Excessive intravascular platelet agglutination in patients with thrombotic thrombocytopenic purpura (TTP) appears to be associated with excessive release from endothelial cells of unusually large von Willebrand factor (vWF) multimers and/or impaired degradation of these multimers by a 'depolymerase' cleaving vWF to smaller, non-agglutinating molecular forms. We studied the activity of a recently described vWF-cleaving protease in four patients, including two brothers, with chronic relapsing TTP. All four patients had lacking or strongly reduced vWF-cleaving protease activity. In another patient with chronic relapsing TTP, the protease deficiency was due to the presence in the patient plasma of an inhibitor that was found to be an IgG. We conclude that constitutional as well as acquired deficiency of vWF-cleaving protease may predispose to clinical manifestation of TTP.