Treatment of massive bleeding with prothrombin complex concentrate: argument for


Kenichi A. Tanaka, Department of Anesthesiology, Emory University School of Medicine, 1364 Clifton Road N.E., Atlanta, GA 30322, USA.
Tel.: +1 404 778 3900; fax: +1 404 778 5194.


See also Godier A, Susen S, Samama C-M. Treatment of massive bleeding with prothrombin complex concentrate: argument against. This issue, pp 2592–5.

Coagulopathies that arise following severe trauma or due to major surgery are a result of heterogeneous hemostatic defects that strongly influence survival. The cycles of hemorrhage, hypotension, resuscitative fluid and blood transfusion collectively contribute to the pathogenesis of such coagulopathies. The initial resuscitation after massive bleeding usually commences with volume resuscitation using crystalloid/colloid solutions, followed by packed red blood cells (RBC) to sustain oxygen carrying capacity. Procoagulant responses are initiated by severe tissue damage and inflammatory cytokines, which initially lead to thrombin generation and fibrin formation. If surgical controls of hemorrhage are not achieved in a timely fashion, continued hypoperfusion and hemodilution can cause progressive worsening of hemostatic function. Among procoagulant factors, fibrinogen reaches the critical level of 1 g L−1 after a loss of about 150% of blood volume, while coagulation factors and platelet count fall to the threshold concentrations after a loss of > 200% of blood volume [1,2]. In hypofibrinogenemia, firm clot formation is not feasible, and thrombin activity is no longer contained within the fibrin clot at the site of vascular injury [3]. Furthermore, low levels of antithrombin (AT) result in prolongation of the half-lives of both thrombin and factor Xa, and thus intravascular coagulation and secondary fibrinolysis can ensue [4]. In the setting of disseminated intravascular coagulopathy (DIC) with hemorrhage, treatment with fresh-frozen plasma (FFP) may be a reasonable choice because it contains all plasma coagulation factors and inhibitors [5]. In a series of retrospective studies involving both military and civilian trauma cases, early large-volume infusion of FFP was found to reduce trauma-induced coagulopathy, and improve early mortality (24–48 h) in severe trauma patients [6,7]. Despite this, there is a paucity of data that support the hemostatic efficacy of FFP. The volume of FFP required to sufficiently raise viable coagulation factor levels is a major concern. Even when one assumes 100% (i.e. 1 U mL−1) coagulation factor activity in FFP, only 2–3% of factor activity is recovered after transfusing one unit (250 mL). Indeed, 12.5 mL kg−1 and 30 mL kg−1 of FFP are required to raise factors II, VII, IX and X by 8–16% and 28–41%, respectively [8].

Prothrombin complex concentrate (PCC) is a sterile, lyophilised concentrate of factors II, VII, IX and X. PCC products with low amounts of FVII (three-factor PCC) were originally used as a treatment for hemophilia B, but PCCs containing clinically relevant FVII levels (four-factor PCC) are mainly used today for acute reversal of vitamin K antagonists in Europe and Canada [9]. Each vial of PCC can be rapidly reconstituted with sterile water (20 mL per 500 IU), and can be infused at 6–10 mL min−1. For example, 3000 IU of PCC (i.e. 120 mL) can be administered within 20 min, and factors II, VII, IX and X are increased by 40–80% without lowering hematocrit and platelet count [10]. Lower volume and infusion time are needed with PCC to achieve target vitamin K-dependent factor levels when compared with FFP (Fig. 1). A rapid restoration of hemostasis is deemed crucial in reducing hematoma formation and rebleeding [11].

Figure 1.

 Estimated changes in coagulation factor levels in severe trauma and after replacement therapy with FFP (20 mL kg−1) or four-factor PCC (20 IU kg−1) [2,8,10,22]. In a 75-kg person, the volumes of FFP and PCC are 1500 and 60 mL, respectively.

Multifactorial deficiencies in massive bleeding may not be fully restored by targeted replacement of vitamin K-dependent factors with PCC [5]. Prior to the use of PCC, fibrinogen levels should be restored to at least 1.5–2.0 g L−1 because hypofibrinogenemia (< 1.5 g L−1) is an important cause of bleeding in coagulopathic trauma and surgical patients [12,13]. In a recent retrospective study of 131 trauma patients (Injury Severity Score, 38 ± 15), Schochl et al. [14] initially administered fibrinogen concentrate (median, 6 g) in 128 patients, then four-factor PCC (median, 1800 IU) in 98 patients using thromboelastometry as a point-of-care test. Only 12 (9.2%) and 29 (22%) patients received FFP and platelet transfusion, respectively, in the 24-h period. Overall, the observed mortality was 24.4%, which was lower than the predicted mortality (28–34%) based on the injury scale. Although these data suggest potential hemostatic efficacies of fibrinogen and PCC in patients receiving 10 U of RBCs in 24 h, the small sample size and retrospective design preclude extraction of any safety information. In massive bleeding, rFVIIa remains an off-label agent. Two prospective randomized trials of rFVIIa in major transfusions (> 8 units of RBCs) after blunt or penetrating injury (n = 143 and 134, respectively) revealed no differences in transfusion of FFP or platelets in 48 h between patients who received rFVIIa (400 μg kg−1 in three divided doses) and those who received placebo [15]. In contrast to rFVIIa, which critically depends on endogenous FX, FII and platelets to increase thrombin generation, PCC restores physiological levels of non-activated FII, VII, IX and X at the vascular injury site [16]. The latter approach with fibrinogen replacement seems to lessen the need for rFVIIa [14].

The premise underlying the use of aforementioned fibrinogen/PCC interventions is the immediate availability of factor concentrates and thromboelastometry. The indication for and dose of each factor concentrate should always be guided by laboratory monitoring as well as clinical assessments [17]. Administering factor concentrates without appropriate monitoring can be both potentially dangerous and costly. The therapeutic response to hemostatic agents can be influenced by coexisting hypothermia or hidden surgical bleeding. Thus, it is important to carefully assess the cause(s) of bleeding.

After a loss of > 200% of blood volume, bleeding may result from thrombocytopenia (< 50 × 109 L−1) and low FV (< 25%), for which platelet or FFP transfusion may be necessary [1,2]. A systemic fibrinolytic state may be diagnosed in trauma patients using thromboelastometry [5], and antifibrinolytic therapy should be considered in such cases [18]. Thrombotic complications are rare when PCC is administered to reverse vitamin K antagonists, but dosing of PCC may need to be reduced to avoid excess thrombin activity because the AT level can be below 40% in massive bleeding [19]. In overt bleeding associated with DIC or advanced liver disease, replacement of AT may be necessary before PCC is administered [20].

There are several clinical advantages in the use of PCC over FFP. The risk of transfusion-related acute lung injury associated with FFP can be minimized by lack of anti-HLA/anti-granulocyte antibodies in PCCs [21]. PCCs are derived from pooled human plasma, but multiple steps of viral inactivation including heat-treatment, solvent/detergent and nano-filtration are routinely applied in addition to the donor screening. A non-lipid enveloped, heat-resistant virus including Parvovirus B19 can be transmitted by transfusion, but such infections are rare and of limited clinical consequences in non-immunosuppressed patients [10].

Admittedly, there are insufficient prospective data at present to support the efficacy and safety of (three-factor or four-factor) PCCs in massive transfusion in trauma and surgery [22]. Outside the European nations, PCCs are generally considered off-label in the management of acquired bleeding. Conversely, high-dose FFP therapy is increasingly used at major trauma centres, but potential long-term complications are of great concern [21].

In conclusion, the use of PCC offers advantages over FFP in efficient and timely replacement of vitamin K-dependent factors. In massive bleeding without DIC, PCC (20–25 IU kg−1) can be administered after the primary fibrinogen replacement (> 1.5 g L−1). This sequence of therapies guided by laboratory monitoring seems to have FFP-sparing effects in trauma patients with hemorrhage [14]. Additional clinical studies will be required to evaluate the efficacy and safety of different PCCs (three-factor vs. four-factor), and their use with other agents (e.g. antifibrinolytics).

Disclosure of Conflict of Interests

K. Tanaka has received honoraria for lectures from CSL Behring and Octapharma.