Basic aspects of bypassing agents

Bypassing agents consist of activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa (rFVIIa). Their main utilization is for prevention and treatment of bleeding complications, which may occur in inhibitor-developing haemophiliacs, although new indications for rFVIIa (e.g. trauma-related and cerebral bleeds) are now under evaluation in clinical trials. The mechanisms of action for these agents are still not fully understood. The relative complexity of the composition of aPCC suggests the possibility of multiple modes of action for achieving haemostasis. Among those possibilities, the contributions of activated factor X and prothrombin have been demonstrated in recent years both in vitro and in animal models for the only aPCC which remains on the market. rFVIIa also exhibits a complex mode of action, improving coagulation through both tissue factor-dependent and -independent pathways. The various mechanisms that occur at the cellular surfaces, particularly on the outer leaflet of the platelet membrane, primarily contribute to Xase complex formation and thrombin generation. The ways in which these agents affect the complex kinetics of fibrin formation at the site of vascular damage need further clarification, although significant progress has been achieved in the last 10 years. In addition, the ex vivo monitoring that would reflect achievement of haemostasis in vivo is still not standardized, although several attempts using thromboelastography, thrombin generation and the kinetics of fibrin formation have been initiated.