In coronary, cerebral and peripheral arteries, thrombotic events underlie acute ischemic syndromes ranging from unstable angina, myocardial infarction, transient ischemic attacks and stroke. occlusive thrombus formation on an unstable atherosclerotic lesion appears to involve mechanisms that promote both platelet aggregation and thrombin formation, as evidenced by the presence of platelets and fibrin in thrombi obtained from patients dying of acute coronary syndromes. We have demonstrated a role for GP Ib receptor mediated platelet adhesion/aggregation in promoting coronary occlusion by thrombosis. Recently we have shown that intravascular formation of thrombin involved coagulation mechanisms, in which Factor IX/IXa probably had a central role. However, the relevance of these mechanisms to intravascular thrombosis in arteries with vascular dysfunction (atherosclerotic changes) or with decreased blood flow (due to multiple sequential lesions or diffuse disease) is not well understood.
The aim of this application is to examine the effect of decreased coronary blood flow on modulating the mechanisms of intravascular thrombin formation or platelet adhesion and aggregation, in the presence of endothelial dysfunction, in an in vivo model of coronary thrombosis, where decreased blood flow will be induced in the circumflex coronary artery by an adjustable hydraulic occluder placed proximal to the site of thrombus formation . Vascular dysfunction will be induced by denudation of the endothelium in the proximal 4 cm of the circumflex coronary artery and by high cholesterol feeding. Thrombus formation will be initiated in the circumflex coronary artery by current application and localized injury of the endothelium. Thrombus formation will also be initiated simultaneously in the left anterior descending coronary artery, which will serve as a control. During coronary occlusion the incorporation of platelets in the thrombus will be measured with 111In-labeled platelets, where as fibrinogen/fibrin incorporation will be measured with 125I-labeled fibrinogen. In the thrombus we will also asses the concentration of clot bound thrombin activity. Specific antagonist to platelet adhesion/aggregation or thrombin formation will be used to elucidate the significant mechanisms that contribute to thrombosis in arteries with decreased blood flow and/or vascular dysfunction. The thrust of these studies is to identify the mechanisms leading to occlusive thrombosis and to determine whether they are accessible to pharmacological manipulation without an increased risk for bleeding complications.
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