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MCC 822

REVIEW

CURRENT
OPINION Coagulation management
Oliver Grottke

Purpose of review
Trauma-induced coagulopathy is a frequent complication in severely injured patients. To correct
coagulopathy and restore haemostasis, these patients have traditionally been treated with fresh frozen
plasma, but in the last decade, there has been a shift from empirical therapy to targeted therapy with
coagulation factor concentrates and other haemostatic agents. This review highlights emerging therapeutic
options and controversial topics.
Recent findings
Early administration of the antifibrinolytic medication tranexamic acid was shown in the multicentre
CRASH-2 trial to be an effective and inexpensive means of decreasing blood loss. Numerous retrospective
and experimental studies have shown that the use of coagulation factor concentrates decreases blood loss
and may be useful in reducing the need for transfusion of allogeneic blood products. In particular, early
use of fibrinogen concentrate and thrombin generators has a positive impact on haemostasis. However, the
use of prothrombin complex concentrate to correct trauma-induced coagulopathy has also been associated
with a potential risk of serious adverse events.
Summary
Current evidence in trauma resuscitation indicates a potential role for coagulation factor concentrates and
other haemostatic agents in correcting trauma-induced coagulopathy. Despite a shift towards such
transfusion strategy, there remains a shortage of data to support this approach.
Keywords
bleeding, coagulation factor concentrates, tranexamic acid, trauma, viscoelastic coagulation monitoring

INTRODUCTION 5) anaemia and low platelet count

Trauma is one of the top 10 causes of death world-
wide, and blood loss is a major cause of death among
trauma patients in the early phase after hospitaliz-
ation [1]. The underlying pathophysiology of
life-threatening bleeding is usually caused by a
combination of traumatic injury and coagulopathy.
On admission to hospital, 2536% of trauma patients
already show signs of coagulopathy [2]. The causes of
coagulopathy are multifactorial and interrelated;
these include consumption and dilution of coagu-
lation factors and platelets, dysfunction of platelets
and the coagulation system, increased fibrinolysis,
disturbance of the coagulation system by the infusion
of solutions (crystalloids and colloids), and hypocal-
caemia [3,4]. The factors contributing to trauma-
induced coagulopathy are as follows:
1) loss and consumption of coagulation factors
2) shock-induced activation of the protein C path-
way
3) hyperfibrinolysis
4) dilution of coagulation factors
6) metabolic changes (acidosis)
7) hypothermia
8) hypocalcaemia
This disturbance of coagulation may aggravate
bleeding, and it has been shown that this effect is
associated with significant morbidity and mortality.
Generally, trauma-induced coagulopathy should
be differentiated from disseminated intravascular
coagulation (DIC) [5]. In contrast to DIC, trauma-
induced coagulopathy is not associated with gener-
alized intravascular coagulation and extensive
consumption of coagulation factors. Instead, tissue
Department of Anesthesiology, RWTH Aachen University Hospital,
Aachen, North Rhine-Westphalia, Germany
Correspondence to Oliver Grottke, MD, MPH, Department of Anesthesi-
ology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074
Aachen, North Rhine-Westphalia, Germany. Tel: +49 241 808 0972; fax:
+49 241 808 2406; e-mail: ogrottke@ukaachen.de
Curr Opin Crit Care 2012, 18:000000
DOI:10.1097/MCC.0b013e328358e254

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MCC 822
Trauma
KEY POINTS
 The results of the CRASH-2 trial strongly indicate that
early use of tranexamic acid is a cost-effective means of
reducing mortality in severely bleeding patients.
 Despite a lack of RCTs, there is a growing body of
evidence showing that early ROTEM/TEG-guided
fibrinogen concentrate may reduce blood loss and
transfusion of allogeneic blood products.
 Despite broad European Union labelling for PCC that
includes trauma-induced coagulopathy, there is a clear
lack of prospective clinical trials investigating the safety
and efficacy of PCCs for this indication.
 Well designed RCTs of haemostatic therapy in trauma
patients are required to improve both coagulation
assays and haemostatic therapy.
damage leads to localized activation of coagulation
with relatively limited consumption of coagulation
factors.
The overall aims of haemostatic therapy are to
reduce blood loss and restore haemostasis, while
minimizing the use of allogeneic blood products.
The transfusion of fresh frozen plasma (FFP) may
directly cause dilutional coagulopathy, and there
are other significant drawbacks (e.g. transfusion-
related lung injury) with the transfusion of alloge-
neic blood products such as FFP, red blood cells
(RBCs), and platelets [69]. In an attempt to
avoid these issues, there has been a shift from an
empirical coagulation therapy (e.g. administration
of RBCs : FFP : platelets with a fixed 1 : 1 : 1 ratio)
towards early, targeted, and more intense replace-
ment of coagulation factors with recombinant and
lyophilized coagulation factor concentrates. The use
of such products is supported by their immediate
availability, low administration volume, rapid
administration, and good viral safety. Studies have
been performed in animals and in human patients
to investigate the effects of coagulation factor con-
centrates. However, due to the limited number of
randomized controlled trials (RCTs), heterogeneous
patient populations and the use of different animal
models, discordant results have been reported. This
review discusses recent evidence from clinical and
experimental studies investigating the use of coagu-
lation factor concentrates and other haemostatic
agents in trauma-induced coagulopathy.
DIAGNOSIS OF COAGULOPATHY
Conventional plasma-based coagulation tests
(i.e. activated partial thromboplastin time and
prothrombin time) are classically used to monitor
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haemostasis. These coagulation tests were devel-
oped to monitor anticoagulation therapy, but they
have never been validated for the prediction of
haemorrhage in life-threatening bleeding. The lack
of correlation with clinically relevant coagulopathy
is in part explained by the fact that these tests only
assess the initiation of coagulation, during which
only a small amount of thrombin is formed. In
addition, they are performed using plasma which
limits the extent to which the results reflect the
in-vivo coagulation of whole blood. Long turn-
around times may be considered as the overriding
drawback with conventional coagulation tests.
Severely bleeding patients require treatment with-
out delay, raising the prospect in clinical practice of
administering empirical therapy before test results
become available. Moreover, coagulation status
changes rapidly in bleeding patients meaning that
test results are unlikely to reflect the patients actual
status when they become available. Another con-
sideration is that in recent years, the classical coagu-
lation cascade has been challenged by the cell-based
model [10]. According to this latter model, both
tissue factor (the initiator of coagulation) and
platelets play pivotal roles in haemostasis. To over-
come the constraints of conventional tests, throm-
boelastometry (ROTEM; Tem International GmbH,
Munich, Germany) and thrombelastography (TEG;
Haemonetics, Massachusetts, USA) are increasingly
used as point-of-care devices. ROTEM and TEG
assess the viscoelastic properties of coagulation in
whole blood under low-shear conditions, providing
a better reflection of the in-vivo situation than
conventional tests. Coagulation testing using
ROTEM-based or TEG-based tests can provide infor-
mation about the dynamics of clot initiation,
kinetics of clot growth and strength, as well as the
lysis of the clot [11]. Several studies have investi-
gated the use of ROTEM-guided haemostatic
therapy in different surgical areas [1215]. Although
these studies have reported reductions in the need
for allogeneic blood products, the use of ROTEM-
based algorithms in severely injured patients needs
further investigation [16].
ANTIFIBRINOLYTIC MEDICATION
Antifibrinolytic agents in current use include the
synthetic lysine analogues e-aminocaproic acid
(6-aminohexanoic acid) and tranexamic acid. The
antifibrinolytic activity of tranexamic acid in vitro is
about 10 times higher than that of aminocaproic
acid [17]. Lysine analogues reversibly bind to the
lysine-binding site of the fibrin clot, thereby inhib-
iting the conversion of plasminogen into plasmin
and subsequent plasmin-mediated fibrinolysis. The
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MCC 822
CRASH-2 RCT included 20 211 major trauma
patients with, or at risk of, severe haemorrhage, to
investigate the effectiveness of tranexamic acid (1 g
over 10 min followed by another gram over 8 h)
versus placebo. Patients were randomized to their
&&
treatment within 8 h of injury [18 ]. Despite com-
parable transfusion requirements, both all-cause
mortality at 4 weeks after admission and the risk
of death resulting from haemorrhage were signifi-
cantly reduced among recipients of tranexamic acid
treatment. A subsequent analysis also revealed that
early infusion of tranexamic acid significantly
reduced the mortality rate compared with adminis-
&
tration at a later time after trauma [19 ]. No differ-
ences in adverse events were observed between the
treatment and placebo group. A cost-effectiveness
study in three countries participating in the
CRASH-2 trial showed that the cost per life-year
gained by the use of tranexamic acid was $48 in
Tanzania, $66 in India, and $64 in the United
Kingdom. These data indicate that the setting
(high-income or low-income countries) makes
relatively little difference to the cost per life-year
gained [20]. Overall, the CRASH-2 trial conclusively
indicates that the early use of tranexamic acid
(within 3 h) is a reasonable and cost-effective means
of reducing blood loss in severely injured patients.
FIBRINOGEN
In severely injured patients with massive bleeding,
fibrinogen reaches critically low plasma concen-
trations at an early stage [21]. Blood loss, consump-
tion and dilution of coagulation factors as well as
hypothermia, acidosis, and hyperfibrinolysis, all
decrease fibrinogen availability or functionality.
Data from clinical pilot studies have shown an
increased tendency towards perioperative and post-
operative haemorrhage when fibrinogen levels are
below 150200 mg/dl [2225]. Data from in-vitro
studies and experimental animal studies have
shown that fibrinogen is effective in restoring clot
firmness and reducing blood loss following liver
injury [2628]. A retrospective military study
reported decreased mortality among seriously
injured soldiers receiving a high fibrinogen-to-
RBC ratio compared with those receiving a lower
ratio [29]. However, as yet there is no evidence from
prospective, controlled clinical trials that fibrinogen
administration enhances outcomes in trauma
patients. Additionally, the critical threshold con-
centration of fibrinogen is presently a matter of
debate. Recent international recommendations
suggest that a trigger of 100 mg/dl may be too low
and that bleeding trauma patients benefit from
supplementation if their plasma fibrinogen levels
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Coagulation management Grottke
&&
fall below 150200 mg/dl [30 ]. The critical
threshold probably depends on other haemostatic
variables, such as whether thrombin generation is
sufficient. Increasing fibrinogen concentration in a
porcine model of liver injury above 150 mg/dl had
no further impact on blood loss [31].
FFP is one potential source to restore low levels
of fibrinogen for treating hypofibrinogenaemia, but
large volumes of this product are needed because the
concentration of fibrinogen is fairly low (typically
around 2 g/l) [32]. As an alternative, cryoprecipitate
may be used, in those countries in which it is
available (e.g., United States, United Kingdom).
Cryoprecipitate contains factor VIII, fibrinogen,
fibronectin, von Willebrand factor, and factor XIII.
Due to safety concerns and variable concentrations
of fibrinogen, cryoprecipitate should be used with
caution for the treatment of trauma-induced coa-
gulopathy [8]. Pasteurized fibrinogen concentrate is
virus inactivated and licensed in some European
countries for congenital and acquired fibrinogen
deficiency. It can be reconstituted quickly without
thawing or cross matching, which enables a short
time to infusion. Despite a good safety profile with a
low risk of thromboembolic events, the current
evidence cannot be regarded as conclusive, due to
the lack of RCTs [33].
PROTHROMBIN COMPLEX CONCENTRATE
Prothrombin plays a pivotal role in the process
of clot formation. The plasma concentration of
prothrombin is normally high, with levels of
11501750 nM, and a significant reduction is likely
to impair haemostasis. Prothrombin complex con-
centrates (PCCs) are concentrates of the vitamin
K-dependent factors II, VII, IX, and X. PCCs are
available with low amounts of factor VII (three-
factor PCCs, used in the United States) and higher
concentrations of factor VII (four-factor PCCs, com-
monly used in Europe). They are approved in the
European Union for the treatment and perioperative
prophylaxis of bleeding in congenital and acquired
deficiency of prothrombin complex coagulation fac-
tors, such as vitamin-K deficiency, treatment with
vitamin-K antagonists, or liver cirrhosis. In the con-
text of debate between specific coagulation factors
versus FFP for treating trauma-induced coagulop-
athy, the application of PCCs has gained new inter-
est. In clinical settings requiring rapid correction of
coagulopathy, coagulation factor concentrates may
offer an advantage over FFP by providing rapid
supplementation of coagulation factors. Retrospec-
tive analyses in trauma have shown that therapy
with fibrinogen and PCC may reduce mortality in
comparison with the predicted rates [34], as well as
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Trauma
reducing blood loss, morbidity, and transfusion of
allogeneic blood products [3537]. Retrospective
data from cardiac surgery showed that a ROTEM-
guided algorithm, also using coagulation factor con-
centrates, significantly reduced the need for trans-
fusion of RBCs and FFP [14]. Further evidence for the
use of PCC has been provided by animal models of
&
liver and spleen injury [3840,41 ,42]. The appli-
cation of 2535 IU/kg PCC reduced blood loss,
shortened bleeding time, and enhanced thrombin
generation. However, one of these studies also
showed that PCC at a dose of 50 IU/kg increased
the risk of thromboembolic events and provoked
& &&
DIC [41 ]. Thrombin generation analyses indicated
that these side effects were related to an imbalance
of procoagulant and anticoagulant proteins. This
observation corresponds to an in-vitro model of
thrombogenicity, which showed that zymogen
overload (i.e., excessive levels of prothrombin)
was the main mechanism for the thrombogenic
potential of older PCC products [43]. Todays com-
mercially available PCCs are suggested to have
improved safety versus products used in the 1970s
and 1980s. This argument is based on the exclusion
of activated factors as well as the inclusion of coagu-
lation inhibitors, which may provide some balance
to the procoagulants avoiding an excessive increase
in thrombin generation. However, a biochemical
comparison of seven commercially available PCCs
revealed substantial differences between their
levels of anticoagulant proteins [44]. The potential
impact of these differences, in relation to the risk
of adverse events, needs further investigation.
Thrombin generation studies indicate that patients
with acute trauma-induced coagulopathy have
impaired haemostasis with thrombin generation
independent of the site of injury [45]. As PCCs are
highly effective thrombin generators, it is essential
to avoid administering PCC to trauma patients with
an existing tendency towards high thrombin gener-
ation. This is challenging in emergency situations
with severe blood loss, as thrombin generation
assays are time consuming, and therefore not feas-
ible. Although thromboelastometry measurements
are useful for rapid detection of coagulation defi-
ciencies, they serve only as a surrogate for thrombin
generation.
ACTIVATED RECOMBINANT FVII
Recombinant activated factor VII (rFVIIa) is a
haemostatic agent originally developed for the treat-
ment of haemophilia patients with inhibitors
against factor VIII or factor IX. During the past
decade, the potential effectiveness of using rFVIIa
off label for the prevention or cessation of
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life-threatening bleeding has been shown in numer-
ous patients, with bleeding related to trauma
or surgery [46]. A multicentre phase II RCT was
performed in patients with trauma-induced coagul-
opathy. The results showed that rFVIIa significantly
reduced RBC transfusion and the need for massive
transfusion in patients with blunt trauma who
survived for more than 48 h [47]. The need for
massive transfusion was reduced by almost 20%.
However, a subsequent multicentre phase III trial
(CONTROL) was stopped after an analysis predicted
that the likelihood of reaching a successful outcome
concerning the primary endpoints (mortality and
morbidity) was very low [48 ].
There is also concern that the use of rFVIIa may
increase the risk of adverse events, especially in
patients with risk factors for thromboembolic
disease or with a history of thrombosis. The Food
and Drug Administration described 185 treatment-
emergent adverse events between 1999 and 2004
[49]. The majority of these studies were associated
with off-label use of rFVIIa, and some of the adverse
events resulted in serious morbidity and mortality. A
subsequent analysis of 35 RCTs from an array of
clinical settings showed a higher rate of arterial
thromboembolic events following rFVIIa therapy
&
[50 ]. Thus, rFVIIa should only be considered as a
last-resort rescue therapy, if first-line treatment with
surgical approaches, coagulation factor concen-
trates, allogeneic blood products, and other haemo-
static agents fail to control bleeding. To optimize
rFVIIa efficacy, the patient should be normothermic
and have haematocrit more than 24%, platelets
more than 50 000 per ml, pH 7.2 or more, and
fibrinogen 150200 mg/dl or more.
CONCLUSION
Coagulation factor concentrates may be useful in
reducing the need to administer allogeneic blood
products, which are associated with adverse out-
comes. Sufficient levels of both fibrinogen and
thrombin generation are required for the correction
of trauma-induced coagulopathy. Empirical treat-
ment with allogeneic blood products may constitute
unnecessary administration of these products, and
specific coagulation deficiencies may not be
addressed. In contrast, targeted therapy with coagu-
lation factor concentrates is based on identifying the
cause of the coagulation deficiency. This approach
allows therapy to be tailored to each patients
specific needs. Conventional plasma-based labora-
tory assays are unlikely to characterize multifactor
deficiencies. Therefore, point-of-care assessments
including ROTEM or TEG tests and, potentially in
the future, thrombin generation may provide the
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MCC 822
best means of guiding coagulation factor concen-
trate therapy and monitoring the effects of therapy
in trauma-induced coagulopathy.
Acknowledgements
None.
Conflicts of interest
O.G. has received research funding and honoraria for
consultancy from CSL Behring, Biotest, Bayer Health-
care, Novo Nordisk and Nycomed. Final-stage editorial
support was provided by Meridian HealthComms, with
funding from CSL Behring.
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