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.
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