Articles

Reversal of trauma-induced coagulopathy using first-line

coagulation factor concentrates or fresh frozen plasma
(RETIC): a single-centre, parallel-group, open-label,
randomised trial
Petra Innerhofer, Dietmar Fries, Markus Mittermayr, Nicole Innerhofer, Daniel von Langen, Tobias Hell, Gottfried Gruber, Stefan Schmid,
Barbara Friesenecker, Ingo H Lorenz, Mathias Ströhle, Verena Rastner, Susanne Trübsbach, Helmut Raab, Benedikt Treml, Dieter Wally,
Benjamin Treichl, Agnes Mayer, Christof Kranewitter, Elgar Oswald

Summary
Background Effective treatment of trauma-induced coagulopathy is important; however, the optimal therapy is still Lancet Haematol 2017
not known. We aimed to compare the efficacy of first-line therapy using fresh frozen plasma (FFP) or coagulation Published Online
factor concentrates (CFC) for the reversal of trauma-induced coagulopathy, the arising transfusion requirements, and April 27, 2017
http://dx.doi.org/10.1016/
consequently the development of multiple organ failure.
S2352-3026(17)30077-7
See Online/Comment
Methods This single-centre, parallel-group, open-label, randomised trial was done at the Level 1 Trauma Center in http://dx.doi.org/10.1016/
Innsbruck Medical University Hospital (Innsbruck, Austria). Patients with trauma aged 18–80 years, with an Injury S2352-3026(17)30065-0
Severity Score (ISS) greater than 15, bleeding signs, and plasmatic coagulopathy identified by abnormal fibrin Department of
polymerisation or prolonged coagulation time using rotational thromboelastometry (ROTEM) were eligible. Patients Anaesthesiology and Intensive
with injuries that were judged incompatible with survival, cardiopulmonary resuscitation on the scene, isolated brain Care Medicine
(Prof P Innerhofer MD,
injury, burn injury, avalanche injury, or prehospital coagulation therapy other than tranexamic acid were excluded. Prof M Mittermayr MD,
We used a computer-generated randomisation list, stratification for brain injury and ISS, and closed opaque envelopes N Innerhofer MD,
to randomly allocate patients to treatment with FFP (15 mL/kg of bodyweight) or CFC (primarily fibrinogen D von Langen MD, V Rastner MD,
S Trübsbach MD, H Raab MD,
concentrate [50 mg/kg of bodyweight]). Bleeding management began immediately after randomisation and continued
D Wally MD, B Treichl MD,
until 24 h after admission to the intensive care unit. The primary clinical endpoint was multiple organ failure in the E Oswald MD), Department of
modified intention-to-treat population (excluding patients who discontinued treatment). Reversal of coagulopathy General and Surgical Intensive
and need for massive transfusions were important secondary efficacy endpoints that were the reason for deciding the Care Medicine (Prof D Fries MD,
G Gruber MD, S Schmid MD,
continuation or termination of the trial. This trial is registered with ClinicalTrials.gov, number NCT01545635.
Prof B Friesenecker MD,
Prof I H Lorenz MD,
Findings Between March 3, 2012, and Feb 20, 2016, 100 out of 292 screened patients were included and randomly M Ströhle MD, B Treml MD), and
allocated to FFP (n=48) and CFC (n=52). Six patients (four in the FFP group and two in the CFC group) discontinued Department of Radiology
(A Mayer MD, C Kranewitter MD),
treatment because of overlooked exclusion criteria or a major protocol deviation with loss of follow-up. 44 patients in
Medical University of
the FFP group and 50 patients in the CFC group were included in the final interim analysis. The study was terminated Innsbruck, Innsbruck, Austria;
early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue and Department of
therapy compared with those in the CFC group (23 [52%] in the FFP group vs two [4%] in the CFC group; odds ratio Mathematics, Faculty of
Mathematics, Computer
[OR] 25·34 [95% CI 5·47–240·03], p<0·0001) and increased needed for massive transfusion (13 [30%] in the FFP
Science and Physics, University
group vs six [12%] in the CFC group; OR 3·04 [0·95–10·87], p=0·042) in the FFP group. Multiple organ failure of Innsbruck, Innsbruck,
occurred in 29 (66%) patients in the FFP group and in 25 (50%) patients in the CFC group (OR 1·92 [95% CI Austria (T Hell PhD)
0·78–4·86], p=0·15). Correspondence to:
Prof Petra Innerhofer,
Department of Anesthesiology
Interpretation Our results underline the importance of early and effective fibrinogen supplementation for severe
and Intensive Care Medicine,
clotting failure in multiple trauma. The available sample size in our study appears sufficient to make some conclusions 6020 Innsbruck, Austria
that first-line CFC is superior to FFP. Petra.Innerhofer@tirol-
kliniken.at
Funding None.

Introduction contribute to the development of trauma-induced

Presence of trauma-induced coagulopathy reflects
severity of injury and correlates with mortality. Trauma-
induced coagulopathy results from blood loss, dilution,
consumption, and increased fibrinolytic activity.
In addition, hypoperfusion-induced activation of the
protein C system, endothelial and platelet dysfunction,
anaemia, acidosis, hypothermia, and hypocalcaemia
coagulopathy.1,2 Thus, effective treatment of trauma-
induced coagulopathy is important and might affect
early mortality of trauma patients by decreasing
avoidable death from haemorrhage. Treatment might
also avoid late morbidity or mortality by minimising
blood loss and exposure to allogeneic blood transfusions,
which should translate into decreased risk for multiple

www.thelancet.com/haematology Published online April 27, 2017 http://dx.doi.org/10.1016/S2352-3026(17)30077-7 1

 Articles
Research in context
Evidence before this study
The literature relevant for protocol creation and discussion of
present results is largely summarised in several published
guidelines on the management of trauma-related and
perioperative bleeding. In addition, we searched PubMed using
the search terms “PCC vs FFP and trauma”, “fibrinogen
concentrate vs FFP and trauma”, and “fibrinogen concentrate
for bleeding a systematic review” to identify articles comparing
coagulation factor therapy and transfusion of FFP in trauma
patients, published before Nov 30, 2016. Neither in 2011 nor
now were we able to identify any published prospective
randomised trial directly comparing FFP and a CFC-based
concept in patients with trauma.
Although the clinical effectiveness of FFP is largely unproven,
most cited guidelines—except that of the Austrian Society and
the European Society of Anaesthesiology guideline on the
management of severe perioperative bleeding—recommend the
use of FFP as first-line therapy for correction of coagulopathy.
As an alternative to transfusion of FFP, CFC have been licensed
for use for the past two decades in many European countries for
treatment of congenital but also acquired deficiency. The last
published meta-analysis on the efficacy and safety of fibrinogen
concentrate in surgical adult and paediatric patients included
14 randomised trials (1035 patients) and reported significant
reduction in bleeding, transfusion requirements and probably
decreased mortality, but criticised a high-to-moderate risk of
bias and the fact that the evidence primarily came from cardiac
surgery.
Uncertainty on the optimal management of trauma-induced
coagulopathy still exists. The updated European guidelines on
the management of bleeding trauma patients published in
2016 recommend that suspected or detected plasmatic
coagulopathy should be corrected by transfusion of FFP or CFC,
or both. In 2011, we published results of a large cohort study
demonstrating low fibrinogen and fibrin polymerisation and
low clot firmness as the predominant pathologies in trauma,
organ failure. However, besides the recommendation
for use of transfusion algorithms, great uncertainty
exists on whether a fresh frozen plasma (FFP)-based or
coagulation factor concentrate (CFC)-based therapy, or
even a combination of the two, should be used for
correction of trauma-induced coagulopathy.2
Previous studies3,4 have shown that decreased fibrin
polymerisation and low clot firmness are the
predominant and outcome-related pathologies in
patients with polytrauma. Observational studies have
suggested that the exclusive use of coagulation factors
decreases transfusion requirements and might improve
outcome.5–9 We therefore designed a randomised clinical
trial comparing the administration of FFP and CFC,
guided by viscoelastic measurements. We hypothesised
that use of CFC would raise coagulation factor levels
2 www.thelancet.com/haematology Published online April 27, 2017 http://dx.doi.org/10.1016/S2352-3026(17)30077-7
and we also found that these pathologies were associated with
mortality and transfusion requirements. In addition, we had
knowledge that the exclusive use of CFC might reduce
transfusion requirements. To provide robust results, we
designed a randomised clinical trial comparing first-line FFP
transfusion and first-line CFC administration in major trauma.
Added value of this study
This randomised trial is the first to our knowledge to compare
first-line use of FFP and CFC for treatment of coagulopathy and
associated bleeding in major blunt trauma. The trial was
terminated early after randomisation of 100 patients, as the
a-priori planned interim analysis showed an unfavourable
risk–benefit balance for patients randomised to the FFP arm.
However, the available sample size appears sufficient to make
some conclusions that first-line CFC is superior to FFP. In our
study, there was an increased risk for development of multiple
organ failure with first-line use of FFP. We observed that first-line
transfusion of FFP is frequently ineffective for correction of
outcome-related pathologies of bleeding, hypofibrinogenaemia,
low fibrin polymerisation, and poor clot strength. Use of FFP was
associated with enduring coagulopathic bleeding, increased
transfusion requirements, and also need for massive transfusion.
Implication of all the available evidence
Considering all the published literature on the treatment of
trauma-induced coagulopathy using FFP, CFC, or both, our
findings confirm results of earlier non-randomised studies
reporting poor correction of coagulopathy with use of first-line
FFP transfusion. By contrast, the early and effective fibrinogen
supplementation, as feasible when using fibrinogen
concentrate, restores clot strength quickly, shortens the phase
of ongoing bleeding, limits transfusion requirements, and
reduces the need for massive transfusion. Results also indicate
that early effective fibrinogen supplementation translates into
improved clinical outcome.
FFP=fresh frozen plasma. CFC=coagulation factor concentrates.
effectively and rapidly, because high concentrations of
clotting factors can be applied quickly and at low
volumes. We also hypothesised that prothrombin
complex concentrate (PCC) would rarely be needed,
because thrombin generation is usually maintained or
even increased in major trauma.10 Furthermore, bleeding
cessation primarily depends on the ability to form stable
clots, and thus on fibrinogen and platelets, rather than
on the speed of coagulation initiation.3,4,11,12 We further
hypothesised that timely correction of trauma-induced
coagulopathy would shorten the bleeding phase, thus
limiting haemodynamic instability and reducing
transfusion requirements, which should decrease the
rate of multiple organ failure.2,13–16 The aim of the study
was to compare the efficacy of FFP and CFC for reversal
of coagulopathy, blood loss-associated transfusion

requirements, and the development of multiple organ
failure as an overall clinical outcome parameter.
Methods
Study design and participants
The RETIC study was a prospective, single-centre, parallel-
group, open-label, randomised study done at the Level 1
Trauma Center in Innsbruck Medical University Hospital
(Innsbruck, Austria) to investigate treatment of trauma-
induced coagulopathy in major blunt trauma. Adult
patients (aged 18–80 years) admitted to the trauma centre
with trauma exhibiting an Injury Severity Score (ISS)
greater than 15 and clinical signs or risk of substantial
haemorrhage were screened for trauma-induced coagulo­
pathy, which was defined as abnormally low fibrin
polymerisation as measured with bedside rotational
thrombo­elastometry (ROTEM) using the FibTEM assay
(10-min value of fibrinogen polymerisation [FibA10]
<9 mm) or prolonged initiation of coagulation in the
extrinsically activated ROTEM (ExTEM) assay (coagulation
time of ExTEM assay [ExCT] >90 s). The main exclusion
criteria were injuries that were judged incompatible with
survival, cardiopulmonary resuscitation on the scene,
isolated brain injury, burn injury, avalanche injury, and
prehospital coagulation therapy other than tranexamic
acid (see appendix for the full list of exclusion criteria).
The study protocol was approved by the Ethics
Committee of the Medical University of Innsbruck (study
code: UN4497 October 2011). The need for initial
informed consent was waived by the Ethics Committee,
but written informed consent was obtained as soon as
the patient regained legal capacity.
Randomisation and masking
Enrolled patients were randomly assigned (1:1) to FFP or
CFC. An independent statistician (Department of Medical
Statistics, Informatics and Health Economics, Medical
University of Innsbruck, Innsbruck, Austria) determined
random codes using permuted blocks with varying block
size and Stata/MP 10.1 for Windows Statistical Software.
Randomisation was stratified for presence or absence of
brain injury, and patients were stratified into three ISS
groups (ISS 16–30, 31–50, or >50).
The study team (PI, DF, MM, NI, DvL, VR, ST, HR,
BTrem, DW, or BTrei) were responsible for group
assignment using closed, opaque envelopes divided into
two containers corresponding to brain injury (yes/no).
All physicians responsible for patient management were
informed about treatment allocation. Patients, the
sponsor, and the Central Laboratory team, as well as
two radiologists (AM, CK) doing lower-extremity venous
duplex ultra­sonography, were blinded to treatment.
Procedures
We used a ROTEM delta device and the appropriate
liquid reagents (TEM International, Munich, Germany).
The measurement principle and interpretation of
www.thelancet.com/haematology Published online April 27, 2017 http://dx.doi.org/10.1016/S2352-3026(17)30077-7 3
Articles
ROTEM parameters have been described in detail
elsewhere.17 In short, the assay visualises the entire
coagulation process, from initiation to final clot stability
(appendix p 4). We analysed blood gas simultaneously to
bedside ROTEM measurements; plasmatic coagulation
tests, coagulation factor XIII (FXIII) concentrations
(appendix p 2), and blood cell count were determined in
the Central Laboratory. We devised a bleeding score
(0: no substantial bleeding; 1: injury-related normal
bleeding with visible clots; 2: diffuse microvascular
bleeding from wound and catheter insertion sites; 3:
massive bleeding with transfusion of >3 U red blood cells
[RBC] per h; appendix p 2) to aid assessment of blood
loss. Before therapy, all patients received tranexamic acid
(20 mg/kg of bodyweight; Pfizer, Vienna, Austria). We
started bleeding management with FFP or CFC
immediately after randomisation and during surgical or
radiological interventions, and continued study-specific
coagulation management during the first 24 h at the
intensive care unit (ICU).
Considering that coagulopathy might reoccur, one or
several treatment loops were administered during the
entire study period (lasting from admission to the
emergency department until 24 h at the ICU) according
to the algorithm defined below. Each single treatment
loop consisted of the administration of a maximum of See Online for appendix
two doses of study drugs according to randomisation and For the study protocol see
eventually single-dose or double-dose rescue medication. https://anaesthesie.tirol-
kliniken.at/data.
For the FFP group, transfusion of FFP (Octapharma,
cfm?vpath=downloads/
Vienna, Austria) delivered by the local blood bank was forschung2/retic_
done in a single dose of 15 mL/kg of bodyweight. For the studienprotokoll
CFC group, patients received fibrinogen concentrate
(50 mg/kg of bodyweight) for abnormal fibrin
polymerisation (FibA10 <9 mm) or four-factor PCC
(20 IU/kg of bodyweight) for delayed initial thrombin
formation (ExCT >90 s or prothrombin time index
[PTI] <35%). FXIII concentrate (20 IU/kg of bodyweight)
was administered with each second fibrinogen dose and
in patients with bleeding score 2–3 exhibiting FXIII
concentrations below 60% (see appendix p 1 for details
on dosages). The fibrinogen concentrate, four-factor
PCC, and FXIII concentrate were all produced by CSL
Behring (Marburg, Germany).
Study drug administration aimed to correct each
coagulopathic bleeding episode within the treatment
period lasting up to 24 h at the ICU. Whenever ROTEM
measurements remained pathological or borderline but
coagulopathic bleeding (bleeding score 2–3) persisted,
the study drug was administered again at the same dose.
Successful reversal of trauma-induced coagulopathy was
defined as just normalised FibA10 (FibA10 >8 mm) and
ExCT (ExCT <78 s) measured after completed single-dose
or double-dose study drug administration, and absence
of diffuse or massive bleeding (bleeding score 0–1).
Treatment failure was registered if even double-dose
study drug administration did not correct ROTEM
pathology or if coagulopathic bleeding persisted at
 Articles
borderline ROTEM measurements. In these patients,
rescue therapy was initiated, meaning CFC (fibrinogen
concentrate or PCC alone or with FXIII concentrate) was
administered to patients in the FFP group and equally
FFP was administered to patients in the CFC group.
The study team (PI, DF, MM, NI, DvL, VR, ST, HR,
BTrem, DW, or BTrei) took all ROTEM measurements
and collected study data. The anaesthesiologist in charge
administered study drugs according to a predefined
dosing scale (appendix p 1). Bleeding score was assessed
after each study drug dosage by the anaesthesiologist and
the surgeon in charge (appendix p 2).
From study inclusion to ICU admission, a member of
the study team assisted the anaesthesiologist in charge to
correctly follow the study protocol. Further study-related
blood samples were sent to the Central Laboratory on
admission to the ICU and at 24 h and 48 h after admission.
Clincal data including fluid supply and transfusion
requirements were collected at each study visit (screening
and first treatment; second and further treatment loops;
admission to the ICU; 24 h, 48 h, and 10 days after
admission, and at hospital discharge or day 30). Massive
transfusion was defined as transfusion of more than
10 RBC during the first 24 h. Patients were followed up
until hospital discharge or day 30, whichever occurred
first. One of the radiologists (AM, CK) did comprehensive
lower-extremity venous duplex ultra­
sonography
examination for detection of clinically non-apparent
venous thromboembolism in all patients within days
7–10 after trauma. Two anaesthesiologists (GG, SS) not
292 patients assessed for eligibility
192 ineligible
154 inclusion criteria not met
19 met exclusion criteria
19 study personnel not available
100 enrolled and randomly assigned
48 assigned FFP 52 assigned CFC
4 discontinued treatment 2 discontinued treatment
3 exclusion criteria (lethal injury) 1 exclusion criteria (lethal injury)
1 major protocol deviation and lost 1 exclusion criteria (age <18 years)
to follow-up
44 treatment ongoing 50 treatment ongoing
44 included in modified intention-to-treat 50 included in modified intention-to-treat
analysis analysis
Figure 1: Trial profile
FFP=fresh frozen plasma. CFC=coagulation factor concentrates.
4 www.thelancet.com/haematology Published online April 27, 2017 http://dx.doi.org/10.1016/S2352-3026(17)30077-7
involved in randomisation of the patients calculated the
Sequential Organ Failure Assessment (SOFA) score daily
at the ICU, with a score of 3 or more in at least two organ
systems defined as multiple organ failure. Other than
coagulation management, patient care was not influenced
by the study protocol. Transfusion of leucocyte-filtered
RBC concentrates and platelet con­centrates followed our
institutional standard practice of restrictive transfusion
aimed to maintain haemoglobin at 8–10 g/dL and platelet
count at 50–100 × 10⁹ platelets per L.
Outcomes
The primary overall clinical endpoint was occurrence of
multiple organ failure during ICU stay as assessed by the
daily SOFA score. As secondary clinical endpoints, we
assessed commonly reported clinical outcome parameters
such as length of ICU stay and hospital stay, need and
duration of haemofiltration, ventilator-free days, and
occurrence of sepsis, infection, venous thromboembolism,
pulmonary embolism, and in-hospital mortality at 24 h
and by day 30. As further secondary efficacy endpoints,
we also addressed numbers of transfusions of RBC and
platelet concentrates during the first 24 h, results of
plasmatic and viscoelastic tests, and clinically relevant
time intervals (time until randomisation, time until start
of first study drug administration, and time until first
normalised ROTEM [together with bleeding score of 0 or
1]). As post-hoc analyses, we calculated the mean SOFA
score adjusted for ISS up to the first 7 days at the ICU,
and did an analysis for the primary endpoint adjusted for
ISS score and brain injury status. We also calculated the
number needed to treat for reversal of coagulopathy, the
number needed to harm for receiving massive
transfusion, assessed the distribution of the bleeding
score after first dosage of study drugs and its relation to
massive transfusion, and reasons for and effects of need
of rescue therapy. We assessed adverse events and serious
adverse events at each study visit, and restricted analysis
of serious adverse events to venous thrombosis and
pulmonary embolism.
We also assessed several other relevant biological and
clinical endpoints (see study protocol), which will be
reported elsewhere.
Statistical analysis
We based our sample size calculation on data from a
previous observational study8 of 246 patients with
polytrauma receiving CFC only or CFC and FFP. 12 (18%)
of 66 patients who received CFC only and 29 (37%) of
78 patients who received CFC and FFP developed
multiple organ failure. Among the 102 patients receiving
no haemostatic therapy, multiple organ failure was
diagnosed in six (6%) patients. Using n Query Advisor
and two-sided Fisher’s exact test and considering a
dropout rate of five patients in each group, at least
100 patients per group needed to be analysed to assess a
difference in occurrence of multiple organ failure
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between groups with a power of 80% and type I error at a per-protocol population exploring the reasons for rescue
global 5% (α=0·05) level. We planned interim analysis for therapy and its effect on multiple organ failure and
final adjustment after inclusion of 100 patients. Primary transfusion requirements refers to comparison of three
analysis—both final and interim—was by modified groups: CFC only (n=48), FFP and rescue therapy (n=23),
intention to treat (ie, excluding patients who discontinued and FFP only (n=21). The two patients in the CFC group
treatment). who received FFP rescue therapy were not considered as a
A mathematician not involved in our trial procedures separate subgroup. The trial was stopped early as the pre-
and patient assessment (TH) did the statistical analyses planned interim analysis showed a significant difference
using R, version 3.2.5. All statistical assessments were in treatment failure combined with an increased risk of For more on R see
two-sided; only completed cases and a significance level massive transfusion in patients in the FFP group. http://www.r-project.org
of 5% were used. Because the hypothesis of normal Patients had a median age of 43 years (IQR 26–54), an
distribution was not reasonable for most of the ISS of 34 (IQR 26–43), and nearly 50% had concomitant
continuous variables (Shapiro-Wilk normality test), we brain injury (table 1). Demographics, pre-hospital
applied the parametric Wilcoxon rank sum test and treatment, haemodynamic, and laboratory parameters on
Fisher’s exact test. We present continuous data as median arrival at the emergency department were balanced
(IQR) and categorical variables as frequencies (%). We between groups (table 1). Time to randomisation was
show effect size and precision with estimated differences 35·5 min (IQR 18·8–77·5) in the FFP group and
between groups for continuous data and odds ratios (OR)
for binary variables, with 95% CIs. We also did post-hoc CFC (n=50) FFP (n=44)
assessments of the endpoints multiple organ failure, Age (years) 42·5 (27·3 to 50·5) 42·5 (24 to 56)
reversal of trauma-induced coagulopathy, and massive
Sex
transfusion by logistic regression analysis adjusted for
Female 12 (24%) 12 (27%)
the stratification variables ISS and brain injury. We
Male 38 (76%) 32 (73%)
applied univariate analysis to identify risk factors for
BMI (kg/m²) 24·69 (23·44 to 26·31) 24·01 (22·84 to 25·73)
multiple organ failure. We included the revealed risk
Time to emergency department (min) 61·5 (40·0 to 89·8) 56·5 (43·8 to 85·0)
factors available before treatment in a logistic regression
ISS 35 (29 to 42) 30 (24 to 45)
model as independent variables for the multiple organ
Brain injury 25 (50%) 21 (48%)
failure outcome. Because of the considerable subgroup
AIS brain >2 14 (28%) 15 (34%)
formation, true treatment effects might be masked.
Glasgow Coma Scale (points) 12 (9 to 15) 11 (7 to 15)
Therefore, we did exploratory post-hoc per-protocol
Prehospital tranexamic acid 3 (6%) 5 (11%)
analysis. Because few patients in the CFC group needed
rescue therapy, the three subgroups (CFC only, FFP with Intubation at the scene 27 (54%) 20 (46%)

rescue, FFP only) were considered using Fisher’s exact Crystalloids prehospital (mL) 500 (250 to 1000) 500 (500 to 1000)

test and the Kruskal-Wallis rank sum test. Colloids prehospital (mL) 400 (0 to 500) 250 (0 to 500)
To comply with Good Clinical Practice, the data Systolic BP (mm Hg) 106 (78 to 130) 108·5 (90·0 to 145·8)
monitoring plan consisted of an initiation visit, a visit Systolic BP <90 mm Hg 19 (38%) 10 (23%)
1 week after inclusion of the first patient, repeat visit after Heart rate (beats per min) 103·5 (82·8 to 117·5) 93·0 (77·5 to 110·0)
inclusion of the fifth patient, following visits at least six Blood pH 7·32 (7·25 to 7·37) 7·32 (7·26 to 7·36)
times a year according to inclusion rate, and a close-out Base excess (mmol/L) −4·35 (−6·17 to −2·17) −4·15 (−7·75 to −1·23)
visit. This trial is registered with ClinicalTrials.gov, Lactate (mmol/L) 2·22 (1·55 to 3·22) 2·28 (1·64 to 3·03)
number NCT01545635. Haemoglobin (g/dL) 11·85 (10·03 to 13·20) 11·70 (9·55 to 12·90)
Prothrombin index (%) 68·0 (57·8 to 79·8) 64·5 (52·5 to 78·5)
Role of the funding INR 1·3 (1·1 to 1·4) 1·3 (1·2 to 1·5)
This study received no funding. All authors had access to Fibrinogen (mg/dL) 196·5 (138·5 to 218·8) 177·0 (140·5 to 222·3)
the data in the study and had final responsibility for the Antithrombin III (%) 68 (58 to 81) 67·5 (56·8 to 76·8)
decision to submit the manuscript for publication. Platelets (× 10⁹ platelets per L) 182·0 (153·5 to 211·5) 183·0 (154·8 to 221·8)
ExCT (s) 56 (49 to 67) 54 (49 to 69)
Results Exalpha (degree) 67 (59 to 71) 67 (61 to 71)
Between March 3, 2012, and Feb 20, 2016, 292 trauma ExA10 (mm) 47 (39 to 50) 46 (41 to 52)
patients with an expected ISS greater than 15 were FibA10 (mm) 8 (6 to 11) 9 (5 to 10)
screened for eligibility, of whom 192 were found ineligible Hyperfibrinolysis 4 (8%) 2 (5%)
(figure 1). 100 patients were enrolled and randomly
Data are n (%) or median (IQR). CFC=coagulation factor concentrates. FFP=fresh frozen plasma. BMI=body-mass index.
assigned to receive either FFP (n=48) or CFC (n=52).
ISS=Injury Severity Score. AIS=Abbreviated Injury Severity Score. BP=blood pressure.INR=international normalised
Six patients dropped out soon after randomisation ratio. ExCT=coagulation time of ExTEM assay. Exalpha=alpha angle of ExTEM assay. ExA10=clot firmness at 10 min.
(figure 1), meaning 94 patients (50 patients CFC, FibA10=fibrin polymerisation at 10 min. ExTEM= extrinsically activated rotational thromboelastometry.
44 patients FFP) were included in the modified intention-
Table 1: Baseline characteristics of study population
to-treat analysis. Post-hoc subgroup analysis in the

www.thelancet.com/haematology Published online April 27, 2017 http://dx.doi.org/10.1016/S2352-3026(17)30077-7 5

 Articles

CFC (n=50) FFP (n=44) Estimated difference p value

or odds ratio* (95% CI)
Multiple organ failure† 25 (50%) 29 (66%) 1·92 (0·78 to 4·86) 0·15
Days of multiple organ failure 4 (2 to 7) 3 (2 to 9) 0 (−2 to 2) 0·68
ISS-adjusted mean SOFA score 0·16 (0·13 to 0·21) 0·20 (0·15 to 0·27) −0·03 (−0·07 to −0·01) 0·019
Haemofiltration† 5 (10%) 7 (16%) 1·69 (0·42 to 7·36) 0·54
Days of haemofiltration 11·0 (5·8 to 21·5) 27·0 (21·5 to 28·5) −13·0 (−23·0 to −1·0) 0·038
Ventilator-free days 23 (13 to 27) 21 (13 to 27) 0 (−2 to 3) 0·99
Sepsis† 9 (18%) 7 (16%) 0·86 (0·25 to 2·91) 1
Infection† 32 (64%) 32 (73%) 1·49 (0·57 to 4·01) 0·39
Venous thrombosis† 4 (8%) 8 (18%) 2·53 (0·62 to 12·42) 0·22
Peripheral pulmonary embolism† 3 (6%) 1 (2·3%) 0·37 (0·01 to 4·78) 0·62
Days in the ICU 9·0 (4·0 to 22·0) 10·0 (4·8 to 23·3) 0 (−4·0 to 3·0) 0·65
Length of hospital stay (days) 28 (18 to 28) 27 (16 to 28) 0 (0 to 1) 0·61
In-hospital mortality† 5 (10%) 2 (5%) 0·43 (0·04 to 2·82) 0·44

Data are n (%) or median (IQR). CFC=coagulation factor concentrates. FFP=fresh frozen plasma. ISS=Injury Severity Score. SOFA=Sequential Organ Failure Assessment.
ICU=intensive care unit. *CF group minus FFP group. †Binary variables presented with odds ratios.

Table 2: Primary outcome in the modified intention-to-treat population

38·5 min (18·3–100·5) in the CFC group (estimated

A difference 3 min [95% CI −8 to 19], p=0·54). Frequency of
100 CFC immediate surgery was similar for both groups (40 [88%]
FFP in the FFP group, 36 [82%] in the CFC group; OR 0·62
90
[95% CI 0·16–2·24], p=0·56), as was type of surgery—
80 except for surgery of the spine, which was more frequent
70 in the CFC group (data not shown). Patients received
60
equal amounts of balanced crystalloid solutions (median
Patients (%)

24 2750 mL [IQR 1500–4025] in the FFP group vs 3275 mL

20
50 (48%)
(46%) [2500–4050] in the CFC group; estimated difference
40 500 mL [95% CI −200 to 1050], p=0·20) and 4% gelatin
12 11 solution (2000 mL [1000–3000] in the FFP group vs
30 11
(24%) 8 (25%)
(22%) 2500 mL [1625–3000] in the CFC group; 500 mL
20 5 (18%)
(11%) 3 [0 to 1000], p=0·12) until arrival at the ICU.
10 (6%) Numerically more patients in the FFP group 29 (66%)
0 of 44 patients had multiple organ failure than in the CFC
0 1 2 3
Effect size 1·59 3·04 –2·41 –2·58 group (25 [50%] of 50 patients), but this difference was
Figure 2: Differences in not significant in unadjusted analysis (OR 1·92 [95% CI
bleeding score between B 0·78–4·86], p=0·15; table 2). A post-hoc logistic regression
treatment groups and 100 No massive transfusion (n=75)
Massive transfusion (n=19)
analysis adjusted for the stratification variables ISS and
association of bleeding score 90 brain injury showed an increased risk for multiple organ
and need for massive
transfusion 80 failure in the FFP group (OR 3·13 [1·19–8·88], p=0·025).
(A) Percentage and numbers Patients with multiple organ failure were older, had a
70
of patients in the the higher ISS score and lower score on the Glasgow Coma
two treatment groups 60 Scale, received more blood components, and more
Patients (%)

showing an escalating 9
bleeding score of 0–3 after 50 (47%) frequently needed massive transfusion and PCC
29 7
first study drug
40 (39%) 24 (37%)
administration than did patients without multiple organ
administration. (32%) failure (appendix p 3). Post-hoc logistic regression
(B) Association of bleeding 30 17
score after first study drug (23%) 3
analysis revealed ISS, Glasgow Coma Scale score, age,
administration with massive 20 (16%) and group allocation as being significantly influential for
5
transfusion. The effect sizes in 10 (7%) development of multiple organ failure (appendix p 3)
both A and B are depicted as 0 We observed a higher mean ISS-adjusted SOFA score
standardised residuals for CFC. 0
CFC=coagulation factor
0 1 2 3 at up to 7 days in the ICU and a longer duration of
Bleeding score
concentrates. FFP=fresh frozen haemofiltration in patients in the FFP group compared
Effect size 2·29 1·88 –0·40 –4·45
plasma. with the CFC group (table 2). The incidence of venous

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thromboembolism and peripheral pulmonary embolism 5·47–240·03], p<0·0001). Logistic regression analysis
was similar among groups; no fatal pulmonary embolism adjusted for stratification factors ISS and brain injury
was observed. revealed a relative OR of 44 (95% CI 10–338, p<0·0001).
Post-hoc subgroup analysis based on rescue therapy
showed a higher incidence of multiple organ failure in 100 Single dose
patients in the FFP with rescue group (18 [78%] of Double dose
23 patients) compared with the CFC only group (23 [48%] 90 Double dose and rescue

of 44 patients; OR 3·84 [95% CI 1·13–15·44], p=0·021), 38

80

Reversal of trauma-induced coagulopathy (%)

and multiple organ failure occurred in 11 (52%) of (76%)

21 patients in the FFP only group (FFP rescue vs FFP only, 70

OR 0·31 [95% CI 0·07–1·34], p=0·11). We further observed
60 23
that patients in the FFP rescue group more frequently
(52%)
needed haemofiltration, although this was not significant 50
(appendix p 3).
Seven (7%) of the 94 study patients did not survive; 40
reasons were severity of brain injury (CFC: n=3; FFP: n=1) 12
30 (27%)
and sepsis (CF: n=2; FFP: n=1). No patient died because of 10 9
(20%) (21%)
exsanguination, and no death occurred within the first 20
24 h. Six (6%) patients had severe hyperfibrinolysis (CFC: 2
10
n=4; FFP: n=2) on admission to the emergency department; (4%)
three of these patients died (CFC: n=2; FFP: n=1). 0
For the first treatment loop, time until start of study CFC FFP

medication was longer in the FFP group than in the CFC Figure 3: Percentage of patients with reversal of coagulopathy after either
group (median 50·5 min [IQR 39·5–70·0] in the FFP single-dose or double-dose study drug administration during the
group vs 10 min [10–16] in the CFC group; estimated first therapy loop, and percentage of patients needing double-dose and
rescue medication during the first 24 h in the intention-to-treat population
difference −40 [95% CI −46 to −33], p<0·0001), as was time CFC=coagulation factor concentrates. FFP=fresh frozen plasma.
to correction of trauma-induced coagulopathy and
normalisation of bleeding (128·0 min [48·3–186·3] vs
22·5  min [13·5–40·0]; estimated difference −97 min CFC (n=50) FFP (n=44) Estimated difference or p value
[−126 to −60], p<0·0001). Comparable numbers of patients odds ratio* (95% CI)
(17 [39%] in the FFP group and 23 [46%] in the CFC group) FFP
showed reoccurrence of coagulopathy during the first 24 h Patients† 2 (4%) 44 (100%) ∞ (126·35 to ∞) <0·0001
and thus received further treatment loops (OR 0·74 [95% Dose (U) 5 (5 to 5) 14 (10 to 14) −9 (−16 to −2) 0·023
CI 0·30–1·82], p=0·53). Fibrinogen concentrate
A coagulopathic bleeding score of 2 or 3 after first study Patients† 50 (100%) 23 (52%) 0 (0 to 0·10) <0·0001
drug administration was more frequently observed in the Dose (g) 8 (5 to 10) 5 (4·5 to 8) 1 (0 to 3) 0·11
FFP group (p=0·0004) and correlated with massive Four-factor PCC
transfusion (p=0·0001; figure 2). A first correction of
Patients† 8 (16%) 2 (5%) 0·25 (0·02 to 1·37) 0·098
coagulopathy and bleeding was accomplished with single-
Dose (IU) 2000 (1875 to 3000) 850 (675 to 1025) 1500 (300 to 4500) 0·046
dose study drug administration in 12 (27%) patients in the
FXIII
FFP group versus 38 (76%) patients in the CFC group. The
Patients† 27 (54%) 11 (25%) 0·29 (0·11 to 0·74) 0·0060
odds in favour of successful reversal of coagulopathy after
Dose (IU) 2000 (2000 to 2500) 1500 (1375 to 2000) 500 (0 to 750) 0·031
single-dose study drug was higher for CFC than for FFP
Red blood cell concentrate‡
(OR 8·22 [95% CI 3·06–23·78], p<0·0001). Nine (20%)
Patients† 45 (90%) 39 (89%) 0·87 (0·18 to 4·08) 1
patients in the FFP group and 10 (20%) patients in the
Dose (U) 4 (2 to 7) 6 (4 to 11) −2 (−4 to 0) 0·028
CFC group needed double-dose administration. Rescue
Massive 6 (12%) 13 (30%) 3·04 (0·95 to 10·87) 0·042
medication was necessary in 23 (52%) of patients in the
transfusion
FFP group and in two (4%) patients in the CFC group (U)§†
(figure 3). The number needed to treat for reversal of Platelet concentrate¶
coagulopathy with CFC only was 2·07 (95% CI 1·6–3·1). Patients† 10 (20%) 21 (48%) 3·60 (1·35 to 10·18) 0·0078
20 (87%) of the 23 patients in the FFP group who Dose (U) 2 (1 to 4) 2 (1 to 3) 0 (−1 to 2) 0·63
required rescue medication needed rescue already in the
first treatment loop, whereas three other patients in the Data are n (%) or median (IQR). CFC=coagulation factor concentrates. FFP=fresh frozen plasma. PCC=prothrombin
complex concentrate. FXIII=coagulation factor XIII concentrate. *CFC group minus FFP group. †Binary variables
FFP group and the two patients in the CFC group received presented with odds ratios. ‡Leucocyte depleted. §≥10 U in 24 h. ¶1 U, 1 apheresis platelet concentrate, or 6 pooled
rescue therapy in later treatment loops. The odds in favour platelet concentrate.
of receiving rescue therapy were higher for patients in the
Table 3: Study drugs and transfusion requirements during the first 24 h after injury
FFP group than in the CFC group (OR 25·34 [95% CI

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The indication for double-dose or rescue medication
was mainly governed by persistent coagulopathy
combined with abnormal bleeding, and was determined
only by a bleeding score of 2 or 3 in seven patients in the
FFP group and six patients in the CFC group. Details on
applied dosages during the first treatment loop are
presented in the appendix (p 2) and the administered
dosages of study drugs during the first 24 h are depicted
in table 3.
Patients in the FFP group received more units of RBC
concentrates in the first 24 h and more frequently
needed platelet concentrates (table 3). The odds in favour
of receiving massive transfusion (RBC ≥10 U in 24 h)
were higher for FFP treatment than for CFC (table 3).
Logistic regression analysis adjusted for ISS and brain
injury confirmed this result with a relative OR of 4·24
(95% CI 1·36–5·09, p=0·017). The number needed to
harm for receiving massive transfusion with FFP was 6
(95% CI 3·0–75·1). Subgroup analysis showed the
highest transfusion requirements for patients in whom
initial FFP administration had failed to correct trauma-
induced coagulopathy (appendix p 4).

A
150 CFC 50
FFP

100 0

Change in ExCT (s)

ExCT (s)

–50
50

p=0·2461 p=0·0133 p=0·4602 –100 p=0·3739 p=0·0166

0
(–11 to 3) (–11 to 1) (–10 to 6) (–8 to 4) (–31 to –4)

100 40

80 20
Change in Exalpha (˚)
Exalpha (˚)

60 0

40 –20

20 p=0·5962 p<0·0001 p<0·0001 p<0·0001 p=0·0002

–40
(–2 to 3) (7 to 13) (8 to 20) (6 to 12) (8 to 22)

20
60

50 10
Change in ExA10 (mm)

40
ExA10 (mm)

30
–10
20

10 p=0·473 p=0·0018 p=0·1047 –20 p=0·0027 p=0·0158

(–1 to 3) (2 to 7) (–2 to 10) (1 to 6) (1 to 11)

20
25
15
20
Change in FibA10 (mm)

10
15
FibA10 (mm)

10 5

5 0
0
p=0·3268 p<0·0001 p<0·0001 –5 p<0·0001 p<0·0001
–5 (0 to 1) (4 to 6) (3 to 7) (4 to 6) (4 to 9)
Baseline Single dose Double dose Rescue Single dose Double dose Rescue

(Figure 4 continues on the next page)

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B
100 CFC 40
FFP

Change in prothrombin index (%)

80
20
Prothrombin index (%)

60
0
40

20 –20

0 p=0·2342 p=0·1873 p=0·0033 p<0·0001 p=0·0009

(–2 to 8) (–9 to 2) (–27 to –8) –40 (–10 to –4) (–23 to –9)

5 1·0

4 0·5

0
3
Change in INR

–0·5
INR

2
–1·0
1
–1·5
p=0·3336 p=0·1839 p=0·0036 p=0·0037 p=0·0262
0 (–0·2 to 0·1) (0 to 0·1) (0·1 to 0·8) –2·0 (0 to 0·2) (0 to 0·5)

100
200

50
150
Change in aPTT (s)
aPTT (s)

100 0

50 –50

0 p=0·3199 p=0·0016 p=0·0012 –100 p<0·0001 p=0·003

(–7 to 2) (2 to 10) (13 to 59) (6 to 12) (12 to 40)

250
300
200
Change in fibrinogen (mg/dL)

150
Fibrinogen (mg/dL)

200
100

50
100
0

–50
0 p=0·488 p<0·0001 p=0·003 p<0·0001 p<0·0001
(–9 to 22) (29 to 71) (16 to 69) –100 (33 to 60) (36 to 75)

40

100
Change in antithrombin III (%)

20
Antithrombin III (%)

0
50
–20

–40
0 p=0·5177 p=0·0021 p<0·0001 p<0·0001 p<0·0001
(–4 to 8) (–14 to 3) (–37 to –19) (–15 to –8) (–31 to –19)
–60
Baseline Single dose Double dose Rescue Single dose Double dose Rescue

(Figure 4 continues on the next page)

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C
150 80 CFC
FFP
60

100 40

Change in FXIII (%)

20
FXIII (%)

0
50
–20

–40
0 p=0·5619 p=0·3199 p=0·7678 p=0·0004 p=0·036
(–5 to 8) (–11 to 5) (–14 to 17) –60 (–14 to –6) (2 to 27)

15
5

Change in haemoglobin (g/dL)

Haemoglobin (g/dL)

10 0

5 –5

p=0·1466 p=0·0004 p=0·0006 p=0·1395 p=0·1042

(–0·2 to 1·3) (0·5 to 1·8) (0·7 to 2·0) (–0·2 to 1·2) (–0·2 to 2·3)

250 50
Change in platelet count (×109)

200
0
Platelet count (×109)

150
–50
100
–100
50

0 p=0·8855 p=0·0085 p=0·184 –150 p=0·0011 p=0·2374

(–16 to 16) (6 to 35) (–11 to 44) (7 to 27) (–8 to 35)

4
Change in lactate (mmol/L)

10
2
Lactate (mmol/L)

5 0

–2
0
p=0·26 p=0·0145 p=0·3221 –4 p=0·0091 p=0·1013
(–0·67 to 0·22) (–0·89 to –0·11) (–1·22 to 0·33) (–0·56 to –0·11) (–1·44 to 0·11)
Baseline Single dose Double dose Rescue Single dose Double dose Rescue

Figure 4: Absolute values and changes from baseline in ROTEM parameters (A), standard plasmatic coagulation tests (B), and FXIII, haemoglobin, platelet
count, and lactate (C) in the intention to treat population
Boxplots show available measurements during the first therapy loop at baseline (CFC: n=50; FFP: n=44), after single-dose study drug administration (CFC: n=50; FFP:
n=44), double-dose study drug administration (CFC: n= 12; FFP: n=32), and after rescue crossover medication (FFP group only: n=20). Dashed lines indicate the lower
normal values (for haemoglobin, the dashed line indicates the threshold for transfusion) and zero change from baseline. The horizontal line in the middle of each box
represents the median. The upper and lower bounds of each box mark the 75th and 25th percentiles, respectively. Whiskers represent the minimum and maximum,
excluding outliers (dots). Estimated difference is CFC group minus FFP group. CFC=coagulation factor concentrates. FFP=fresh frozen plasma. ExCT=coagulation time
of ExTEM assay. Exalpha=α angle of ExTEM assay. ExA10=clot firmness at 10 min. FibA10=fibrin polymerisation at 10 min. INR=international normalised ratio.
aPTT=activated partial prothrombin time. FXIII=coagulation factor XIII concentration. ExTEM= extrinsically activated rotational thromboelastometry.

At randomisation (baseline) all ROTEM parameters whereas they normalised quickly in patients receiving
were comparable between groups (figure 4). Initiation CFC. Fibrin polymerisation (FibA10) and fibrinogen
of coagulation (ExCT) was shortest with CFC. concentration increased insufficiently with FFP,
Propagation of coagulation (Exalpha) and clot firmness whereas values well above thresholds were achieved
at 10 min (ExA10) worsened after FFP treatment, with CFC.

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Results of standard plasmatic coagulation tests although inconclusive because of sample size, indicate
improved after repeated FFP treatment and remained at an increased risk for development of multiple organ
baseline values with CFC (figure 4). Antithrombin III failure with first-line use of FFP. We observed that more
levels increased after FFP administration but decreased patients in the FFP group had multiple organ failure
with CFC. FXIII concentrations were similar and above compared with the CFC group. This difference was not
60% in both groups. Haemoglobin values were lower statistically significant in unadjusted analysis, but
with FFP treatment than with CFC treatment, and the achieved significance with adjustment for the
lowest platelet counts were observed with FFP. Lactate
levels increased with FFP and decreased or remained CFC (n=50) FFP (n=44) Estimated difference p value
unchanged with CFC (figure 4). Rescue medication in (95% CI)
FFP patients improved ExCT, Exalpha, FibA10, and ExCT (s)
fibrinogen, whereas ExA10, haemoglobin, platelet count, Admission 46·0 (42·0 to 50·0) 52·0 (47·0 to 56·3) −6·0 (−9·0 to −2·0) 0·0016
and FXIII remained lower and lactate higher than in 24 h 50·0 (45·0 to 57·0) 56·0 (50·0 to 59·0) −4·0 (−8·0 to −1·0) 0·019
patients treated with first-line CFC. 48 h 53·5 (49·3 to 57·0) 54·0 (48·8 to 63·3) −1·0 (−7·0 to 3·0) 0·61
On admission to the ICU, patients in the FFP group Exalpha (°)
showed significant differences in ROTEM parameters Admission 74·0 (69·0 to 78·0) 69·0 (62·0 to 73·0) 5·0 (1·0 to 8·0) 0·0072
and plasmatic coagulation tests compared with patients 24 h 75·0 (69·5 to 76·0) 72·0 (67·0 to 75·0) 2·0 (0 to 5·0) 0·0515
in the CFC group (table 4). Most of these differences 48 h 76·0 (72·5 to 79·0) 77·0 (72·0 to 78·0) 0 (−2·0 to 2·0) 1
persisted until 24 h after admission, except Exalpha, PTI, ExA10 (mm)
international normalised ratio (INR), and lactate, which Admission 48·0 (43·0 to 51·0) 43·0 (39·0 to 47·3) 4·0 (1·0 to 7·0) 0·0027
were comparable already at 24 h after admission. At 48 h 24 h 50·0 (45·0 to 54·0) 46·0 (41·0 to 48·8) 5·0 (2·0 to 8·0) 0·0012
after admission, platelet counts were still significantly 48 h 52·0 (45·0 to 58·0) 50·0 (43·8 to 56·0) 2·0 (−2·0 to 6·0) 0·28
lower in the FFP group than in the CFC group. All other FibA10 (mm)
laboratory parameters were comparable between groups. Admission 14·0 (11·0 to 16·0) 11·0 (9·0 to 12·5) 2·0 (1·0 to 4·0) 0·0019
Exploratory subgroup analysis revealed that patients in 24 h 16·0 (14·0 to 19·0) 15·0 (13·0 to 16·0) 2·0 (0 to 3·0) 0·030
the FFP-only group had milder coagulopathy but similar 48 h 22·0 (16·3 to 24·8) 21·0 (16·5 to 23·0) 1·0 (−1·0 to 3·0) 0·23
lactate compared with patients in the FFP group receiving
Prothrombin index (%)
rescue therapy. When compared with the CFC-only
Admission 53·0 (45·0 to 61·0) 63·5 (48·0 to 72·0) −8·0 (−15·0 to −2·0) 0·0077
subgroup, the FFP-only subgroup had higher PTI, lower
24 h 59·0 (47·0 to 67·0) 63·5 (49·8 to 72·3) −4·0 (−11·0 to 1·0) 0·11
INR, and lower activated partial prothrombin time
48 h 71·5 (61·8 to 83·3) 72·0 (62·5 to 81·5) 1·0 (−7·0 to 8·0) 0·91
(aPTT) after treatment with FFP; however, Exalpha,
INR
FibA10, and haemoglobin were lower with FFP-only
Admission 1·5 (1·3 to 1·6) 1·3 (1·2 to 1·5) 0·1 (0 to 0·2) 0·010
treatment than with CFC-only treatment (data not
24 h 1·4 (1·2 to 1·5) 1·3 (1·2 to 1·5) 0 (0 to 0·1) 0·26
shown).
48 h 1·2 (1·1 to 1·4) 1·2 (1·1 to 1·3) 0 (−0·1 to 0·1) 0·77
aPTT (s)
Discussion
Admission 53·0 (42·0 to 64·0) 38·5 (33·0 to 55·3) 9·0 (4·0 to 15·0) 0·0012
This randomised trial is the first to our knowledge to
compare first-line use of FFP and CFC for treatment of 24 h 50·0 (42·0 to 59·0) 43·0 (38·0 to 53·0) 6·0 (1·0 to 11·0) 0·024

coagulopathy and associated bleeding in major blunt 48 h 46·0 (38·0 to 51·5) 44·0 (37·5 to 50·5) 1·0 (−3·0 to 5·0) 0·72

trauma. The study aimed to compare the efficacy of Fibrinogen (mg/dL)

haemostatic treatment in correcting trauma-induced Admission 213 (191 to 238) 199·5 (167·8 to 227·8) 18·0 (−1·0 to 38·0) 0·068
coagulopathy, consequently arising blood loss-associated 24 h 367 (314 to 416) 334·0 (302·0 to 366·5) 25·0 (−5·0 to 56·0) 0·090
transfusion requirements, and clinical outcome. The 48 h 518·5 (391·0 to 571·25) 499·0 (426·0 to 584·5) −8·0 (−59·0 to 47·0) 0·81
trial was terminated early after randomisation of Antithrombin III (%)
100 patients, as the a-priori planned interim analysis Admission 45·0 (32·8 to 51·5) 62·5 (50·0 to 73·0) −19·0 (−25·0 to −12·0) 0
showed an unacceptably high incidence of treatment 24 h 43·0 (36·0 to 55·0) 56·5 (46·0 to 64·3) −11·0 (−17·0 to −4·0) 0·0038
failure and increased risk for massive transfusion for 48 h 46·5 (39·3 to 61·8) 58·0 (41·5 to 64·0) −5·0 (−12·0 to 3·0) 0·20
patients randomly allocated to the FFP group. However, FXIII (%)
the available sample size appears sufficient to make Admission 78·0 (58·0 to 97·0) 79·5 (69·0 to 93·0) −4·0 (−13·0 to 5·0) 0·40
some conclusions that first-line CFC is superior to FFP. 24 h 61·0 (50·3 to 74·0) 68·0 (54·5 to 76·0) −2·0 (−9·0 to 4·0) 0·46
We observed that transfusion of FFP is frequently 48 h 53·5 (47·0 to 61·0) 55·0 (48·0 to 65·0) −2·0 (−8·0 to 4·0) 0·44
ineffective for correction of the outcome-related Haemoglobin (mg/dL)
pathologies of bleeding, hypofibrinogenaemia, low Admission 9·5 (8·8 to 10·2) 9·2 (8·1 to 10·0) 0·3 (−0·2 to 0·9) 0·26
fibrin polymerisation, and poor clot strength. Second, 24 h 9·0 (8·1 to 9·7) 8·8 (8·2 to 9·9) −0·1 (−0·6 to 0·5) 0·83
use of FFP is associated with enduring coagulopathic 48 h 8·8 (8·1 to 9·2) 8·8 (8·3 to 9·8) −0·2 (−0·7 to 0·2) 0·25
bleeding, increased transfusion requirements, and also (Table 4 continues on next page)
need for massive transfusion. Third, available results,

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CFC (n=50) FFP (n=44) Estimated difference
(95% CI)
(Continued from previous page)
Platelets (×10⁹ platelets per L)
Admission 110·5 (86·8 to 144·3) 87·0 (69·8 to 117·3) 23·0 (9·0 to 37·0)
24 h 97·0 (73·0 to 123·0) 74·0 (59·0 to 89·0) 23·0 (11·0 to 37·0)
48 h 92·5 (61·5 to 115·8) 79·0 (60·0 to 93·0) 15·0 (1·0 to 29·0)
Lactate (mmol/L)
Admission 1·89 (1·22 to 2·66) 2·44 (1·67 to 3·14) −0·56 (−0·89 to 0)
24 h 1·22 (0·92 to 1·55) 1·00 (0·83 to 1·55) 0·11 (−0·11 to 0·33)
48 h 1·00 (0·78 to 1·30) 0·89 (0·67 to 1·11) 0·11 (0 to 0·33)
Data are median (IQR). Estimated difference is CFC group minus FFP group. CFC=coagulation factor concentrates.
FFP=fresh frozen plasma. ExCT=coagulation time of ExTEM assay. Exalpha=alpha angle of ExTEM assay. ExA10=clot
firmness at 10 min. FibA10=fibrin polymerisation at 10 min. INR=international normalised ratio. aPTT=activated
partial prothrombin time. FXIII=coagulation factor XIII concentrate. ExTEM=extrinsically activated rotational
thromboelastometry.
Table 4: Laboratory measurements on arrival at the intensive care unit, and 24 h and 48 h thereafter
stratification variables ISS and brain injury. Additionally,
exploratory subgroup analysis showed a higher incidence
of multiple organ failure in patients in whom initial FFP
failed when compared with patients receiving CFC only,
whereas no difference occurred between the the FFP
patients who had rescue therapy and those who did not.
Confirming earlier reports on the independent influence
of transfusion rates on the development of multiple
organ failure,2,13–16 univariate analysis showed an
association between multiple organ failure and the
numbers of transfused blood components. Multivariate
analysis revealed group allocation, ISS, Glasgow Coma
Scale score, and age as significantly influential factors
for development of multiple organ failure. Considering
that ISS, Glasgow Coma Scale score, and age were
comparable between groups at baseline, we strongly
assume a possibly increased risk for the occurrence of
multiple organ failure following first-line FFP
transfusion. We believe that with inclusion of more
patients or the use of an algorithm with continued FFP
transfusion and no CFC rescue therapy, we could have
established an even more distinct result.
We found an unexpectedly large rate of treatment
failure of 52% following FFP transfusion, whereas the
number needed to treat (2·07) was remarkably low in the
CFC arm. This number indicates that, on average,
100 of 207 patients undergoing CFC treatment would
show reversal of trauma-induced coagulopathy, which
would not have been the case with FFP treatment.
Transfusion of FFP resulted in no clinically relevant
improvement or even worsening of fibrin polymerisation
and clot firmness. As INR and aPTT are very sensitive in
detecting even small changes in concentrations of
coagulation factors, plasmatic test improved with FFP.
Despite this, the phase until a first correction of
coagulopathy and a halt in microvascular bleeding was
achieved was significantly longer in the FFP group than
in the CFC group. In addition, patients in the FFP group
12 www.thelancet.com/haematology Published online April 27, 2017 http://dx.doi.org/10.1016/S2352-3026(17)30077-7
more frequently showed diffuse microvascular or
p value
massive bleeding after first study drug administration
than did patients receiving CFC. These findings explain
why patients in the FFP group needed significantly more
RBC units and were more frequently exposed to massive
0·0034
transfusion and transfusion of platelet concentrates
0·0004 despite treatment groups being comparable at baseline.
0·036 The number needed to harm for receiving massive
transfusion was 5·7, meaning that about six patients
0·044 would have to be treated with FFP instead of CFC to
0·19 result in one extra harmful event.
0·18 Our data show poor efficacy of FFP in limiting blood loss
or correcting trauma-induced coagulopathy—a finding
that is in agreement with results of meta-analyses18,19 and
several studies using FFP but no comparator.20–23 A study21
reported that neither lactate levels nor any ROTEM
parameter improved in 106 patients receiving mixed
transfusion packages with late or no fibrinogen
supplementation. The percentage of coagulopathic
patients increased from 43% on admission to up to 68%
after patients had received 12 U of RBC and FFP, with
FFP–RBC ratios between 0·5 and 0·9. Bleeding continued
and clot firmness was partially corrected on day 1.21 Study
population, frequency of surgery, and use of crystalloids
were quite comparable to ours, but overall mortality was
35% compared with 7% in our study. Why the observed
mortality in that study was five times higher remains
unclear. However, the last published meta-analysis of the
efficacy and safety of fibrinogen concentrate in surgical
patients found a reduced rate of all-cause mortality in the
fibrinogen group.24 We can only speculate that besides
other differences in patient management, fibrinogen
deficiency might have persisted in their patients, resulting
in the enduring low clot firmness—a condition that
promotes ongoing bleeding and poor outcome.3,4,11,12
The limits of the study need to be discussed. In order to
avoid any financial support, we conducted a single-centre
study using an algorithm that might not be generally
applicable. We administered study medications without
masking, because the obvious difference in the process
of study drug administration is impossible to mask,
especially in the challenging clinical situation of treating
unstable major trauma patients. The known variability in
indication for transfusion might bias the observed
differences in transfusion rates. We reject this argument
because blood cell count was closely monitored in all
patients, and results during treatment and on arrival at
the ICU confirm compliance with institutional practice
of restrictive transfusion and, moreover, haemoglobin
was even lower in the FFP group than in the CFC group.
The endpoint FibA10 as an indicator for successful
reversal can be questioned. To assess efficacy of
haemostatic therapy, a measurable parameter of success
needed to be defined. In addition to ExCT, we used
FibA10, which more exactly predicts need for massive
transfusion than total clot firmness.3,4,12 We also used a
pragmatic bleeding score, which is obviously subjective

and had not been validated so far, but we were not aware
of another possibility for assessment of the bleeding
situation. In fact, actual analysis showed a significant
difference between groups and a significant correlation
with massive transfusion. The study could also be
criticised because patients in the FFP arm received the
first dose about 40 min later than did those in the CFC
arm. In our opinion, elimination of the intrinsic CFC
benefits of faster therapy by artificially prolonging the
time to start of therapy would have been incorrect, both
to the patients and for the analysis. Additionally, the start
time of 40 min is already relatively early when considering
the data of the PROMMTT study,25 which showed survival
benefit with early FFP transfusion that was achieved
sufficiently at about 3 h. The study could be further
criticised because we compared the combined use of
FXIII, PCC, and fibrinogen concentrate to FFP only.
Because FFP is not a single substance, but a mixture of
all coagulation factors, withholding FXIII or PCC in the
CFC arm would have introduced a negative bias.
Administering only fibrinogen could not have corrected
FXIII or thrombin deficiency. FXIII supports fibrin
polymerisation and increases clot resistance to
fibrinolytic attack. As summarised in a review,26 increased
bleeding was reported in surgical patients with FXIII
levels below 60% and at constant fibrinogen concentration
fibrin polymerisation declines below such FXIII levels.
Observational data show that nearly 30% of trauma
patients exhibit FXIII of less than 60% on admission,
and its association with blood loss (own unpublished
results) and FXIII levels is well maintained with FFP.8
We thus aimed to maintain similar levels at about 60% in
both groups in order to minimise further bias. The actual
results show that our chosen algorithm was appropriate.
The FFP dose might also be questioned as being too low,
thereby explaining the poor correction of coagulopathy.
The dose was chosen according to the European
guidelines on trauma treatment (published in 2010).27
In addition, factor concentrations should be maintained
at about 30%. As reported in the literature, 1 mL/kg
bodweight of FFP increases the activity of factors by
about 1%. Thus, the recommended dose cited in the
European guidelines seems appropriate. Furthermore,
transfusion of 30 mL/kg bodyweight nearly equals one
normal plasma volume of adults.
Data collected on the incidence of deep vein thrombosis
and pulmonary embolism revealed no differences
between groups, but the sample size was probably too
small to work out statistically significant differences
between groups. However, if mainly fibrinogen
concentrate is used, the risk for thromboembolism is
rather low because fibrinogen and fibrin are also
known as antithrombin I.28 Finally, the early study
discontinuation raises some issues concerning the
unbiased estimation of treatment effects. Nevertheless,
the available data appear sufficient to make some
conclusions that CFC is superior to FFP.
www.thelancet.com/haematology Published online April 27, 2017 http://dx.doi.org/10.1016/S2352-3026(17)30077-7 13
Articles
In conclusion, our results underline the importance of
early fibrinogen supplementation for severe clotting
failure in multiple trauma. A CFC-based algorithm
guided by viscoelastic tests is considerably superior to
FFP transfusion. Correction of trauma-induced
coagulopathy fails in only 4% of patients who receive
CFC early compared with 52% of patients receiving FFP
first line. Persistent low fibrin polymerisation due to
uncorrected hypofibrinogenaemia leads to poor clot
strength, which results in prolonged bleeding, increased
transfusion requirements, massive transfusion, and
ultimately increased risk for multiple organ failure.
Considering all the published data and our data, we
suggest that the recommendation for first-line FFP
transfusion be critically reassessed towards a goal-
directed therapy focusing on early and effective
fibrinogen replacement.
Contributors
PI designed the study with input from DF and MM and wrote the study
protocol. TH provided statistical analysis and constructed figures and
tables. GG and SS calculated daily SOFA scores at the ICU. AM or CK
performed duplex sonography of the legs at days 7–10 after trauma. All
other authors (NI, DvL, BF, IHL, MS, VR, ST, HR, BTrem, DW, BTrei,
and EO) recruited patients or assisted the anaesthesiologist in charge to
correctly follow the study protocol, organised study-related blood
sampling, and collected data. NI, DvL, and PI contributed to data
integrity. PI drafted the manuscript considering critical comments from
DF, MM, BF, IHL, and EO. All authors commented on and approved the
final version of the manuscript.
Declaration of interests
PI has received personal fees from Baxter GmbH, CSL Behring GmbH,
Fresenius Kabi GmbH Austria, Bayer GmbH Austria, and LFB, and non-
financial support from TEM International, outside the submitted work.
DF has received grants and personal fees from CSL Behring, LFB, and
BBraun, outside the submitted work. MM has received personal fees from
CSL Behring GmbH, outside the submitted work. IHL has received
personal fees and non-financial support from Fresenius Austria, and non-
financial support from MSD and Pfizer, outside the submitted work. SS
has received personal fees from Fresenius Kabi GmbH Austria, outside
the submitted work. All other authors declare no competing interests.
Acknowledgments
We thank all included patients, all doctors and nurses at the Department
of Anaesthesiology and Intensive Care Medicine, the Department of
General and Surgical Intensive Care Medicine, and the Department of
Trauma Surgery for supporting us in conducting this study. We also
thank Pamela Schech, CRA, for comprehensive study monitoring.
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