Proteolytic activation of complement proteins C3 and C5 is known to occur in association with thrombus formation, and activators of both classical and alternative complement pathways can initiate platelet secretion and accelerate blood clotting. The research described in this Proposal aims to deduce the molecular pathways leading to proteolytic activation of C3 and C5 at the surface of stimulated platelets, and to investigate the role of the C3/C5-convertase reaction in expression of platelet procoagulant activity. In this Project we will use gel-fil-tered human platelets and purified proteins of the human complement and coagulation systems in experiments that aim: 1) to identify which components of the AP or CP convertase reaction directly initiate platelet secretion and expression of platelet prothrombinase activity; 2) to identify the signal-transduction pathways involved in platelet triggering mediated by C3/C5-convertases or their activated products; 3) to determine the topological distribution of C3b on the platelet surface, and its relationship to platelet activation; 4) to deduce the mechanism by which platelet activation alters the regulatory control of the CP and AP C3/C5-convertases at the cell surface ; 5) to determine how complement activation occurring spontaneously during collection and storage of platelets for transfusion affects platelet function and procoagulant activity. It is proposed that the data obtained from these experiments will significantly contribute to our understanding of the interrelationships of the cell-assembled enzyme reactions of the complement and hemostatic systems.
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