Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura☆
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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Dynamic and functional linkage between von Willebrand factor and ADAMTS-13 with aging: an Atherosclerosis Risk in Community study
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2022, Small Animal Critical Care MedicineVon Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans
2015, BloodCitation Excerpt :However, this effect was restricted to the absence or inhibition of ADAMTS13 in these in vitro settings.42 As it is postulated that ULVWF fibers may only occur by profound EC activation combined with absence of ADAMTS13 activity,25,43-45 we postulate local inhibition or deficiency of ADAMTS13 activity in tumor vessels. The following arguments support our hypothesis: our own studies demonstrated that melanoma cells activate ECs,3-5 followed by a profound release of VWF fibers, and may therefore imbalance the ratio between ADAMTS13 and ULVWF fibers.
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Supported in part by grants from the National Institutes of Health (1P50 HL 65967) and the Mary Rodes Gibson Foundation.