MECHANISMS OF ENDOTHELIAL CELL INJURY IN TTP/HUS

血栓性血小板减少性紫癜是一种多系统疾病 其特征在于微血管病性溶血性贫血，血小板减少症， 神经系统异常，以及较不常见的发热和肾脏异常。 当与成人急性肾功能衰竭相关时，术语“溶血性” 尿毒症综合征（HUS）是一个常见的症状。 TTP/HUS是一个知之甚少的 尽管最近有重大的治疗进展， 严重的发病率和死亡率。 已经提出了一些机制来解释这种疾病的发病机制 虽然在这方面做了大量的努力， 大部分的发病机制仍不清楚，病因不明。 这项提案将试图探索患者的疾病机制 关于TTP/HUS 基本前提是， 各种形式的TTP/HUS是内皮细胞的扰动， 血小板和凝血酶的二次活化，导致微血管 血栓形成 具体目标是： 1.研究原发性和继发性TTP/HUS患者是否存在 影响血小板的免疫球蛋白和非免疫球蛋白因子， 内皮细胞和表征这些的作用机制 介导微血管血栓形成的因素。 2. 开发体外模型以评估内皮细胞损伤和/或 活化，其响应于目的1中鉴定的免疫球蛋白活性。 3. 明确临床病程、实验室检查结果、对 经典TTP的治疗和临床结果，并将其与HIV- 相关TTP 这项研究的长期目标是提高对 TTP/HUS的发病机制以其各种形式的部分或全部。 在 在这一过程中，研究将试图确定是否存在差异， HIV相关TTP与更典型的TTP/HUS的发病机制。

Thrombotic thrombocytopenic purpura (TTP) is a multi-system disorder characterized by micro angiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, and less commonly, fever and renal abnormalities. When associated with acute renal failure in adults, the term "hemolytic uremic syndrome" (HUS) is often used. TTP/HUS is a poorly understood disease that despite recent major therapeutic advances, still has significant morbidity and mortality associated with it. A number of mechanisms have been proposed to explain the pathogenesis of this disease process, but despite a great deal of effort devoted to this, the pathogenesis for the most part remains unclear and the etiology unknown. This proposal will attempt to explore mechanisms of disease in patients with TTP/HUS. The basic premise is that the unifying feature of the various forms of TTP/HUS is perturbation of the endothelial cell with secondary activation of platelets and thrombin, leading to microvascular thrombosis. The specific aims are: 1. To study patients with primary and secondary TTP/HUS for the presence of immunoglobulin and non-immunoglobulin factors that affect platelets and endothelial cells and characterize the mechanisms of action of these factors in mediating microvascular thrombosis. 2. To develop an in vitro model to assess endothelial cell injury and/or activation in response to immunoglobulin activity identified in aim 1. 3. To define the clinical course, laboratory findings, response to therapy, and clinical outcome of classical TTP and compare it with HIV- associated TTP. The long-term goal of this research is to improve the understanding of the pathogenesis of TTP/HUS in some or all of its various forms. In the process, the study will attempt to determine if there are differences in the pathogenesis of HIV-associated TTP vs. more typical TTP/HUS.