Prothrombin Complex Concentrates for Bleeding in the Perioperative Setting

Abstract

Prothrombin complex concentrates (PCCs) contain vitamin K-dependent clotting factors (II, VII, IX, and X) and are marketed as 3 or 4 factor-PCC formulations depending on the concentrations of factor VII. PCCs rapidly restore deficient coagulation factor concentrations to achieve hemostasis, but like with all procoagulants, the effect is balanced against thromboembolic risk. The latter is dependent on both the dose of PCCs and the individual patient prothrombotic predisposition. PCCs are approved by the US Food and Drug Administration for the reversal of vitamin K antagonists in the setting of coagulopathy or bleeding and, therefore, can be administered when urgent surgery is required in patients taking warfarin. However, there is growing experience with the off-label use of PCCs to treat patients with surgical coagulopathic bleeding. Despite their increasing use, there are limited prospective data related to the safety, efficacy, and dosing of PCCs for this indication. PCC administration in the perioperative setting may be tailored to the individual patient based on the laboratory and clinical variables, including point-of-care coagulation testing, to balance hemostatic benefits while minimizing the prothrombotic risk. Importantly, in patients with perioperative bleeding, other considerations should include treating additional sources of coagulopathy such as hypofibrinogenemia, thrombocytopenia, and platelet disorders or surgical sources of bleeding. Thromboembolic risk from excessive PCC dosing may be present well into the postoperative period after hemostasis is achieved owing to the relatively long half-life of prothrombin (factor II, 60-72 hours). The integration of PCCs into comprehensive perioperative coagulation treatment algorithms for refractory bleeding is increasingly reported, but further studies are needed to better evaluate the safe and effective administration of these factor concentrates.

Figure 1

A depiction of the coagulation cascade with focus on factor-enzyme complexes (Tenase, Prothrombinase) and target locations for direct factor repletion by Prothrombin Complex Concentrates, Activated Prothrombin Complex Concentrates, Activated Recombinant Factor VII, and Cryoprecipitate. Extrinsic Tenase contains Tissue Factor (TF), Factor X, and Factor VIIa whereas intrinsic Tenase contains Factor X, Factor IXa, and Factor VIIIa. Both types of Tenase influence the production of Factor Xa, which then joins with Factor Va to form Prothrombinase. Prothrombinase converts the substrate prothrombin (Factor II) into thrombin (Factor IIa). Thrombin facilitates (1) the conversion of fibrinogen to fibrin monomers and (2) converts fibrin-stabilizing factor (XIII) into its activated form (XIIIa) in order to facilitate fibrin polymerization and cross-linkage (scanning electron micrographic image insert of normal, dense fibrin deposition). These two reactions occur independent of one another in the presence of thrombin. The color-coded legend below the coagulation model delineates which factor concentrates replete individual factor constituents. Fibrinogen concentrate repletes fibrinogen alone but for purposes of clarity, is not illustrated. In addition, Activated Prothrombin Complex Concentrates contain clinically negligible concentrations of Factors IIa, IXa, and Xa (not illustrated). Abbreviations: aPCCs= Activated prothrombin complex concentrates, FGN = Fibrinogen, PCCs = Prothrombin Complex Concentrates, rFVIIa = Activated Recombinant Factor VII, TF = Tissue Factor, Xase = Tenase

Figure 2

Reduced concentrations of coagulation Factors II, VII, IX, and X as a result of administration of vitamin K antagonists and its impact on thrombin generation and fibrin polymerization (scanning electron micrographic image insert of weak fibrin cross-linkage). Vitamin K antagonists also act to reduce the synthesis of coagulants downstream from the Vitamin K-dependent coagulation factors, therefore weakening the resultant fibrin cross-linkage. Vitamin K-dependent anticoagulants (protein C and S) are not illustrated. Abbreviations: FGN = Fibrinogen, VKA = Vitamin-K Antagonist(s), TF = Tissue Factor, Xase = Tenase

Figure 3

Reduced coagulation factor concentrations due to direct oral anticoagulants: direct thrombin inhibitors and Factor Xa inhibitors. Factor Xa inhibitors directly reduce Factor Xa activity and indirectly reduce thrombin generation (downstream). Direct thrombin inhibitors, as the name implies, directly inhibit Factor IIa production and block downstream fibrin stabilization (scanning electron micrographic image insert of weak fibrin cross-linkage). Abbreviations: DTI = Direct Thrombin Inhibitor, FGN = Fibrinogen, FXai = Factor Xa inhibitor, TF = Tissue Factor, Xase = Tenase