially irre-
versible, leading to worsening endotheliopathy and setting
a vicious circle in motion. In between these 2 extremes lies a
series of mixed thrombotic-bleeding phenotypes. E
DISCLOSURES
Name: Patricia Duque, MD, PhD.
Contribution: This author helped with idea and outline, data inter-
pretation, drafting the article, and final approval of the version to
be published, and agrees to be accountable for all aspects of the
work in ensuring that questions related to the accuracy or integrity
of any part of the work are appropriately investigated and resolved.
Conflicts of Interest: None.
Name: Lidia Mora, MD.
Contribution: This author helped with the conception and design
of the work, data interpretation, critical revision and final approval
of the version to be published, and agrees to be accountable for all
aspects of the work in ensuring that questions related to the accu-
racy or integrity of any part of the work are appropriately investi-
gated and resolved.
Conflicts of Interest: None.
Name: Jerrold H. Levy, MD, FAHA, FCCM.
Contribution: This author helped with additional editing and criti-
cal revisions of the article and final approval of the version to be
published, and agrees to be accountable for all aspects of the work
in ensuring that questions related to the accuracy or integrity of any
part of the work are appropriately investigated and resolved.
Conflicts of Interest: J. H. Levy serves on steering committees for
Boehringer Ingelheim, CSL Behring, Instrumentation Labs, and
Octapharma.
Name: Herbert Schöchl, MD, PhD.
Contribution: This author helped with the conception and design
of the work, data interpretation, critical revision of the article
and final approval of the version to be published, and agrees to
be accountable for all aspects of the work in ensuring that ques-
tions related to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.
Conflicts of Interest: H. Schöchl has received honoraria for partici-
pation in advisory board meetings for Bayer Healthcare, Boehringer
Ingelheim and Tem International, and has received study grants
from CSL Behring.
This manuscript was handled by: Richard P. Dutton, MD.
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