The binding of fibrinogen to stimulated platelets plays a central role in platelet aggregation. Considerable attention has focused on events leading to and supporting platelet-fibrinogen interactions, but little is known about the fate and function of platelet-bound fibrinogen. Fibrinogen can link platelets into aggregates and becomes irreversibly associated with the platelet surface. The present study proposes to investigate post fibrinogen binding events involved in irreversible fibrinogen binding to human platelets using previously established methods for platelet adhesion, aggregation, secretion, ligand-receptor interactions, SDS-polyacrylamide gel electrophoresis, immunoelectrophoresis, and cell sorting. The biochemistry of irreversible platelet- fibrinogen interactions will be elucidated by 1) defining the requirements for irreversible fibrinogen binding, including the importance of an active energy metabolism, membrane fluidity, cytoskeleton formation, and the release reaction, 2) identifying platelet binding sites for irreversibly bound fibrinogen, and 3) testing the hypothesis that the stabilization of platelet-fibrinogen interactions is associated with changes in fibrinogen assessibility/conformation using monoclonal antibodies, (Fab'2') and Fab fragments directed against defined fibrinogen epitopes. The function of irreversibly bound fibrinogen will be explored by correlating stabilization of fibrinogen binding with irreversible platelet aggregation and the development of platelet refractoriness. Results from these studies will enhance present understanding of the mechanism of platelet cohesion, and may have general implications for cell-cell recognition, as the fibrinogen receptor belongs to a family of cell surface receptors for adhesive proteins.
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