Blood coagulation factor V plays a critical role in the regulation of hemostasis. Regulation of the clotting process is achieved, in part, by the selective inactivation of factor Va with activated protein C. This application is designed to elucidate in greater detail the events which control factor Va activity. Factor V inactivation by activated protein C requires another vitamin K-dependent factor, protein S. Protein S circulates in plasma both free and bound to a regulatory protein of the complement system C4BP. Plasma experiments indicate that the C4BP-protein S complex cannot function in concert with activated protein C to elicit anticoagulant activity. This application seeks to determine whether the C4BP-protein S complex still binds activated protein C, whether the complex is an inhibitor of protein S-activated protein C interaction on liposomes, the platelet surface and/or the endothelial cell surface and whether C4b influences any of these interactions. Preliminary studies indicate that factor Va, but not factor V, is required to support both protein S and activated protein C binding to the platelet surface. More detailed studies will be undertaken to determine which of the factor V derived peptides are required to support activated protein C and protein S binding to either the platelet or endothelial cell surface, or whether, in the case of the endothelial cell, antibodies to factor V/Va block binding. The possibility that factor Va induces formation of a binding site for the protein S-C4BP complex on the surface of platelets, endothelial cells, monocytes and/or lymphocytes will also be examined. These studies may provide an important biochemical link between complement activation and the coagulation system and explain the hypercoagulable states recently observed in several patients. Recent studies provide further evidence that factor Va interaction with prothrombin is an important part of expression of factor Va activity. Studies on the interaction of factor Va with prothrombin will be completed by employing sedimentation equilibrium analysis and by re-examining the influence of prothrombin on factor Va interaction with cell surfaces.
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