Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura

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Abstract

Thrombotic thrombocytopenic purpura (TTP) is a severe, occlusive, microvascular “thrombotic microangiopathy” characterized by systemic platelet aggregation, organ ischemia, profound thrombocytopenia, and erythrocyte fragmentation. Failure to degrade “unusually large” (UL) von Willebrand factor (VWF) multimers as they are secreted from endothelial cells probably causes most cases of familial TTP, acquired idiopathic TTP, thienopyridine-related TTP, and pregnancy-associated TTP. The emphasis in this review is the pathophysiology of familial and acquired idiopathic TTP. In each of these entities, there is a severe defect in the function of a plasma enzyme, VWF-cleaving metalloprotease (ADAMTS-13), that normally cleaves hyper-reactive ULVWF multimers into smaller and less adhesive VWF forms. In familial TTP, mutations in the ADAMTS13 gene cause absent or severely reduced plasma VWF-cleaving metalloprotease activity. Acquired idiopathic TTP, in contrast, is the result in many patients of the production of autoantibodies that inhibit the function of ADAMTS-13. Established, evolving, and some of the unresolved issues in TTP pathophysiology will be summarized.

Section snippets

TTP and other thrombotic microangiopathies

TTP is a severe microvascular occlusive “thrombotic microangiopathy.” It is characterized by systemic platelet aggregation, organ ischemia, profound thrombocytopenia (with increased marrow megakaryocytes), and fragmentation of erythrocytes.4 The red blood cell fragmentation occurs, presumably, as blood flows through turbulent areas of the microcirculation partially occluded by platelet aggregates. Schistocytes, or “split” red blood cells, appear on the peripheral blood smear as an indication of

The ADAMTS-13-Deficient types of TTP

In 1982, “unusually large” (UL) VWF multimers were found in plasma samples taken repeatedly from four patients with chronic relapsing TTP. The ULVWF multimers were proposed to be the “agglutinative” substances in this rare disorder13 (Fig 1). The 1982 report concluded that patients with chronic relapsing TTP have a defect in the “processing” of ULVWF multimers that makes them susceptible to periodic relapses.13 Supporting evidence for ULVWF multimers as the platelet-clumping agents in TTP

Assays of plasma ADAMTS-13: lessons and limitations

Most clinical series reported to date have depended on nonphysiologic laboratory estimates of plasma ADAMTS-13 activity. The divalent cation-dependent disappearance of large plasma-type VWF multimers in the presence of test citrate-plasma is evaluated directly (using porous sodium dodecyl sulfate [SDS]-agarose gel electrophoresis)12, 37, 38 or indirectly (using collagen-binding).58, 64 The conditions are static (that is, not under flowing conditions). The assay is often performed using

Clues from the empirical (and usually successful) treatment of TTP

In 1977, before there was any inkling of the pathophysiologic processes underlying TTP, Byrnes and Khurana65 reported that relapses of the disease could be prevented or reversed by the infusion of only a few units of fresh-frozen plasma or its cryoprecipitate-poor fraction (cryosupernatant), without concurrent plasmapheresis. It was shown in 1985 that the processing of ULVWF multimers was restored in patients with familial, chronic relapsing TTP by transfusing fresh-frozen plasma,

Looking ahead

Twenty-five years ago, the familial and acquired idiopathic types of TTP were enigmatic and almost always fatal. Information about the molecular basis for these disorders is now accumulating at a dizzying rate, and most affected patients are treated successfully. In contrast, the pathophysiology of occlusive microvascular thrombus formation in Shiga-like toxin-induced HUS and the chemotherapy/transplant-associated thrombotic microangiopathies remains elusive, and therapy frequently ineffective.

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    Supported in part by grants from the National Institutes of Health (1P50 HL 65967) and the Mary Rodes Gibson Foundation.

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