Acute coronary syndromes account for significant morbidity and mortality. The clinical syndromes of stable and unstable angina, myocardial infarction and reocclusion of a coronary artery following thrombolytic therapy, form a spectrum of thrombotic related diseases in the coronary circulation. The role of platelets in these syndromes has been the subject of major therapeutic advances in recent years. The current understanding of thrombosis occurring in the coronary circulation is that: following a plaque rupture or damage to the endothelium, the circulating multimeric protein von Willebrand factor (vWF) adheres to exposed subendothelium; this is followed by platelet adherence mediated via the GPIba subunit of the platelet receptor glycoprotein complex GPIb-IX. Following platelet adhesion, platelets aggregate and an occlusive thrombus develops. While there is evidence for a role of vWF in thrombotic syndromes the role of the platelet receptor GPIba has not been clearly defined. The canine cardiovascular system is similar to man and well understood. Canine models of cyclic flow, electrically induced thrombosis, and reocclusion following thrombosis are well established and simulate the clinical conditions of unstable angina and acute myocardial infarction. The role of the platelet receptor GPIba has not been defined in these or other animal model systems. While the interaction of vWF and GPIba has been extensively studied in vitro, the corresponding pathophysiological conditions have not been defined. The long-term aim of this proposal is to understand in the canine coronary circulation, and the role of the platelet adhesive receptor GPIb.
The specific aims are: 1) to inhibit the binding of vWF to the canine platelet receptor in vitro. To accomplish this, synthetic and recombinant peptides and monoclonal antibodies will be developed based on the recently described canine sequence. The function of these reagents will be characterized in vitro in (i) platelet binding assays (ii) by binding to heterologous cells in which the canine GPIba cDNA is expressed (iii) in perfusion chambers with variable shear rates: 2) to investigate the effects of these peptides and monoclonal antibodies in a canine model in vivo under conditions which mimic (i) unstable angina, (ii) acute myocardial infarction and (iii) reocclusion following thrombolysis. The role for GPIba has been assumed in these syndromes, to date there is no data on the effect of GPIba based species specific peptides or monoclonal, in any of these syndromes in vivo. This proposal offers a unique integrative approach to further our understanding of coronary pathophysiology and the role of the GPIba receptor, based on a detailed understanding of function both in vivo and in vitro.
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