VON WILLEBRAND FACTOR AND THE PATHOPHYSIOLOGY OF TTP

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This project is a collaborative arrangement among investigators who are active in clinical and basic research work on the paradigm arterial thrombotic disease, thrombotic thrombocytopenic purpura (TTP). The investigators have access to patients with TTP and clinically related syndromes in the public, private and government hospitals of 3 large population centers. Although geographically separate, the investigators have a close, productive working association. They also have developed a network of clinical research interactions with physicians involved in the care of these patients in other parts of the U.S.A. The project is focused on the role of von Willebrand factor (vWF) multimers in the pathophysiology of relapsing and non-relapsing types of TTP. The association between plasma vWF multimer abnormalities and other disorders clinically related to TTP (e.g., the hemolytic-uremic syndrome), and between abnormal vWF forms and defects in prostacyclin (PGI2) production and stabilization will also be examined. The experimental work includes: development of a test system for acute TTP; identification of a "vWF cofactor" present in blood during acute TTP episodes; isolation and characterization of the unusually large vWF multimers produced by endothelial cells and found in the plasma of chronic relapsing TTP patients; isolation and characterization of the "unusually large vWF converting activity" in normal cryosupernatant; and evaluation of the hypothesis that the relapsing form of TTP is a disease of aberrant immune regulation. We expect that more effective prophylaxis and therapy for TTP will emerge from the work proposed. We anticipate that the results will be applicable to the study of common arterial thrombotic disorders involving regions of the coronary or cerebrovascular circulation. We also expect that the results of our study will make possible molecular level on TTP and related disorders.