Thrombotic thrombocytopenic purpura: understanding a disease no longer rare.

Serial studies of plasma samples from patients during episodes of thrombotic thrombocytopenic purpura (TTP) have often shown either the presence of unusually large (UL) von Willebrand factor (vWf) multimers or, alternatively, absence of the largest plasma vWf forms. The presence of ULvWf multimers in TTP patient plasma may reflect impaired processing of the ULvWf forms released from endothelial cells. The disappearance of ULvWf and large vWf multimers in some TTP patient plasma samples during acute TTP episodes may be predominantly because these ULvWf forms, along with the largest vWf multimers, bind to platelets and cause aggregation. Serial flow cytometry studies of EDTA-whole blood samples from patients with initial episode, intermittent, and chronic relapsing types of TTP confirm that vWf is the likely aggregating agent, perhaps in association with fluid shear stress. The amount of vWf bound to single platelets has been found to be significantly increased during TTP relapses relative to remission periods in patients with all types of TTP. A substance in normal platelet-poor plasma and the cryoprecipitate-depleted fraction of normal plasma (cryosupernatant) is capable in vitro of reversibly reducing the size of ULvWf multimeric forms released by endothelial cells into the somewhat smaller vWf multimers ordinarily in circulation. This activity has characteristics of a limited disulfide bond reductase. The process of ULvWf breakdown may be made irreversible by the tandem proteolysis, catalyzed by a vWf metalloproteinase, of partially reduced vWf multimers. Several patients with chronic relapsing TTP have decreased or absent plasma vWf metalloproteinase activity, apparently on a congenital basis. Adult initial episode and intermittent TTP patients have been found to have vWf metalloproteinase activity inhibited by an autoantibody during, but not after, TTP epidsodes.