Investigations in this laboratory will continue to be directed toward development of knowledge on blood platelet function in normal hemostatis, their role in the pathogenesis of inherited and acquired bleeding disorders, and their contribution to vascular injury, thrombosis and atherosclerosis. Analytical, scanning and transmission electron microscopy, freeze-fracture, cytochemistry and immunocytochemistry combined with cyclic nucleotide, adenine nucleotide and prostaglandin biochemistry and advanced physiological techniques, including micropipette elastimetry and lumi-aggregometry, will be used to develop new information on these problems and related areas. Particular emphasis has been placed on achievement of six specific aims. New approahes to the study of membrane ultrastructure will be used to identify physical alterations in platelet membranes and membrane systems not evident previously. Giant platelets with normal function from patients with the May-Hegglin anomaly will permit study of platelet membrane deformability before and after activation and surface receptor mobility (capping and patching) for the first time. Freeze-fractue and other sophisticated technology will be used to solve basic problems presented by inherited disorders of platelet function. A new mechanism of membrane modulation regulating platelet activation and the phenomenon of disaggregation and reaggregation of irreversibly aggregated platelets were recently discovered in this laboratory. They offer excellent opportunities to gain new knowledge of platelet biochemistry and physiology. Megakaryocytes can be concentrated and purified. We will recover them from a dog model permitting in depth sutyd of each stage of maturation and use of the techniques of structural physiology. Accomplishment of these aims will allow us to gain the knowledge required to control or prevent hemorrhagic and thrombotic disease.
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