PATHOPHYSIOLOGY OF VON WILLEBRAND FACTOR (VWF) PROCESSING IN THROMBOTIC THROMBOCYTOPENIC PURPURA WITH CONGENITAL ADAMTS13 DEFICIENCY: IN SEARCH OF A NOVEL VWF CLEAVING PROTEASE

Thrombotic thrombocytopenic purpura (TTP) is a disease of microangiopathic hemolytic anemia and thrombocytopenia. ADAMTS13 (a protease that cleave von Willebrand factor (VWF) multimers) activity has been found deficient in a large group of patients with TTP. Two primary mechanisms for the deficiency of ADAMTS13 activity have been identified: a constitutive defect, due to homozygous or double heterozygous mutations in the corresponding gene; and an acquired deficiency, due to the presence of circulating inhibitory antibodies. However, despite the absence of this protease we have documented that the most consistent abnormality in the acute phase of TTP is an increased VWF fragmentation, suggesting that other mechanisms could be involved in the pathogenesis of these diseases. ADAMTS13 may not be the only protease capable of cleaving VWF multimers. In agreement with this concept, the plasma from some patients with undetectable ADAMTS13 activity can cleave VWF in vitro, leading to the generation of apparently normal fragments. Most likely an unknown protease(s) may be the responsible for the VWF cleavage in patients lacking ADAMTS13 activity and it is tempting to speculate that this protease may generate multimers with an increased capacity to induce thrombus formation. The general aim of this application is to characterize the VWF fragments that are formed in patients with congenital ADAMTS13 deficiency, to isolate the protease responsible for the cleavage and to study its effect on thrombus formation. The studies proposed in this application will advance our knowledge not only of the etiology and pathogenesis of thrombotic microangiopathies but also of general mechanisms of VWF handling relevant to the process of arterial thrombosis.