Factor VIII and Factor V Membrane Bound Complexes.

Abstract

The formation of membrane-bound complexes between specific coagulation factors at different cell surfaces is required for effective blood clotting. The most important of these complexes, the intrinsic Tenase and Prothrombinase complexes, are formed on the activated platelet surface during the propagation phase of coagulation. These two complexes are highly specific in their assembly mechanism and function modulated by anionic membranes, thus offering desirable targets for pharmaceutical interventions. Factor V (FV) and factor VIII (FVIII) are highly homologous non-enzymatic proteins. In their active state, FVa and FVIIIa serve as cofactors for the respective serine proteases factor Xa (FXa) and factor IXa (FIXa), significantly increasing their catalytic activity. This is achieved by forming well organized membrane-bound complexes at the phosphatidylserine rich activated platelet membrane in the presence of Ca2+ ions. The tenase (FVIIIa/FIXa) complex, catalyzes the proteolytic conversion of FX to FXa. Subsequently the prothrombinase (FVa/FXa) complex catalyzes the conversion of prothrombin to thrombin, required for efficient blood clotting. Although significant knowledge of FV and FVIII biochemistry and regulation has been achieved, the molecular mechanisms of their function are yet to be defined. Understanding the geometric assembly of the tenase and prothrombinase complexes is paramount in defining the structural basis of bleeding and thrombotic disorders. Such knowledge will enable the design of efficient pro- and anticoagulant therapies critical for regulating abnormal hemostasis. In this chapter, we will summarize the findings to date, showing our achievement in the field and outlining the future findings required to grasp the complexity of these proteins.