Platelet membrane receptors mediate the interactions between platelets and the blood vessel wall (adhesion) and between platelets and other platelets (aggregation). These interactions are crucial in hemostasis and thrombosis. This project is designed to increase our knowledge of these receptors and to directly apply that knowledge to improving the diagnosis and treatment of hemorrhagic and thrombotic disease. The studies will rely on the monoclonal antibodies we have previously developed to the platelet GPIIb/IIIa receptor (7E3 and 10E5), The GPIb receptor (6D1), and most recently, the GPIa/IIa receptor for collagen (6F1), Specific aims are 1) To expand our previous studies showing the F(ab')2 fragments of our anti-GPIIb/IIIa monoclonal antibodies are the most potent antiplatelet agents in animal models of thrombosis by assessing the safety of such therapy in humans and, if safe, attempting to treat humans with thrombotic diseases such as preinfarction angina. Additional animal studies are designed to increase our data on the biology of thrombosis, including the optimal combination of recombinant tissue plasminogen activator, heparin, and 7E3-F(ab')2 for he rapid induction of thrombolysis without reocclusion of the vessel, and with minimal hemorrhagic risk. The passivation process, by which damaged blood vessels lose their platelet reactivity, will also be studied. 2) To obtain additional basic information on the GPIIb/IIIa receptor using polyclonal and monoclonal antibodies and newly-designed synthetic peptides; peptides with therapeutic potential will be tested in vivo, 3) To continue to define the protein and genetic abnormalities in patients with Glanzmann thrombasthenia and to offer carrier detection and prenatal diagnosis. 4) To characterize our new monoclonal antibody to GpIa/IIa that inhibits collagen-platelet interactions, and to assess the physiologic role of this receptor with in vivo studies. 5) To expand our studies showing that plasma glycocalicin is an aid in the diagnosis of thrombocytopenia, determining the survival of plasma glycocalicin, when in the course of thrombopoiesis it is formed, and the alterations in its plasma levels in different disease states. 6) To provide a continuing supply of purified antibody without charge to other investigators (now numbering more than 140) to support their own independent studies. Thus, the studies contained in this proposal are designed to generate new basic data and to apply those data to the diagnosis and therapy of important diseases.
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