Review Article

Management of traumatic haemorrhage – the European

perspective

H. Sch€ochl,1 W. Voelckel2 and C. J. Schlimp3

1 Consultant, 2 Head of Department, Department of Anaesthesiology and Intensive Care, AUVA Trauma Centre,Salzburg, Austria3 Consultant, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Centre,Vienna, Austria

SummaryTrauma-induced coagulopathy represents a life-threatening complication in severely injured patients. To avoid ex-

sanguination, rapid surgical bleeding control coupled with immediate and aggressive haemostatic treatment is man-

datory. In most trauma centres, coagulation therapy is established with transfusion of high volumes of fresh frozen

plasma. Due to logistic issues, only busy trauma facilities store pre-thawed plasma ready for immediate transfusion.

Thus, substantial time delays have been reported between the first unit of red blood cells transfused and the adminis-

tration of fresh frozen plasma. An alternative for rapid improvement of haemostatic capacity is purified coagulation

factor concentrates. They contain a well-defined concentration of coagulation proteins, carry a low risk for transfu-

sion-related lung injury and virus transmission, and are available for immediate use without the need for blood

group matching. In some European trauma centres, treatment algorithms have been developed for the administration

of coagulation factor concentrates based on visco-elastic test results..................................................................................................................................................................

Correspondence to: H. Sch€ochl; Email: herbert.schoechl@auva.at; Accepted: 9 September 2014

IntroductionExsanguination represents a significant cause of

trauma-related mortality [1]. Notably, trauma-induced

coagulopathy (TIC) starts immediately after the initial

insult, and is strongly linked to injury severity and

shock [2]. Compared with non-coagulopathic trauma

patients, early TIC is associated with higher transfu-

sion requirements, increased rates of multiple organ

failure, longer intensive care unit stay and a fourfold

higher mortality [3, 4]. Approximately, one third of all

deaths after emergency room admission are attribut-

able to massive blood loss, and about 20% of these

deaths are potentially preventable with rapid surgical

bleeding control and aggressive treatment of the

underlying coagulopathy [5].

Traditionally, TIC has been attributed to blood

loss, and consumption and dilution of the remaining

coagulation factors, as well as to additive confounders

of haemostasis, such as hypothermia and acidosis [6].

However, recent studies indicate that TIC is primarily

driven by hypoperfusion, endothelial cell damage,

inflammation, and tissue trauma [7]. This so-called

endogenous TIC is mediated via activation of the

protein C pathway, which consequently results in

anticoagulation and pro-fibrinolytic stimulation [8].

A more detailed understanding of the pathophysi-

ology of severe trauma-related bleeding has challenged

the ability of standard coagulation tests to sufficiently

portray the multifaceted nature of TIC [9, 10]. Visco-

elastic tests, such as ROTEM� (Tem International,

102 © 2014 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia 2015, 70 (Suppl. 1), 102–107 doi:10.1111/anae.12901

Munich, Germany) or TEG� (Hemonetics, Braintree,

MA, USA), are increasingly used as diagnostic tools

for rapid identification of bleeding disorders. The

results of these tests are available within minutes, and

serve as guidance for haemostatic decision-making

[10–12]. Based on visco-elastic measurements, treat-

ment algorithms have been developed to individualise

patients’ haemostatic therapy according to their actual

deficiencies and needs [11–15].

Diagnosis of trauma-inducedcoagulopathyWhen a patient is admitted to the emergency room, it

is often challenging to determine whether ongoing

blood loss is attributable to surgical causes, or is as a

result of ongoing haemostatic deficiencies. Moreover,

every patient who suffers from uncontrolled surgical

blood loss will acquire coagulopathic bleeding at a later

stage. Since TIC is a life-threatening complication of

major injury, rapid diagnosis of the underlying coagul-

opathy is mandatory. The typical clinical presentation

of TIC is diffuse, uncompressible, microvascular bleed-

ing from wound surfaces, mucous membranes or cath-

eter insertion sites.

In most trauma facilities, haemostatic competence

of bleeding patients is assessed by conventional

plasma-based coagulation tests, such as prothrombin

time (PT), international normalised ratio (INR) and

activated partial thromboplastin time (aPTT). This is

of particular interest as standard coagulation tests

were primarily designed to evaluate anticoagulation

rather than coagulopathy [16, 17]. A recent system-

atic review found no evidence that standard coagula-

tion tests are predictive for bleeding or have the

potential to guide coagulation therapy [18]. Impor-

tantly, standard coagulation tests are determined in

plasma, thus excluding corpuscular elements of blood,

such as platelets, erythrocytes and tissue factor bear-

ing cells, which have been identified as important

contributors to the whole coagulation process [19].

The read-out of such tests stops when only as little

as 5% of the entire amount of thrombin is generated

[20]. Therefore, these tests provide only an initial

snapshot of the whole coagulation process. Moreover,

they do not deliver any information about the quality

and stability of the clot, which have been recognised

as important components of TIC [21]. Even in large

hospitals, median turnaround times between 80 and

90 min for standard coagulation test results to

become available have been reported [22, 23].

In contrast, visco-elastic tests appear to be more

appropriate to characterise the complex nature of TIC

[9, 10]. They allow a comprehensive overview of the

entire coagulation process, including the initiation

phase of coagulation, the speed of clot formation up to

the maximum clot strength and the premature dissolu-

tion of the clot. Visco-elastic tests are run in whole

blood, thus the corpuscular blood constituents are

present and the samples do not need any pre-analytic

preparation. A bundle of diverse reagents allows for a

differentiation of the underlying causes of coagulopa-

thy [24]. Studies revealed that visco-elastic tests have

the potential to identify haemostatic deficiencies more

accurately and substantially faster than standard coag-

ulation tests [25–28]. First test results that enable treat-

ment decisions are available after a running time of

10 min [9, 23]. Figure 1 demonstrates normal ROTEM

measurements and typical pathological findings of

various origins.

The concept of a high plasma andplatelet concentrate-transfusion ratioStudies from both military and civilian trauma centres

have shown that early, high-ratio fresh frozen plasma

(FFP) and platelet concentrate to red cell transfusions

are linked to improved outcomes in trauma patients

with severe haemorrhage [29–31]. However, if red

cells, FFP and platelet concentrate are reconstituted in

a 1:1:1 unit ratio, the administered fluid carries a hae-

matocrit of 29%, the activity of the coagulation factors

is approximately 60% of normal, and platelet count is

roughly 90 9 109.l�1 [32]. Since the activity of coagu-

lation factors in plasma is relatively low, it is essential

to transfuse large quantities [33, 34]. Even in large

trauma centres, substantial time delays have been

reported between transfusion of the first red cells and

administration of the first unit of plasma [35]. Data

from the PROMMTT study indicated that survival

benefits were only apparent when high volume plasma

transfusion was carried out within the first 6 h after

injury [36]. Only busy trauma centres, with high num-

bers of severe casualties, store pre-thawed plasma for

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Sch€ochl et al. | Coagulation factor concentrates in trauma in Europe Anaesthesia 2015, 70 (Suppl. 1), 102–107

immediate use [37–39]. Moreover, high volume plasma

transfusion may be accompanied by significant side

effects, such as acute lung injury, sepsis and multiple

organ failure [40].

Concept of goal-directed coagulationtherapy based on visco-elastic testresultsThe concept of individualised, goal-directed coagula-

tion therapy is based on the ability of visco-elastic tests

to rapidly diagnose the underlying coagulation disor-

der. Purified coagulation factor concentrates serve as

haemostatic components, which can be applied accord-

ing to the actual deficiencies of the patient. Compared

with FFP, coagulation factor concentrates have several

advantages: they can be stored in the emergency room;

they are available for immediate use; they contain a

well-defined concentration of coagulation proteins;

they do not require cross-matching before application;

and they carry only minimal risk of infection, transfu-

sion-associated cardiac overload and transfusion-

related acute lung injury. Essentially, three treatment

steps/options for different pathologies of TIC can be

addressed:

Inhibition of (hyper) fibrinolysis – improvementof clot stabilityHyperfibrinolysis is integral to major trauma. Recent

studies indicated that even low-grade fibrinolysis (> 3%)

detected by visco-elastic tests are associated with an

increased tendency to bleed, higher transfusion require-

ments, and higher mortality rate, compared with trauma

patients without any lysis [41–44]. Currently available

visco-elastic tests have inadequate sensitivity to detect

small increments in pro-fibrinolytic activation [45–47].

Thus, antifibrinolytic therapy should be initiated based

on pragmatic clinical aspects, such as pronounced

shock, hypothermia and substantial tissue trauma rather

than guided by visco-elastic tests (Figs. 1 and 2) [48].

Tranexamic acid allows sufficient and cost-effective

inhibition of fibrinolysis. Data derived from the Crash-

2 study indicated that, compared with placebo, early

application of tranexamic acid reduced the risk of death

in trauma patients by 1.5% (p = 0.0035) [49]. Notably,

a post-hoc analysis of the Crash-2 database discovered

that tranexamic acid administered beyond 3 h follow-

ing injury increased mortality [50]. Thus, early applica-

tion of tranexamic acid is recommended [51]. In

military emergency resuscitation, tranexamic acid

therapy resulted in a reduction in overall mortality

rates of 6.5% compared with the placebo group

(a)

(b)

(c)

(d)

Figure 1 Examples of ROTEM analyses of patientsadmitted to the emergency room. Panel a: normal RO-TEM results. Panel b: poor fibrin polymerisation: Sig-nificantly reduced FIBTEM A10 (6 mm) and reducedEXTEM A10 (36 mm); EXTEM CT is normal. Thisfinding may be an indication to increase fibrinogenconcentration. Panel c: thrombocytopenia: EXTEMA10 is diminished (< 41 mm) and FIBTEM A10 is inthe normal range. This can be interpreted as an indi-cation for platelet concentrates. Panel d: global severecoagulopathy: The CT and CFT in EXTEM are signifi-cantly extended and the A10 in both EXTEM(24 mm) and FIBTEM (4 mm) are massively reduced.A10 (20), clot amplitude after 10 (20) min runningtime; alpha, alpha angle; CFT, clot formation time; CT,clotting time; EXTEM, extrinsically activated test; FIB-TEM, fibrin polymerisation test (extrinsically activatedtest with additional inhibition of platelet componentby cytochalasin D); MCF, maximum clot firmness

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Anaesthesia 2015, 70 (Suppl. 1), 102–107 Sch€ochl et al. | Coagulation factor concentrates in trauma in Europe

(p = 0.03). This benefit was most pronounced in a sub-

group of patients who received massive transfusion

(14.4% vs 28.1%; p = 0.004). However, not all studies

were able to confirm these positive results. A recent ret-

rospective analysis of 300 trauma patients found an

increased, rather than reduced, mortality that was inde-

pendent of the time tranexamic acid was administered

[52]. The authors suggested that tranexamic acid infu-

sion aggravates hypotension in haemorrhaging trauma

patients, which might result in increased fluid require-

ments and the observed higher mortality rates.

Optimisation of clot strengthClot firmness is determined by the interaction of fibrin,

platelets and activated Factor XIII [10]; a depletion of

these components results in reduced clot strength. A

series of observational studies reported that diminished

clot strength is associated with an increased bleeding

tendency, higher transfusion requirements and a higher

mortality rate [13, 53–56]. Thus, an improvement in

maximum clot strength can be achieved by the admin-

istration of one or more of these constituents.

Fibrinogen has been identified as the most vulnera-

ble coagulation factor. It reaches critically low levels

earlier than any other coagulation protein, and is prob-

ably the most common initial coagulation defect in

trauma [57, 58]. This is of particular interest as fibrino-

gen is not only the precursor of fibrin, but also is inte-

gral to platelet aggregation [59]. Therefore, both fibrin

formation and platelet aggregation are compromised by

low fibrinogen concentrations. Moreover, low fibrino-

gen concentration on hospital arrival is associated with

an increased risk of diffuse microvascular bleeding,

high hazard for massive transfusion, and is strongly

linked to higher mortality rates [53, 60]. Schlimp et al.

investigated 675 trauma patients and found that criti-

cally low fibrinogen (< 1.5 g.l�1) on admission to the

emergency room strongly correlated with shock severity

as determined by low base excess, low haemoglobin,

and high injury severity score [61]. Maintaining fibrin-

ogen levels appears to positively influence the mortality

of trauma patients. A retrospective study, including 252

massively transfused casualties, indicated that adminis-

tration of high total amounts of fibrinogen were associ-

ated with improved survival rates [62]. Morrison et al.

investigated the impact of fibrinogen-containing cryo-

precipitate in addition with tranexamic acid on survival

in severely injured combat casualties. Tranexamic acid

and cryoprecipitate were independently associated with

a similarly reduction in mortality, suggesting a central

role for fibrinogen in trauma-related bleeding [63].

Importantly, the combination of both tranexamic acid

and cryoprecipitate yielded the best survival rate.

The concentration of fibrinogen in both FFP and

solvent-detergent plasma varies between 2.0 and

2.9 g.l�1 [33, 34, 64]. Thus, large quantities of plasma

are required to sufficiently increase plasma fibrinogen

levels [65]. Clinical studies have revealed that transfu-

sion of red cells and FFP in a 1:2 ratio was insufficient

to preserve fibrinogen concentration in multiple trans-

fused recipients. Only additional supplementation with

cryoprecipitate resulted in maintenance of an adequate

fibrinogen content [60]. Consequently, the recent

European guidelines for massive trauma-related bleed-

ing recommend fibrinogen concentrate (3–4 g) or

cryoprecipitate (50 mg.kg�1) to restore appropriate

plasma fibrinogen levels [51]. According to our institu-

tional algorithm, fibrinogen concentrate should be

administered to bleeding patients if clot amplitude in

the FIBTEM assay after 10 min running time (A10) is

< 7 mm. We aim for an A10 target level of 10–12 mm

(Fig. 3) [66].

(a) (b)

Figure 2 ROTEM traces showing hyperfibrinolysis ina patient with severe trauma and shock on admissionto the emergency room. Note the typical spindle of theEXTEM, INTEM and FIBTEM tracing. The in vitroaddition of aprotinin (APTEM test: extrinsically acti-vated test with aprotinin) fully inhibits hyperfibrinoly-sis resulting in a stable clot. Coagulation therapy withtranexamic acid is indicated.

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Improvement in thrombin generationThrombin is the central enzyme of the whole coagula-

tion process and is paramount to the structure and

quality of the clot [67]. Immediately after injury,

thrombin generation is up-regulated and, with the

exception of seriously injured patients, is not an initial

problem at the time of admission to the emergency

room [68, 69]. The diagnosis of compromised throm-

bin formation remains challenging. Neither prolonged

PT or aPTT, nor an extended clotting time in visco-

elastic tests, sufficiently portrays the magnitude of

thrombin generation [68, 70]. Indeed, Dunbar and

Chandler found that trauma patients with prolonged

PT (> 18 s), which is suggestive of TIC, had a three-

fold higher thrombin generation compared with indi-

viduals with normal PT (p = 0.01) [68].

A number of animal studies have indicated that

administration of prothrombin complex concentrate

increased thrombin generation and decreased blood

loss in trauma-related bleeding compared with placebo

and recombinant factor VIIa [71–73]. To improve

thrombin generation, prothrombin complex concen-

trate is increasingly used in many European trauma

centres [74–78]. According to the treatment algorithm

developed by our group (Fig. 4), thrombin generation

should be augmented only if the ROTEM shows pro-

longed clotting time (EXTEM CT) > 80 s [15]. This

threshold is chosen because the EXTEM CT exceeds

the upper limit of 80 s when the activity of coagulation

factors is decreased to < 35% [79]. It should be noted

that administration of fibrinogen concentrate might

also result in a shortening of the EXTEM CT below

the threshold of 80 s due to higher availability of sub-

strate for initial clot formation. Therefore, we do not

recommend administration of prothrombin complex

concentrate before normalisation of the FIBTEM A10.

In a retrospective study of severely injured patients

who received ≥ 5 units of red cells within 24 h,

favourable outcomes were reported after ROTEM-

guided haemostatic therapy with fibrinogen concen-

trate (median dose 6 g) and prothrombin complex

concentrate (median dose 1800 U). The observed mor-

tality was lower than predicted by the Revised Injury

(a) (b)

Figure 3 ROTEM analysis of major trauma patient(injury severity score 31) on admission to the emer-gency room. Panel a: significant reductions in EXTEMA10 (40 mm) and FIBTEM A10 (3 mm). Panel b: RO-TEM analysis following treatment with 5 g fibrinogenconcentrate. Note fibrinogen concentrate administra-tion resulted in a substantial improvement of clotamplitudes (A10, A20 and MCF) in both, EXTEM andFIBTEM and a normalisation of the EXTEM CT.

Figure 4 Treatment algorithm based on ROTEM testresults from AUVA Trauma Centre, Salzburg, Austria[84]. BGA, blood gas analysis; BW, body weight; CT,clotting time; FFP, fresh frozen plasma; ISS, injuryseverity score; ML, maximum lysis; PC, plateletconcentrate; PCC, prothrombin complex concentrate;TXA, tranexamic acid

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Severity Classification Score and the Trauma Injury

Severity Score [80]. Another study by the same group

showed that coagulation therapy based on fibrinogen

concentrate and prothrombin complex concentrate was

associated with less frequent exposure to allogeneic

blood products compared with patients who received

FFP, but had no effect on mortality [81].

Outside vitamin K antagonist reversal, sound

safety data are still lacking on the use of prothrombin

complex concentrate in bleeding trauma patients.

Joseph et al. reported an incidence of thrombo-

embolic events in the range of 6% after prothrombin

complex concentrate administration in a heteroge-

neous group of trauma patients [82]. Our group

showed recently that prothrombin complex concen-

trate administration resulted in a substantial and pro-

longed increase in endogenous thrombin generation

compared with patients who received no coagulation

therapy or fibrinogen concentrate only [83]. The

recent European guidelines for massive trauma-related

bleeding recommend administration of prothrombin

complex concentrate primarily for the emergency

reversal of vitamin K-dependent oral anticoagulation.

In bleeding trauma patients with thrombo-elastomet-

ric signs of delayed initiation of the coagulation

process, prothrombin complex concentrate can be

considered [51].

Figure 4 depicts the treatment algorithm for bleed-

ing trauma patients, which was established at the

AUVA Trauma Centre in Salzburg [84].

ConclusionsIn contrast to FFP, coagulation factor concentrates

allow tailored haemostatic therapy according to the

actual deficiencies of individual patients. Tranexamic

acid administration should be guided primarily by

clinical signs of shock and injury severity rather than

by visco-elastic test results. Poor clot quality at the

time of admission to the emergency room is primarily

linked to fibrinogen deficiencies. When fibrinogen lev-

els are low, fibrinogen concentrate allows a faster and

more sufficient increase in fibrinogen levels compared

with plasma transfusion. Prothrombin complex con-

centrate may be considered for severely bleeding

patients with diminished thrombin generation. How-

ever, outside reversal of vitamin K antagonists, sound

safety data for prothrombin complex concentrate in

trauma patients are still lacking.

AcknowledgementsHS has received lecture fees and study support from

the following companies: CSL Behring, TEM Interna-

tional, Baxter and AOP Orphan. CJS has received lec-

ture fees and study support from CSL Behring, as well

as study support from TEM International.

Competing interestNo other conflicts of interest.

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