von Willebrand Factor-Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic-Uremic Syndrome

doi:10.1056/NEJM199811263392202

Volume 339:1578-1584		November 26, 1998		Number 22

von Willebrand Factor–Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic–Uremic Syndrome

Miha Furlan, Ph.D., Rodolfo Robles, Miriam Galbusera, Sc.D., Giuseppe Remuzzi, M.D., Paul A. Kyrle, M.D., Brigitte Brenner, Manuela Krause, M.D., Inge Scharrer, M.D., Volker Aumann, M.D., Uwe Mittler, M.D., Max Solenthaler, M.D., and Bernhard Lämmle, M.D.

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ABSTRACT

Background Thrombotic thrombocytopenic purpura and the hemolytic–uremicsyndrome are severe microvascular disorders of platelet clumpingwith similar signs and symptoms. Unusually large multimers ofvon Willebrand factor, capable of agglutinating circulatingplatelets under high shear stress, occur in the two conditions.We investigated the prevalence of von Willebrand factor–cleavingprotease deficiency in patients with familial and nonfamilialforms of these disorders.

Methods Plasma samples were obtained from 53 patients with thromboticthrombocytopenic purpura or hemolytic–uremic syndrome.Von Willebrand factor–cleaving protease was assayed indiluted plasma samples with purified normal von Willebrand factoras the substrate. The extent of the degradation of von Willebrandfactor was assessed by electrophoresis in sodium dodecyl sulfate–agarosegels and immunoblotting. To determine whether an inhibitor ofvon Willebrand factor–cleaving protease was present, wemeasured the protease activity in normal plasma after incubationwith plasma from the patients.

Results We examined 30 patients with thrombotic thrombocytopenicpurpura and 23 patients with the hemolytic–uremic syndrome.Of 24 patients with nonfamilial thrombotic thrombocytopenicpurpura, 20 had severe and 4 had moderate protease deficiencyduring an acute event. An inhibitor found in 20 of these patientswas shown to be IgG in five of five tested plasma samples. Of13 patients with nonfamilial hemolytic–uremic syndrome,11 had normal levels of activity of von Willebrand factor–cleavingprotease during the acute episode, whereas in 2 patients, theactivity was slightly decreased. All 6 patients with familialthrombotic thrombocytopenic purpura lacked von Willebrand factor–cleavingprotease activity but had no inhibitor, whereas all 10 patientswith familial hemolytic–uremic syndrome had normal proteaseactivity. In vitro proteolytic degradation of von Willebrandfactor by the protease was studied in 5 patients with familialand 7 patients with nonfamilial hemolytic–uremic syndromeand was normal in all 12 patients.

Conclusions Nonfamilial thrombotic thrombocytopenic purpurais due to an inhibitor of von Willebrand factor–cleavingprotease, whereas the familial form seems to be caused by aconstitutional deficiency of the protease. Patients with thehemolytic–uremic syndrome do not have a deficiency ofvon Willebrand factor–cleaving protease or a defect invon Willebrand factor that leads to its resistance to protease.

Source Information

From the Central Hematology Laboratory, University Hospital, Bern, Switzerland (M.F., R.R., M.S., B.L.); Mario Negri Institute for Pharmacological Research, Bergamo, Italy (M.G., G.R.); the Department of Internal Medicine I, General Hospital, Vienna, Austria (P.A.K., B.B.); University Hospital, Frankfurt, Germany (M.K., I.S.); and University Children's Hospital, Magdeburg, Germany (V.A., U.M.).

Address reprint requests to Dr. Furlan at the Central Hematology Laboratory, University Hospital, Inselspital, CH-3010 Bern, Switzerland.

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von Willebrand Factor–Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic–Uremic Syndrome
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N Engl J Med 1999; 340:1368-1369, Apr 29, 1999. Correspondence

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