The specific binding of fibrinogen and calcium to human blood platelets is essential for aggregation. Although this binding has been characterized and some receptors identified, the molecular basis of platelet aggregation is still incompletely understood.
The aim of the proposed study is to investigate two aspects of platelet function: (1) the mechanism of fibrinogen receptor exposure and (2) the molecular and functional aspects of irreversible fibrinogen binding. Results from these studies may ultimately help to establish more rational approaches to the prevention of hemorrhage and thrombosis in man. Specific experiments will focus on 1) the interaction between fibrinogen and individual platelets using a fluorescence activated cell sorter and platelets stimulated with physiologic agonists, chymotrypsin, or dithiothreitol, platelets refractory to stimulation and platelets inhibited by local anesthetics, 2) the hypothesis that surface bound and cytosolic Ca2+ support fibrinogen binding using calcium and the Ca2+ indicators quin-2 and aequorin, and 3) characterizing the molecular aspects of irreversible fibrinogen binding by: (a) analyzing the development of irreversible platelet fibrinogen interactions in the presence of ADP, chymotrypsin, or dithiothreitol using both purified, low solubility fibrinogen and previously characterized plasma fibrinogen fractions and derivatives lacking intact AAlpha chains, and (b) correlating irreversible fibrinogen binding with irreversible platelet aggregation.
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