GENETIC AND FUNCTIONAL STUDY OF ADAMTS13 IN HEMOLYTIC UREMIC SYNDROME AND THROMBOTIC THROMBOCYTOPENIC PURPURA

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are diseases of microangiopathic hemolytic anemia and thrombocytopenia with signs of renal (HUS) and brain involvement (TTP). Typical D+ HUS associated with E.coli infection should be considered a distinct syndrome and kept separated from all the other forms of HUS and TTP that are believed to have an hereditary predisposition to microvascular thrombosis. Only 30% of HUS patients do have Factor H mutations indicating that other genes may be involved. ADAMTS13 (a vWF-cleaving protease) activity has been found deficient in TTP, and linkage analysis and mutation screening provided evidence that mutations in ADAMTS13 gene lead to an inactive enzyme and to TTP. Recently, we and others found complete deficiency of ADAMTS13 activity also in HUS patients, confirming that the protease defect cannot be narrowed to specific subtypes of thrombotic microangiopathies. These data support the concept that deficiency of ADAMTS13 activity may result in either the TTP or the HUS phenotype. The general aim of the application is to study ADAMTS13 abnormalities in HUS and TTP and to investigate the functional significance of this protease in the pathogenesis of the microangiopathic process in HUS and TTP. This study will hopefully allow a better understanding of mechanisms underlying the pathogenesis of HUS and TTP as well as the identification of genetic markers associated with hereditary predisposition of these diseases which may prove essential for genetic consueling and ante natal diagnosis.