VON-WILLEBRAND FACTOR-CLEAVING PROTEASE IN THROMBOTIC THROMBOCYTOPENIC PURPURA AND THE HEMOLYTIC-UREMIC SYNDROME

Background Thrombotic thrombocytopenic purpura and the hemolytic-uremi c syndrome are severe microvascular disorders of platelet clumping wit h similar signs and symptoms. Unusually large multimers of von Willebr and factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevale nce of von Willebrand factor-cleaving protease deficiency in patients with familiar and nonfamilial forms of these disorders. Methods Plasma samples were obtained from 53 patients with thrombotic thrombocytopen ic purpura or hemolytic-uremic syndrome. Von Willebrand factor-cleavin g protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dod ecyl sulfate-agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor-cleaving protease was present, we m easured the protease activity in normal plasma after incubation with p lasma from the patients. Results We examined 30 patients with thrombot ic thrombocytopenic purpura and 23 patients with the hemolytic-uremic syndrome. Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, 20 had severe and 4 had moderate protease deficiency during a n acute event. An inhibitor found in 20 of these patients was shown to be IgG in five of five tested plasma samples. Of 13 patients with non familial hemolytic-uremic syndrome, 11 had normal levels of activity o f von Willebrand factor-cleaving protease during the acute episode, wh ereas in 2 patients, the activity was slightly decreased. All 6 patien ts with familial thrombotic thrombocytopenic purpura lacked von Willeb rand factor-cleaving protease activity but had no inhibitor, whereas a ll 10 patients with familial hemolytic-uremic syndrome had normal prot ease activity. In vitro proteolytic degradation of von Willebrand fact or by the protease was studied in 53 patients with familial and 7 pati ents with nonfamilial hemolytic-uremic syndrome and was normal in all 12 patients. Conclusions Nonfamilial thrombotic thrombocytopenic purpu ra is due to an inhibitor of von Willebrand factor-cleaving protease, whereas the familial form seems to be caused by a constitutional defic iency of the protease. Patients with the hemolytic-uremic syndrome do not have a deficiency of von Willebrand factor-cleaving protease or a defect in von Willebrand factor that leads to its resistance to protea se. (N Engl J Med 1998;339:1578-84.) (C)1998, Massachusetts Medical So ciety.