Pathogenesis of Thrombotic Microangiopathy



 DESCRIPTION (provided by applicant): Deficiency of plasma ADAMTS13 activity, either hereditary or acquired, causes thrombotic thrombocytopenic purpura (TTP). However, the triggering events and mechanisms underlying the pathogenesis of TTP are not fully understood. Emerging data suggest that complement activation may be associated with both hemolytic uremic syndrome (HUS) and TTP. In Aim 1, we propose to determine the effects of CFH on ADAMTS13- mediated VWF proteolysis and its adhesive function under flow. We will also determine the kinetics and mechanism of such interactions and how such an interaction affects complement activation/inactivation. In Aim 2, we will determine the role of genetic or acquired deficiency of CFH on the occurrence, progression, and outcome of acquired TTP (with inhibitors) in murine models. In Aim 3, we propose to determine the prevalence of mutations in genes in complement components and regulators in patients with acquired TTP patients with inhibitors. We pursue the hypothesis that by inhibiting complement activation with anti-complement therapy either alone or in combination with rADAMTS13 one can better prevent the onset and progression of the disease pathology or accelerate its recovery. The results of the proposed study will advance our understanding of the fundamental role of CFH in regulation of VWF function under physiological shear stress, shed new light on the mechanisms of acquired TTP, and provide invaluable tools for testing the efficacy of novel therapeutics.