The human platelet is an important component in the pathophysiology of several immunohematologic disorders.
The aim of this research proposal is to study the platelet receptors for the Fc fragment of IgG and to study the interaction of human complement with platelets. We will study the nature of the interaction between radiolabeled IgG ligand and its platelet binding site and examine the modulation of this interaction by plasma proteins (Hageman factor, C3b, fibronectin) and other molecules present during inflammation (variation interferon). We will isolate and characterize the platelet Fc (IgG) binding site and produce antibodies to epitopes on this receptor. We will explore whether the expression of this receptor is altered in immune thrombocytopenic purpura (ITP), ITP associated with systemic lupus erythematosis and heparin-associated thrombocytopenia. Immune complex-platelet Fc (IgG) receptor interactions likely play a role in the pathophysiology of these disorders. We will evaluate the effect of glucocorticoids, danazol and vinblastine on platelet Fc (IgG) receptor expression in ITP and ITP associated with systemic lupus, as these drugs may mediate their activity, in part, by an effect on this receptor. Complement platelet interactions play a role in immune platelet disorders and may predispose to thrombosis. Complement will be activated by platelet alloantibidy, heparin-dependent antibody, complement dependent ITP autoantibody, and oligomeric IgG bound to the platelet Fc (IgG) receptor. We will explore possible mechanisms by which complement-platelet interactions amy lead to thrombosis by determinin the precise complement components necessary to activate platelets and to increase platelet responsiveness to ADP. Furthermore, we will begin studies aimed at identifying the locus of complement deposition in the platelet membrane. We will extend our studies in ITP and pregnancy, ITP caused by IgM antibody and complement, and on the mechanisms of action of glucocorticoids and their analogues. We will study the effect of steroid analogues on the platelet Fc (IgG) receptor, on platelet-complement interaction and on immune clearance. These studies should be helpful in elucidating the pathogenesis of, and several of the abnormalities observed in, immune platelet disorders and immunohematologic disease. Furthermore, they should be helpful in developing approaches for therapeutic intervention.
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