DECREASE IN CORONARY BLOOD FLOW--POSSIBLE MECHANISMS

在冠状动脉、脑动脉和外周动脉中，血栓形成事件是 急性缺血性综合征，包括不稳定型心绞痛、心肌梗塞、 梗塞、短暂性脑缺血发作和中风。 闭塞性血栓 在不稳定的动脉粥样硬化病变上的形成似乎涉及 促进血小板聚集和凝血酶形成的机制， 如在获得的血栓中存在血小板和纤维蛋白所证明的 死于急性冠状动脉综合症的患者。我们展示了一个 GP Ib受体介导的血小板粘附/聚集在 通过血栓形成促进冠状动脉闭塞。最近我们已经证明， 血管内凝血酶的形成涉及凝血机制， 其中因子IX/IXa可能起着核心作用。然而， 血管内血栓形成的这些机制 功能障碍（动脉粥样硬化变化）或血流减少（由于 多个连续性病变或弥漫性疾病）并没有得到很好的理解。 本申请的目的是检查冠状动脉减少的影响， 调节血管内凝血酶的机制 形成或血小板粘附和聚集， 内皮功能障碍，在冠状动脉血栓形成的体内模型中， 将在回旋冠状动脉中引起血流减少 放置在血栓部位近端的可调节液压封堵器 阵血管功能障碍将通过剥脱 冠状动脉回旋支近端4 cm处的内皮， 高胆固醇饮食血栓形成将在 旋支冠状动脉局部损伤 内皮细胞血栓形成也将同时启动 在左冠状动脉前降支，这将作为一个 控制在冠状动脉闭塞期间，血小板在 将使用111 In标记的血小板测量血栓，其中， 纤维蛋白原/纤维蛋白掺入将用125 I标记的 纤维蛋白原。在血栓中，我们还将评估凝块的浓度 结合凝血酶活性血小板特异性拮抗剂 粘附/聚集或凝血酶形成将用于阐明 导致动脉血栓形成的重要机制 血流减少和/或血管功能障碍。这些的主旨 研究的目的是确定导致闭塞性血栓形成的机制， 以确定它们是否可以进行药理学操作 而不会增加出血并发症的风险。

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.