DECREASE IN CORONARY BLOOD FLOW--POSSIBLE MECHANISMS

在冠状动脉、脑动脉和外周动脉中，血栓事件是潜在的 急性缺血综合征，包括不稳定型心绞痛、心肌梗死 脑梗塞、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形成似乎涉及 同时促进血小板聚集和凝血酶形成的机制， 血栓中血小板和纤维蛋白的存在证明了这一点 来自死于急性冠脉综合征的患者。我们已经展示了一个 糖蛋白Ib受体介导的血小板黏附/聚集在心力衰竭中的作用 血栓形成促进冠状动脉闭塞。最近我们已经证明了 凝血酶的血管内形成涉及凝血机制 哪个因子IX/IXa可能起了核心作用。然而，这种关联性 血管内血栓形成的这些机制 功能障碍(动脉粥样硬化性改变)或血流减少(由于 多个连续病变或弥漫性疾病)还不是很清楚。 这项应用的目的是检查冠状动脉病变减少的影响 血流对血管内凝血酶调节机制的研究 在以下情况下形成或血小板黏附和聚集 在冠状动脉血栓形成的活体模型中，内皮功能障碍 冠脉回旋支血流量减少 放置在血栓部位近端的可调式液压封堵器 队形。剥离血管会导致血管功能障碍。 冠状动脉回旋支近端4 cm处内皮细胞 高胆固醇饮食。血栓的形成将在 旋支冠状动脉的应用现状及局部损伤 内皮细胞。血栓的形成也将同时启动 在左冠状动脉前降支，它将作为一个 控制力。冠脉闭塞期间血小板在血管内皮细胞中的掺入 血栓将用111In标记的血小板测量，其中AS 纤维蛋白原/纤维蛋白掺入将用125I标记 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 黏附/聚集或凝血酶形成将用于阐明 动脉血栓形成的重要机制 血流减少和/或血管功能障碍。这些东西的主旨是 研究是确定导致闭塞性血栓形成的机制和 以确定它们是否可以进行药物操作 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.