PROJECT SUMMARY Immune thrombotic thrombocytopenic purpura (iTTP) is a rare but potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13, a plasma metalloprotease that cleaves endothelial von Willebrand factor. Despite progresses being made in past decades, major gap remains in our understanding the pathogenesis of iTTP. The proposed study will test the hypotheses that: 1) distinct molecular signatures in the complementarity determining region (CDR)-3 and the VDJ rearrangements in the variable regions of immunoglobulins (Ig) against ADAMTS13 determine their functionalities (e.g., the inhibitory vs. activating) in patients with iTTP; 2) the abnormalities in ANKRD26 and 36 gene family, initially identified to associate with hereditary thrombocytopenia, may also play a role in pathogenesis of iTTP, likely through disruption of megakaryocytopoiesis and enhanced immune inflammatory responses. The proposed study will use various cutting-edge tools and animal models to test these hypotheses. The results of the proposed study will shed new light on pathogenesis of iTTP and other immune thrombotic disorders. The findings may help develop novel strategies for therapeutic interventions for such disorders.