Recent investigations in this laboratory have established existence of a novel mechanism capable of securing irreversible platelet aggregation independent of ADP secretion, prostaglandin synthesis or the generation of platelet activating factor (PAF). The new mechanism, termed membrane modulation, is associated with the platelet surface, mediated through Alpha adrenergic receptors and stimulated by exposure to epinephrine. Platelets rendered refractory to a variety of aggregating agents can be restored to a normal state of sensitivity through activation of the mechanism of membrane modulation. This includes platelets treated with aspirin in vivo or in vitro, and the aspirin treated platelet will serve as a principal model for the studies to be carried out during this investigation. The purpose of this proposal is to explore and define the mechanism of platelet membrane modulation in detail. It is possible that generation of products of the lipoxygenase pathway in aspirin treated platelets, elevation of endogenous levels of cyclic GMP, exposure of fibrinogen receptors, mobilization of calcium, phosphorylation of membrane associated proteins or reduction of heme proteins may underly the epinephrine induced activation of membrane modulation and correction of membrane sensitivity in aspirin treated cells. Appropriate biochemical, physiological and morphological methods will be used to study each of these possibilities in detail. Accomplishment of these specific aims will reveal the fundamental mechanisms underlying the platelet modulation. The ability to gain pharmacological control of this newly discovered mechanism regulating platelet membrane activation and capable of securing irreversible aggregation of refractory cells in the absence of prostaglandin synthesis or ADP secretion may provide a new approach to the management and prevention of thrombotic disease.
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