Abnormalities of von willebrand factor multimers in drug‐associated thrombotic microangiopathies

Abstract

Six patients with thrombotic microangiopathy associated with drug therapy had serial analyses of von Willebrand factor (vWF) multimeric patterns in their EDTA-plasma samples by sodium dodecyl sulfate-1% agarose gel electrophoresis and autoradiography. In the plasma of five patients (one with chronic myelogenous leukemia, two with prostatic cancer, and two with lymphoma), vWF abnormalities were observed during evolution of the thrombotic microangiopathy. These abnormalities were either the presence of unusually large (UL)vWF multimers of the type similar to those found within, and released or secreted by, endothelial cells (three patients) or a relative decrease in the largest plasma vWF multimers of the type that can be induced to attach to platelets (one patient) or both vWF abnormalities in different serial samples (one patient). In the one cardiac transplant patient who did not develop vWF multimeric abnormalities associated with thrombotic microangiopathy, vWF antigen levels were elevated more than threefold. This later individual received therapy with cyclosporin A alone. The other five thrombotic microangiopathy patients received cyclosporin A in combination with other chemotherapeutic agents (two patients); mitomycin-C, along with other chemotherapy (two patients); or multiple chemotherapeutic drugs, but not cyclosporin A or mitomycin C (one patient). The finding of vWF multimeric abnormalities during serial analysis of plasma samples from five of six patients with drug-associated thrombotic microangiopathy suggests the possibility that ULvWF forms derived from damaged or stimulated endothelial cells, along with the largest plasma vWF multimers, may be involved in the intravascular platelet clumping that is an essential part of the pathophysiology of this disorder.

von Willebrand Factor–Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic–Uremic Syndrome

“…Reduced production of prostacyclin, impaired fibrinolysis, and platelet-aggregating agents have been implicated in the development of thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome. Moake et al 5,6 and Charba et al 13 attributed the enhanced intravascular platelet clumping in these syndromes to the presence of unusually large polymers of von Willebrand factor. Systemic endothelial-cell injury may lead to excessive release from endothelial cells of extremely large polymers of von Willebrand factor that cannot be processed to smaller forms by a specific "depolymerase."…”

Abnormally large von Willebrand factor multimers in Henoch-Schönlein purpura

“…Pharmacological conditions, such as drug administration [25], autoimmune vasculitis, or connective tissue diseases [26] have been associated with vascular injury and the appearance of vWf multimers larger than those normally present in circulation.…”

Drug-Induced Thromboembolic Events in Patients with Malignancy

“…This complication is usually developed within weeks to months after the first exposure to the drug, and endothelial injury is believed to be the triggering mechanism. Von Willebrand factor multimers may be implicated in the pathogenesis of these drug-induced thrombotic microangiopathies but the exsting data are still contradictory [90,91].…”