Trends in Anaesthesia and Critical Care 5 (2015) 23e27

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Trends in Anaesthesia and Critical Care

journal homepage: www.elsevier.com/locate/tacc

REVIEW

Coagulation in trauma
Oliver M. Theusinger a, *, Werner Baulig b, Jerrold H. Levy c
a

Institute of Anesthesiology, University and University Hospital of Zurich, Zurich, Switzerland

Department of Anesthesia and Intensive Care, Klinik Im Park, Zurich, Switzerland
c
Department of Anesthesiology and Intensive Care, Duke University School of Medicine, Durham, NC, USA
b

s u m m a r y
Keywords:
Trauma induced coagulopathy
Hyperbrinolysis
Massive transfusion
Protein C
Coagulopathy

Uncontrollable bleeding is the major cause of possible preventable death after traumatic injury. Up to one
third of patients admitted to the emergency room will develop the so-called trauma induced coagulopathy (TIC) which has been shown to be associated with massive transfusions, increased morbidity and
mortality. Several recent studies contribute to our present understanding of the pathophysiological
mechanisms of TIC.
In the literature the lethal triad of trauma (hypothermia, acidosis, and coagulopathy), dilution and
hypoperfusion including the role of the protein C pathway activation are well described. Recent studies
offer evidence for the mechanisms which induce TIC that include platelet dysfunction, endothelial
activation/anticoagulation, hypobrinogenaemia and hyperbrinolysis which develop very early after
traumatic injury. One of the major limitations of the current literature regarding TIC is that most data
presented are associations from observational databases, and only a few prospective observational
studies exist and causative aspects are only shown by haemorrhagic shock in animal models.
TIC represents a complex interplay between coagulation, inammation, and cellular dysfunction
(platelets, leukocytes, and endothelium). Mechanisms include anticoagulation by the thrombinthrombomodulin protein C system, platelet dysfunction and hyperbrinolysis. The understanding of
TIC has improved immensely in recent years but many questions remain that need to be answered by
other prospective studies and animal models to further dene this complex syndrome.
2014 Elsevier Ltd. All rights reserved.

1. Introduction
Bleeding following major trauma leading to haemorrhagic shock
remains one of the major causes of death. The simplistic theory of
the so-called lethal triad including hypothermia, dilution and
acidosis does not explain all the pathophysiological mechanisms
which lead to acute hypocoagulability and early hypercoagulability
following major trauma. The term trauma induced coagulopathy
(TIC) was introduced to describe a process that impairs blood
coagulation and increases blood loss by a possible dysregulation of
the intrinsic coagulation system in trauma patients. The aetiology
and mechanism of TIC is complex and has not been fully claried. In
addition, Acute Traumatic Coagulopathy (ATC) is the initial process
that leads to TIC. Known factors for ATC are tissue hypoperfusion
due to blood loss, major tissue injury, inammation, cellular

* Corresponding author. Institute of Anesthesiology, University Hospital and

mistrasse 100, CH-8091 Zurich, Switzerland. Tel.: 41 44
University of Zurich, Ra
255 27 10; fax: 41 44 255 44 09.
E-mail address: oliver@theusinger.de (O.M. Theusinger).
http://dx.doi.org/10.1016/j.tacc.2014.10.006
2210-8440/ 2014 Elsevier Ltd. All rights reserved.

dysfunction (including platelet dysfunction), hyperbrinolysis,

brinogen consumption and anticoagulation. All these aspects are
associated with increased transfusion needs, morbidity, length of
stay, and negative outcomes. The purpose of this review is to
elucidate the different aspects which lead to TIC including animal
models that may help better dene the different mechanisms
involved. We will also briey review different uids used during
resuscitation, hypothermia, and acidosis that are other critical
components of this pathologic process.
2. Acute traumatic coagulopathy and the clinical implication
Acute traumatic coagulopathy (ATC) develops within minutes
following trauma. In a French study by Floccard et al.1 45 trauma
patients had blood samples taken at the scene of their accident and
in the emergency room (ER). The laboratory and coagulation test
performed showed that in more than 50% of the patients an
abnormal coagulation status could be found within 25 min after
injury. Carrol et al.2 measured TEGs (thromboelastography) in 160
patients where blood was also taken at the scene and could also
show that TEGs were partially abnormal. These two studies indicate

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O.M. Theusinger et al. / Trends in Anaesthesia and Critical Care 5 (2015) 23e27

that patients will have ATC when arriving in the ER. Severe tissue
injury combined with hypoperfusion could be the factors implicated in ATC. In a study including 5000 patients admitted to trauma
centres Frith et al.3 reported that neither variable alone independent of their severity was associated with clinical coagulopathy.
Increased bleeding relevant prolongations of the prothrombin time
were found in combination of a high ISS and acidosis as dened as a
base deciency. A study of 450 patients injured in combat by explosions or gunshots were similar regarding their demographic
data (age, GCS, ISS, body temperature, haemoglobin levels, SBP and
mortality).4 Patients implicated in explosions presented more
tachycardia, had worse base deciencies, higher INRs and a higher
incidence of coagulopathies compared to the gunshot patients. This
suggests that shock is the main driver for ATC but tissue injury is
necessary in addition. Other factors leading to TIC are hypothermia,
acidosis, and haemodilution which all develop over time due to
injury as consequences of bleeding, hypoperfusion, and resuscitation with products that haemodilute patients contribute to the
hypocoaguable state. These aspects are discussed later in this
article. To date, all studies regarding ATC have conrmed that this
condition is associated with higher transfusion needs and also with
a fourfold increase in mortality.5,6 Frith et al.3 reported that there
was a signicant and even dose dependent increase in mortality
and blood product use in trauma patients for those arriving in the
ER with a PT higher than 1.2.3 A large outcome study with 8724
polytrauma patients performed by Maegele et al. showed that 1/3
of the patients with ATC had multi-organ failure during their hospitalization compared to 10% in the control group.7 Mechanical
ventilation, length of ICU and hospital stay were also longer in
patients with ATC compared to the control group with normal
coagulation. ATC leads to increased blood loss in these patients and
thus early normalization of coagulation should be achieved to
improve patients' outcome.
3. Endothelial dysfunction
Under normal conditions the endothelial cells produce or
activate anticoagulants which down-regulate thrombin generation, and include thrombomodulin, endothelial protein C, heparin
sulfate and chondroitin. Recent ndings have shown that high
plasma levels of sydecan-1 are present after trauma.8e10 This
proteoglycan is part of the glycocalyx and its liberation into the
circulation could lead to an anticoagulating effect by thrombomodulin inhibition of thrombin and heparin sulfate which increases thrombin inhibition by antithrombin III.11,12 Endogenous
heparinization was shown in 5% of the trauma patients by
comparing kaolin versus heparinase TEG.13 The degree of endogenous heparinization correlates with the levels of sydecan-1
indicating that the cause is the destruction of the endothelial
glycocalyx.13 This nding potentially increases vascular permeability, inammation, and tissue oedema. A study in rats noted
that resuscitation with FFP leads to a restoration of the destroyed
glycocalyx.14 These ndings conrm the results of other
studies10,15 and are used to argue why FFP should be used in
trauma resuscitation. Another study by Sillesen et al.16 describes
an improvement of platelet function, an increase of brinogen
(max level of 2 g/l is possible as FFP does not contain more
brinogen) and endothelial activation. Even in a swine model with
haemorrhagic shock where FFP versus saline was used to
compensate a 40% blood loss, platelet aggregation measured by
APD and arachidonic acid as well as TEG results were better in the
FFP group. Furthermore a reduction of the endothelial activation
as well as reduced platelet dysfunction was suggested by the authors.16 What all these studies do not take into consideration is the
fact that FFP itself is associated with adverse events that include

increased infection rates, higher morbidity and mortality, prolonged length of stay in hospital, TRALI and TACO etc. Although
arguments in favour of FFP on a cellular basis are interesting but
need to be considered in the context of using blood products and
their adverse effects, and ~70% of patients receiving FFP will
develop adverse effects and complications.
4. Activated protein C
The function of activated protein C (APC) includes anticoagulation and cytoprotection, and is involved in the early phase
of injury leading to TIC. Its generation is linked to thrombin formation and thrombomodulin complex which activate protein C via
an endothelial protein C receptor. The APC seems to stimulate the
antiapoptoic and anti-inammatory pathway including a reduction
in the endothelial permeability. By inactivating factors V and VIII,
APC inhibits thrombin generation and has a potential brinolytic
effect as it inhibits plasminogen activator inhibitor (PAI-1). Due to
PAI-1 inhibition, tPA and uPA can continue to promote the generation of plasmin and brinolysis. As mentioned earlier, high levels
of APC by admission with coagulopathy is an indicator for increased
transfusion needs and mortality.17 In a mouse model the inhibition
of the anticoagulant function of APC protected against TIC whereas
the inhibition of the cytoprotective and anticoagulant function lead
to death.18 The reduction of coagulation factors activity (FII, FVII,
FIX, FX, FXI) has been proven to be dependent on the degree of
shock.19 The only factor independent of the level of shock regarding
its loss of activity was factor V. The anticoagulant effect of APC is
important regarding TIC but is probably not the only mechanism of
procoagulant inactivation.
5. Oxidative modications
A new theory on the inactivation of coagulation factors was
published by Burney et al.20 They provided evidence that a modication in the brin activated C-subdomain is needed for the lateral
aggregation of brin during its polymerization. This results in
inadequate polymerization and thus in a reduced clot strength.20
This modication is made by oxidative damage which occurs via
oxidative stress induced by haemorrhagic shock. Cells releasing
reactive oxygen species are platelets, leukocytes, and endothelial
cells after injury, inammatory signal and hypoperfusion as in
shock.21,22 The release of oxygen free radicals seems to have a major
inuence on coagulation as PAI-1, protein C and thrombomodulin
are to be inuences by oxidation.23e26 This phenomenon might
thus also have an important inuence on the process of TIC.
6. Hyperbrinolysis
Hyperbrinolysis is known to be associated with a higher
mortality in trauma patients even though only a small subset will
present with systemic activation. Its diagnosis is difcult as there
are no clear laboratory tests to identify it quickly and to determine
the degree of brinolysis.27 Viscoelastic tests such as ROTEM and
TEG are the only devices to rapidly and effectively identify this
pathophysiological process28,29 Raza et al.30 showed that hyperbrinolysis was not due to hypothermia or iatrogenic inuences,
and thus should be considered as a distinct problem that must be
identied and treated early as it contributes to TIC. Plasminogen
which is needed for hyperbrinolysis is activated by tPA and uPA
and transformed to plasmin. Plasmin cleaves the cross links of the
brin clot which can be inhibited by PAI-1. PAI-1 inactivates tPA and
uPA.31e33 An excessive increase of tPA without an upregulation of
PAI-1 leads to an imbalance resulting in hyperbrinolysis.34 Activated protein C inhibits PAI-1 and is thus links the protein C system

O.M. Theusinger et al. / Trends in Anaesthesia and Critical Care 5 (2015) 23e27

to hyperbrinolysis in trauma.35 Acidosis enhances hyperbrinolysis by tPA whereas hypothermia seems to blunt it,36 and as
a result acidosis should be reversed as soon as possible. On the
other hand the rapid correction of hypothermia to normothermia
as recommended could potentially lead to an exacerbated hyperbrinolysis. Recently the function of thrombin-activatable brinolysis inhibitor (TAFI) was reported showing that it is activated by
thrombin and down-regulates brinolysis.37 Patients with TIC had
reduced levels of circulating TAFI activity when admitted to the ER.
The TAFI activity is inversely correlated with the number of red
blood cells and FFP units transfused in the rst 24 h.37 This suggests
that low levels of thrombin generation can downstream TAFI activation and inhibit brinolysis. The inuence of hyperbrinolysis on
TIC and the high mortality associated with it raises the question if
research should be focused on molecular mechanisms and optimal
diagnosis to have better tools and therapeutic options. Actually no
standard laboratory test allows diagnosis of hyperbrinolysis,
neither if present or its degree. The only possibility is given by
ROTEM and TEG. Antibrinolytics such as TXA are effective as
proven by the CRASH 2 study but controversy has emerged
regarding inhibiting and potential side effects of TXA in these
settings.38,39
7. Systemic anticoagulation
As mentioned earlier, systemic anticoagulation might be mediated by APC and is an important contributor regarding ATC.18,35 A
prolonged PT and aPTT is associated with reduced or even depleted
protein C and for this reason an implication in ATC seems evident.18
Furthermore a reduction in factor V can be observed which is
down-regulated by APC. In a study by Johansson et al.40 increased
APC following trauma was reported but only 12 patients in this
study were coagulopathic and the authors did not differ between
those having or not having ATC. There remains thus an urgent need
to further dene this association and the clinical signicance.
8. Procoagulant impairment
In some countries the use of FFP for bleeding trauma patients is
increasing as one theory states that the impairment of coagulation
due to injury can improve haemostasis, might reduce blood loss,
and may improve outcomes. Coagulation factors are depleted in
ATC and there are different retrospective studies which are in
favour of high FFP ratios, reporting better outcomes and lower
mortality. New studies also support the statement that thrombin
generation is enhanced after trauma.41,42 The rst coagulation
factor to drop in trauma is brinogen but this will also be the factor
reaching supraphysiological levels in the days after injury.43,44
There are clinical studies on ATC which conrm this fact and also
shock models with swine were able to demonstrate the reduction
of brinogen by thromboelastography/thromboelastometry reected by a reduced clot strength.45,46 For this reason the European
Trauma Guidelines recommend brinogen levels of 1.5e2.0 g/l. The
use concentrated brinogen such as cryoprecipitate of brinogen
concentrates allows precise correction of this problem without
having the harmful side effects of plasma itself and the huge volume overload associated with it.47
9. Hypothermia
Hypothermia remains one of the major problems in trauma patients.48 In nearly two thirds of those patients, body temperature
drops to such an extent that hypothermia is present between
treatment on scene by the emergency medical services and arrival in
the emergency room.48 Additionally an increase of hypothermia can

25

be achieved by the administration of infusions which have room

temperature. In the literature a decrease of 0.5  C body temperature per litre of infusion has been described.49 As most coagulation
factors are enzymes their function is impaired once the temperature
starts getting below 35  C. In addition platelets are also inhibited
with decreased temperature.50 Below 34  C coagulation is clinically
relevant impaired and from 32  C on mortality due to bleeding
disorders is signicantly increased as shown in the literature.51,52
10. Acidosis
The second factor inuencing coagulation according to the so
called lethal triad is acidosis. Hypoperfusion of tissues induced by
shock leads to an increased anaerobic metabolism in these areas
causing acidosis. In addition to the coagulation disorders created by
hypothermia, acidosis, and thus pH further impair the enzymatic
function of coagulation factors and the speed of clot formation.53 A
direct inuence of the pH on thrombin function and platelet activity has been shown.54 Other studies have proven that the presence of acidosis in trauma patients arriving in the emergency room
is a factor predisposing for negative outcomes. A direct correlation
between base excess and survival has also been reported.55 Of note,
correcting the acidosis does not lead to a complete remission of the
impaired coagulation system56 and perhaps irreversible enzymatic
damage occurs. As a result, acidosis should be recognized as early as
possible and treated.
11. Dilution as well as the use of crystalloids and colloids
Initially following blood loss in trauma, patients are often treated
with crystalloids and to a certain extent colloids. This leads to a
dilution of the circulating coagulation factors.57 Different studies
in vitro, in animal models, in volunteers and in patients have been
reported, and colloids impair coagulation potentially even more
than crystalloids.58e61 Theusinger et al.62 reported that hydroxyl
ethyl starch (HES) has a higher inuence on coagulation than gelatin,
and HES coagulopathy is not completely reversible compared to
gelatin.62 This seems to be due to disturbances in the brin polymerization, platelet coating and reduction of the clot stability.58,63
The rst coagulation factor which will drop below normal values
and needs early adequate substitution is brinogen.64 The severity
of injury seems to correlate with the decrease of brinogen levels.
12. Platelet dysfunction
Thrombocytopenia in trauma also seems to be associated with
negative outcomes. In a retrospective study by Brown et al.65 ~400
trauma patients with massive transfusions were analysed using a
regression model in which ISS, base excess, platelet count and GCS
were included. The odds ratio of death within 24 h decreased by
12% for each increase of 50,000  106 platelets, however no clear
cut off level regarding coagulopathy and platelet count exists.40,66
In the bleeding patient the critical level for trauma patients was
set at 50,000  106 by Theusinger et al.67 Two studies indicate that
high ratios of platelets to red blood cells might be associated with
better outcome in trauma, a nding that may be due to a possible
survival bias.68e71 The question in this context which has to be
answered is whether there is a functional impairment of platelets
provoked by trauma. The rst suggestion for this is from a study of
163 patients showing a difference in platelet aggregometry between survivors versus non-survivors.72 Another study reporting
platelet function in trauma patients using a point of care device
(TEG platelet mapping)73 before starting resuscitation noted that
the ADP inhibition in trauma patients compared to healthy volunteers was 86.1% versus 4.2% and by arachidonic acid 44.9 versus

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O.M. Theusinger et al. / Trends in Anaesthesia and Critical Care 5 (2015) 23e27

0.5%. Further work is needed to understand the possible platelet

dysfunction and its implication in acute trauma coagulopathy. A
new point of care device has been introduced recently (ROTEM
platelet, TEM international GmbH, Munich, Germany) which allows
on the same device to monitor whole blood coagulation by 4
channels for thromboelastometry (ROTEM, TEM international
GmbH, Munich, Germany) and two channels for platelet function
analysis and this within 10 min. This should allow further studies in
the near future to nd an explication for this phenomenon.

Pentapharm AG, Mnchen, Germany, TEM International, Mnchen,

Germany.
Werner Baulig has received honoraria or travel support for
consulting or lecturing from the following companies: CSL Behring
Schweiz, Zurich, Switzerland; Fresenius-Kabi AG, Bad Homburg,
Germany; B.Braun Melsungen AG, Melsungen, Germany; OrPha
Swiss GmbH, Ksnacht, Switzerland and SenTec AG, Therwil,
Switzerland.
Jerrold L. Levy has no conict of interest with this manuscript.

13. Animal models

References
The ideal animal model to support the clinical understanding of
TIC has not yet been found. ATC, as mentioned earlier, is due to
tissue injury and haemorrhagic shock leading to activated inammatory processes as well as an imbalance between pro- and anticoagulants. In addition the lethal triad adds derangements to a
system which is already in imbalance and thus leads to TIC. These
different aspects have been studied separately in animals with
normal biological systems. There is a lack of initial tissue injury in
these models and the combination with haemorrhagic shock is
missing. Another question to be answered is which species should
be used. Rodent models including mice, have small volumes, are
cheap and offer different possibilities to manipulate specic pathways in transgenic models and to investigate individual aspects
even though they are to some extend reductionist. Regarding large
animals the porcine model is used extensively and is thought to
better reect coagulation changes after trauma and possible interventions to correct coagulopathies. Certain concerns regarding
the porcine model include: i) they are hypercoagulable compared
to humans; ii) they have reduced protein C levels compared to
humans.74 ATC described in mice and rats was not to be shown in
pigs even with the identical model. Animals not often used in
trauma research are sheep and rabbits even though they may be
better models of TIC. Results found in animal studies regarding TIC
have to be targeted in clinically relevant species especially as the
use of POC devices such as rotational thromboelastometry is
increasing as laboratory values like PT and prothrombin will be
superseded by this technology in acute trauma. So far no animal
model was able to demonstrate the severity of ATC observed in
human patients. This may relate to the sensitivity of coagulation
assays used. Species-specic thromboplastins and coagulation
factor assay tools should be developed to resolve this.
14. Conclusions
ATC is occurring within the rst minutes after traumatic injury.
In addition, hypothermia, acidosis, and dilution will lead to TIC.
Prevention and early treatment of TIC improves survival of these
patients. The pathophysiology and the exact mechanism have not
been identied up to now. Pro- and anticoagulant effects as well as
the oxidative process seem to play a role in TIC. Animal models used
up to now cannot be completely translated to what we see in
humans. Thus there is a lack of robust animal models reecting
pathology mechanisms in humans, optimize bleeding management
and developing new drug therapy options. There is a clear need for
further studies in large animals which allow translating ndings
and therapeutic options to patients.
Conicts of interest
Oliver M. Theusinger has received honoraria or travel support
for consulting or lecturing from the following companies: CSL
^ne,
Behring Schweiz, Zurich, Switzerland, Vifor SA, Villars-sur-Gla
Switzerland, Roche Pharma (Schweiz) AG, Reinach, Switzerland,

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