Thrombotic thrombocytopenic purpura (TTP) is a fatal disorder that is characterized by the presence of systemic hyaline thrombi in the arterioles and capillaries. The incidence is estimated to be 4-30 cases/million/year. Plasma exchange has been the mainstay of treatment for TTP, preventing a fatal outcome in 70%-90% of the cases. However, among the patients who achieve remission, 30%-60% develop relapses. A subset of patients develops frequent relapses or refractory disease that require long-term, debilitating plasma exchange. Recent advances in biochemical and genetic studies have demonstrated that deficiency of a novel zinc metalloprotease, ADAMTS13, due to autoimmune inhibitors or genetic mutations, causes TTP. The long -erm goals of this research include improvement of the survival outcome, prevention of relapse, easier therapeutic alternatives and the identification of the causes of autoimmune reaction to ADAMTS13. As a first step towards these goals, this project will focus on applying the new knowledge in pathogenesis obtained in recent years to strengthen the results expected from an ongoing clinical trial conducted by the Canadian Apheresis Group. The clinical trial compares solvent-detergent treated plasma with cryosupernatent plasma as the replacement fluid during plasma exchange. The laboratory investigation of this project includes measurement of ADAMTS13 activity, determination of the titer of its inhibitors, and analysis of the von Willebrand factor multimer pattern. Samples obtained prior to plasma exchange, at the end of the first treatment cycle (day 9) and at 1 and 6 months will be investigated. By correlating the results of these laboratory studies with the clinical features of the patients and the therapeutic outcomes, this project will provide a better understanding of the mechanism of action of plasma exchange, the natural history of ADAMTS13 inhibitors, and the directions for developing new therapeutic alternatives.
