Journal of Thrombosis and Haemostasis, 16: 170–174 DOI: 10.1111/jth.

13893

RECOMMENDATIONS AND GUIDELINES

Use of factor concentrates for the management of

perioperative bleeding: guidance from the SSC of the ISTH
A . G O D I E R , * A . G R E I N A C H E R , † D . F A R A O N I , ‡ J . H . L E V Y § and C . M . S A M A M A ¶
*Department of Anesthesiology and Intensive Care Medicine, Fondation Adolphe de Rothschild and INSERM UMRS-1140 Facult
e de
Pharmacie, Descartes University, Paris, France; †Department of Immunology and Transfusion Medicine, Universit€atsmedizin Greifswald,
Greifswald, Germany; ‡Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Canada;
§Departments of Anesthesiology, Surgery, and Critical Care, Duke University School of Medicine, Durham, NC, USA; and ¶Department of
^ pitaux de Paris, Cochin University Hospital, Paris Descartes University,
Anesthesiology and Intensive Care Medicine, Assistance Publique-Ho
Paris, France

To cite this article: Godier A, Greinacher A, Faraoni D, Levy JH, Samama CM. Use of factor concentrates for the management of perioperative
bleeding: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16: 170–4.

availability of lower-quality evidence, which the clinician

may or may not adopt.

Perioperative bleeding is a common complication follow-

ing major surgery. Despite surgical measures to minimize
bleeding, patients develop acquired hemostatic defects as
a result of multiple factors that include hemorrhagic loss,
consumption, dilution of coagulation factors and plate-
lets, hypothermia, acidosis, and activation of fibrinolytic
and inflammatory pathways. Therapeutic approaches for
restoring hemostasis include allogeneic blood product
administration. However, there is increasing use of clot-
ting factor concentrates that not only include fibrinogen
and prothrombin complex concentrate (PCC), but also
factor XIII (FXIII) and recombinant activated factor VII
(rFVIIa).
In this guidance document, we review available evi-
dence for clotting factor concentrate administration in the
management of perioperative bleeding to provide practi-
cal guidance for clinicians. The wording used herein to
reflect the strength of recommendations is based on a
standardized format used in guidance documents by the
International Society on Thrombosis and Haemostasis [1].
Thus, the wording «we recommend» indicates a strong
consensus among the panel members and/or the availabil-
ity of high-quality evidence, which the clinician should
consider adopting into practice in most cases. The word-
ing «we suggest» reflects a weak guidance statement with
moderate consensus among the panel members and/or the
Correspondence: Anne Godier, Service d’Anesth
esie-R
eanimation,
Fondation Rothschild, 25-29 rue Manin, 75019 Paris, France
Tel.: +33 1 4803 6776
E-mail: agodier@fo-rothschild.fr
Received: 7 September 2017
Manuscript handled by: M. Levi
Final decision: F. R. Rosendaal, 25 October 2017
Fibrinogen concentrates
Fibrinogen is a critical factor for hemostasis in the con-
text of perioperative bleeding [2]. Depending on the coun-
try and availability of cryoprecipitate, fibrinogen
concentrates (FCs) are often the standard of care in
patients with fibrinogen deficiency [2]. The normal plasma
fibrinogen concentration ranges from 2 to 4 g L 1, and
without supplementation, fibrinogen is the first coagula-
tion factor to fall to critically low levels (< 1.0 g L 1)
during major hemorrhage [2]. Moreover, a decrease in fib-
rinogen concentration is a predictor of the severity of the
hemorrhage in trauma patients and with postpartum
hemorrhage [2]. Multiple in vitro and clinical studies
reported that low fibrinogen levels impair fibrin clot
strength and that clot strength is restored with fibrinogen
repletion [2].
The efficacy of FCs in stopping bleeding remains
unproven. Small uncontrolled studies evaluating FCs for
perioperative use have yielded conflicting results, but
most have been negative [2]. When compared with pla-
cebo in seven randomized double-blind studies, FCs failed
to reduce bleeding or the need for allogeneic transfusion
in cardiac surgery [3–5], urologic surgery [6], obstetric
procedures [7], orthotopic liver transplantation [8] and
trauma [9]. Conversely, two single-center, randomized tri-
als showed results that were at least partly positive. After
complex cardiac surgery, FC administration guided by
viscoelastic tests induced a decrease in postoperative
bleeding, albeit weakly clinically relevant (300 mL vs.
355 mL), leading to a reduction in allogeneic blood pro-
duct transfusions [10]. In coagulopathic trauma patients,
administration of clotting factor concentrates (primarily
FC) guided by viscoelastic tests failed to reduce the

© 2017 International Society on Thrombosis and Haemostasis

 Factor concentrates for perioperative bleeding 171

primary endpoint, namely multiple organ failure, but Prothrombin complex concentrates (PCCs)
decreased the need for massive transfusion [11]. Of note,
Non-activated PCCs are lyophilized human plasma-derived
positive studies are mainly based on an initial dose of
vitamin K-dependent coagulation factor concentrates.
25–50 mg kg 1, often individualized using viscoelastic
According to the content of coagulation factors, they are
tests [2].
categorized as three-factor PCCs (FII, FIX and FX) and
However, despite considerable work in this area, there
four-factor PCCs (also including FVII). Several commer-
may be several reasons why FC alone is unlikely to be of
cial PCC products are available, which differ in their com-
benefit. They include the use of a single coagulation fac-
position of coagulation factors and inhibitors, the presence
tor to treat a coagulopathy characterized by a decrease in
of heparin and antithrombin, and their purity.
all factors, prophylactic administration before any hemor-
In most jurisdictions, the clinical indications for PCCs
rhage, and the mixed inclusion of high and low-bleeding-
are limited to the perioperative prophylaxis and treatment
risk surgeries that may dilute the potential FC efficacy.
of bleeding in the setting of acquired deficiency of pro-
Further, instead of single preemptive administration, FC
thrombin complex coagulation factors, such as that
should rather be used in patients with major bleeding and
caused by vitamin K antagonist therapy. However, the
as part of multimodal therapy, including other treatments
off-label use of PCCs is increasing for the management of
for coagulopathy and bleeding. The use of point-of-care
trauma and perioperative bleeding based on multiple pub-
testing should be considered to guide therapy, but this
lished but non-validated algorithms [13]. PCC represents
has to be further studied, and the target for repletion
an important option compared with fresh frozen plasma
remains unknown, even if lower quality studies suggest a
(FFP): PCC is immediately available because it does not
target fibrinogen level of 1.5–2.0 g L 1.
require ABO compatibility or thawing; it can be rapidly
Regarding safety, epidemiologic studies suggest a
administered; and it is not associated with transfusion-
strong association between long-term hyperfibrinogene-
associated circulatory overload or transfusion-related
mia and both arterial and venous thrombosis, but it
acute lung injury [13]. However, PCC only supplies fac-
remains unknown whether hyperfibrinogenemia is only
tors II, VII, IX and X and does not replace fibrinogen or
a biomarker of the cardiovascular risk or is a causative
factor V. In addition, PCC is typically administered
mechanism of thrombosis [2]. Nevertheless, in a mouse
together with crystalloid or colloid for intravascular vol-
model, fibrinogen infusion, increasing fibrinogen concen-
ume resuscitation, which may induce hemostatic abnor-
tration up to 4 g L 1, directly promoted thrombosis
malities related to dilutional effects on coagulation
after vascular injury, with a dose-ranging effect, which
factors, but also related to interference with platelet activ-
supports a causative role for short-term hyperfibrino-
ity, decreased activity of von Willebrand factor or impair-
genemia in thrombosis [12] and suggests the monitoring
ment of fibrin polymerization.
of fibrinogen concentration and limitation of the
Administration of PCC for the management of periop-
amount of fibrinogen concentrates administrated. Of
erative bleeding is based on low-quality evidence.
note, the FC doses used in clinical studies did not pro-
Whereas preclinical studies in animal models demon-
duce significant increases in postoperative plasma fib-
strated that PCC reduced blood loss or improved survival
rinogen concentrations. However, no study has been
[13], trials in patients with bleeding are lacking. Retro-
adequately designed to assess the thrombotic risk of
spective studies reported that PCC alone might attenuate
FC supplementation and to account for multiple poten-
bleeding [13]. Five studies assessed the use of PCC as part
tial causes of thrombosis in the complex setting of peri-
of a concentrate-based approach guided by a viscoelastic
operative bleeding.
point-of-care device for management of bleeding after
trauma or surgery [13]. Although favorable results were
Guidance for use of FC for perioperative bleeding reported, the studies were observational and mainly retro-
management spective in design. In the only randomized trial that com-
pared a concentrate-based approach with FFP in trauma
We suggest against FC preemptive administration.
patients, only 16% of patients received PCC. Therefore,
We suggest that FC should only be used as part of multi-
no conclusion could be drawn about efficacy and safety.
modal therapy.
There is an urgent need, therefore, for randomized con-
We suggest laboratory assessment of fibrinogen concentra-
trolled trials to assess PCC for the management of peri-
tion or viscoelastic monitoring of functional fibrinogen
operative bleeding.
before FC administration.
PCC may be associated with thromboembolic compli-
We recommend against FC administration if the plasma fib-
cations, but the risk of PCC-associated thromboembolic
rinogen concentration is over 1.5 g L 1 or if there is no evi-
events in non-anticoagulated patients is uncertain. Never-
dence of functional fibrinogen deficiency on viscoelastic
theless, two randomized studies performed in a porcine
point-of-care analysis.
model of hemodilution and hepatic injury highlighted the
If FC is given, we suggest using an initial dose of 25–
thromboembolic risk [14,15]. In the first one, PCC
50 mg kg 1.

© 2017 International Society on Thrombosis and Haemostasis

172 A. Godier et al
(35 IU kg 1) with FC (200 mg kg 1) reduced blood loss
compared with saline, but a fatal thromboembolic com-
plication was reported in 1 of the 10 treated animals [14].
In the second study, animals randomly received PCC (35
or 50 IU kg 1) or saline. PCC reduced blood loss but
thromboembolism was found in all animals treated with
50 IU kg 1 PCC; moreover, 44% of animals also showed
signs of disseminated intravascular coagulation (DIC)
[15]. These side-effects may be attributable to an imbal-
ance of prohemostatic factors and inhibitors, specifically
an insufficient level of antithrombin compared with the
potential for thrombin generation [13,15]. Historically,
DIC and other thrombotic complications were reported
with older PCCs, which contained traces of activated fac-
tors in the concentrate. These PCCs were withdrawn but
today’s PCCs are still not balanced regarding their pro-
and anticoagulants [16]. These data suggest a potential
increased risk of thromboembolic complications with
PCC, especially with high, repeated or rapidly infused
doses, and special caution is advocated with the use of
PCC in patients with acquired procoagulant status,
including ongoing DIC.
Guidance for use of PCC for perioperative bleeding
management
We suggest against the use of PCC as a monotherapy for
perioperative bleeding management.
We suggest against the use of PCC in bleeding patients
with DIC.
FXIII concentrates
Plasma-derived FXIII concentrate and recombinant
FXIII (rFXIII) are two forms of FXIII concentrate avail-
able for FXIII supplementation [17,18]. The first one is a
highly purified, pasteurized, plasma-derived concentrate,
whereas the second is a recently marketed recombinant
FXIII-A subunit that binds to the endogenous FXIII-B
subunit in plasma and forms a stable FXIII heterote-
tramer. Both agents are indicated for patients with
congenital FXIII deficiency, which is a rare, autosomal-
recessive bleeding diathesis that is associated with
impaired wound healing, intracranial hemorrhage and
recurrent miscarriages [17]. FXIII supplementation has
also been suggested for perioperative bleeding manage-
ment, although there are few data to support this indica-
tion [17]. FXIII is a pivotal enzyme in the coagulation
process because once activated it stabilizes clots by cross-
linking them and rendering them more resistant to degra-
dation. Acquired FXIII deficiency (defined as a FXIII
plasma concentration < 60% of normal) has been
reported with perioperative bleeding and postpartum
hemorrhage, and several clinical studies have observed an
increased bleeding tendency in surgical patients with
FXIII deficiency [17,19]. In cardiac surgery, a reduction
in FXIII concentration occurs after cardiopulmonary
bypass (CPB) and an inverse relationship between FXIII
levels and postoperative blood loss has been reported
[20]. The association between FXIII deficiency and post-
operative hemorrhage has also been assessed in a series of
1264 patients who underwent neurosurgery [21]. Measure-
ment of FXIII activity was performed postoperatively in
34 patients in whom coagulopathy was suspected despite
normal platelet counts, fibrinogen levels, prothrombin
times and partial thromboplastin times, and eight of them
had FXIII deficiency.
As acquired FXIII deficiency and perioperative bleeding
are related, a few studies assessed whether FXIII supple-
mentation decreased perioperative bleeding. None demon-
strated improved hemostasis or reduced need for other
prohemostatic therapies. In a preliminary study of patients
undergoing myocardial revascularization, Levy et al.
showed that rFXIII at doses of 25–50 IU kg 1 effectively
restored FXIII plasma levels to normal after CPB without
apparent safety issues [22]. Their data suggested that
35 IU kg 1 may be the appropriate dose for replacement
therapy. The efficacy of rFXIII was assessed in a double-
blinded, placebo-controlled, multicenter trial: 409 cardiac
surgical patients at moderate risk of transfusion received
either rFXIII (17.5 IU kg 1 or 35 IU kg 1) or placebo
after CPB [23]. [7] Although rFXIII significantly increased
post-CPB FXIII levels, it had no effect on transfusion
requirements nor did it influence the rate of surgical
re-exploration for bleeding. FXIII supplementation was
also assessed in 22 patients undergoing elective surgery for
gastrointestinal cancer who were at risk of intraoperative
bleeding. Patients were randomized to receive either FXIII
(30 U kg 1) or placebo early during surgery [24]. The study
confirmed that although compared with saline, intraopera-
tive FXIII administration maintained clot firmness mea-
sured using viscoelastic assays, it had little effect on blood
loss and no effect on red blood cell transfusion require-
ments. No studies have assessed the efficacy of FXIII sup-
plementation in postpartum hemorrhage. Lastly, FXIII
supplementation may increase the risk of thrombotic
events, but this potential has not been adequately assessed
[25]. To summarize, the benefit of FXIII supplementation
on bleeding and transfusion requirement remains unproven
in the context of acquired FXIII deficiency.
Guidance for use of FXIII concentrate for perioperative
bleeding management
We suggest against the use of FXIII concentrate.
rFVIIa
rFVIIa is approved for the prevention and treatment of
bleeding events in patients with hemophilia A and B with
inhibitors. For this indication, the approved dose is
90 lg kg 1 every 2–3 h until cessation of bleeding. In
© 2017 International Society on Thrombosis and Haemostasis

patients with congenital FVII deficiency, a rFVIIa dose
of 15–30 lg kg 1 every 6 h is recommended until cessa-
tion of bleeding, and then every 12 h, and in patients
with Glanzmann’s thrombasthenia with antibodies to
HLA and/or GPIIb/IIIa, 39 bolus 80–120 lg kg 1 before
and during interventions with 2 h between dosing [26].
rFVIIa is also effective in other inherited platelet disor-
ders (e.g. Bernard-Soulier syndrome and severe storage
pool disease). The above-mentioned dosing of rFVIIa
should also be used for perioperative management in
these patients with rare bleeding disorders.
The off-label use of rFVIIa has been studied in the
treatment of severe bleeding after surgery, obstetric proce-
dures or trauma [27]. The rationale for using rFVIIa for
such indications is based on its local action at the site of
vascular injury. Under physiologic conditions, ~1% of
circulating FVII is in the activated form. This concentra-
tion is markedly increased after intravenous administra-
tion of rFVIIa. This allows interaction of rFVIIa with
tissue factor (TF) exposed at sites of vascular injury, and
binding of rFVIIa to activated platelets, where it induces
TF-independent activation of FX and enhanced thrombin
generation. To be effective, rFVIIa requires fibrinogen
concentrations ≥1 g L 1, platelet counts ≥ 50 9 109 L 1,
pH ≥ 7.2 and body temperature > 34 °C [28].
The efficacy of rFVIIa for these off-label indications
remains unclear and randomized controlled trials are
scarce. In trauma patients with severe bleeding, rFVIIa
reduced transfusion requirements and acute respiratory dis-
tress syndrome compared with placebo, but it did not
reduce mortality [27]. For adult cardiac surgery, there was
a trend toward reduced transfusion requirement with
rFVIIa, but there was no mortality difference [27]; how-
ever, there was reduced surgical re-exploration in patients
who bled postoperatively. In severe postpartum hemor-
rhage, rFVIIa (60 lg kg 1) reduced the need for specific
second-line therapies, including artery embolization, artery
ligation and hysterectomy, compared with control [29]. A
meta-analysis of randomized trials confirmed that there
was no mortality reduction with rFVIIa [27]. Thus, current
data suggest that rFVIIa has a potential role in minimizing
bleeding or blood product use during major hemorrhage
management but overall survival may not improve.
Although several observational studies and case reports
suggested that in patients with massive bleeding rFVIIa
(one or more boluses of 90–140 lg kg 1) helps to control
bleeding, off-label use of rFVIIa has been associated with
venous and especially arterial thromboembolic complica-
tions [27,29,30], although these complications are very rare
in the approved indications (< 1:25 000).
Guidance for use of rFVIIa for management of perioperative
bleeding
We suggest using rFVIIa in patients with hereditary plate-
let disorders and HLA or anti-HPA antibodies to control
© 2017 International Society on Thrombosis and Haemostasis
Factor concentrates for perioperative bleeding 173
bleeding over transfusion of platelets, as platelet transfu-
sions may induce further alloantibodies.
We recommend against the off-label use of rFVIIa as first-
line therapy.
We suggest the use of rFVIIa only if all other options to
control hemostasis have failed, with special caution in
patients with risk factors for arterial thrombosis (e.g. arte-
riosclerosis, trauma/surgery-induced vessel lesions).
If rFVIIa is used, we suggest that measures should first be
taken to increase the fibrinogen > 1.5 g L 1, platelet
count ≥ 50 9 109 L 1, pH ≥ 7.2 and body temperature
> 34 °C.
Addendum
All of the authors developed the initial outline for the
manuscript. A. Godier, A. Greinacher, D. Faraoni, and
C. M. Samama wrote the first draft. J. H. Levy con-
tributed to the critical writing and revision of the first
draft. All of the authors contributed to revision of the
intellectual content and final approval of the published
version of this article.
Disclosure of Conflict of Interests
C. M. Samama reports personal fees from LFB and Octa-
pharma, during the conduct of the study. A. Godier reports
personal fees from CSL Behring, LFB, Octapharma, Boeh-
ringer Ingelheim, Bayer, and Sanofi; and personal fees and
non-financial support from BMS Pfizer, outside the submit-
ted work. A. Greinacher reports grants and non-financial
support from Aspen, Boehringer Ingelheim, MSD, BMS,
Paringenix, Bayer Healthcare, Gore Inc., Rovi, Sagent, and
Biomarin/Prosensa; personal fees from Aspen, Boehringer
Ingelheim, MSD, Macopharma, BMS, Chromatec, and
Instrumentation Laboratory; and non-financial support
from Boehringer Ingelheim and Portula, outside the submit-
ted work. J. H. Levy has sat on advisory boards or steering
committees for Boehringer Ingelheim, CSL Behring, Gri-
fols, and Octapharma, during the conduct of the study; and
has also sat on advisory boards or steering committees for
Janssen, Pfizer, and Portola, outside the submitted work.
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