In thrombotic thrombocytopenic purpura (TTP), a multimeric form of von Willebrand factor (vWf) that is larger than ordinarily found in the plasma causes systemic platelet aggregation under the high-shear conditions of the microcirculation. A divalent cation–activated, vWf-cleaving metalloprotease that metabolizes large vWf multimers to smaller forms in normal plasma is severely reduced or absent in most patients with TTP. The vWf-cleaving metalloprotease either is not produced or is defective in children with chronic relapsing TTP. When the enzyme is provided by the infusion of normal plasma, these patients remain free of TTP symptoms for about three weeks. An IgG autoantibody to the vWf-cleaving metalloprotease is found transiently in many adult patients with acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. These patients require plasma exchange, i.e., concurrent replacement of the inhibited vWf-cleaving metalloprotease by plasma infusion and plasmapheresis. The vWf-cleaving metalloprotease is present in fresh-frozen plasma, in cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy–associated thrombotic microangiopathy, and in the hemolytic-uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWf–cleaving metalloprotease activity.