Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndrome

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Abstract
Objective.—To evaluate the usefulness and feasibility of measuring plasma von Willebrand factor (vWF)-cleaving metalloprotease activity (ADAMTS 13) in the differential diagnosis of thrombotic thrombocytopenic purpura (TTP), the hemolytic uremic syndrome, and other thrombotic microangiopathies. Data Sources.—Articles published in the medical literature. Data Extraction and Synthesis.—In TTP, a multimeric form of vWF that is larger than that ordinarily found in the plasma may cause systemic platelet aggregation under the high-shear conditions of the microcirculation. ADAMTS 13 is a divalent cation-activated, vWF-cleaving metalloprotease that converts unusually large vWF multimers derived from endothelial cells into smaller vWF forms in normal plasma. ADAMTS 13 is severely reduced or absent in most patients with TTP. The vWF-cleaving metalloprotease is present in fresh-frozen plasma, cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The enzyme is defective in children with chronic relapsing TTP. Infusion of any of the plasma products that contain the vWF-cleaving metalloprotease stops or prevents (for about 3 weeks) TTP episodes in these patients. An immunoglobulin (Ig) G autoantibody to the vWF-cleaving metalloprotease is found transiently in many adult patients with acquired acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. Patients with acquired TTP require plasma exchange, that is, both infusion of a plasma product containing vWF-cleaving metalloprotease and removal of autoantibody and/or unusually large vWF multimers by plasmapheresis. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy-associated thrombotic microangiopathy, as well as in hemolytic uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWF-cleaving metalloprotease activity, as there is in TTP. Conclusions.—The presently available lengthy and complicated procedure for estimation of plasma vWF-cleaving metalloprotease activity is not yet practical for rapid diagnostic use. This test has supplanted the equally lengthy and difficult, less specific analysis of plasma vWF multimeric pattern. If the clinical distinction between TTP and hemolytic uremic syndrome is uncertain, it is appropriate to acquire (before therapy) a citrate-plasma sample for the ultimate determination of vWF-cleaving metalloprotease activity.