Thrombotic thrombocytopenic purpura--then and now

Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and formation of microthrombi in several organs. The disease may manifest once in a lifetime or may relapse after complete recovery of the initial episode; in these recurrent cases, death or neurological sequelae are common final outcomes. Accumulation of unusually large (UL) von Willebrand factor (VWF) multimers was described in the plasma of patients with TTP. Such ULVWF multimers are synthesized in endothelial cells and megakaryocytes and are secreted into the blood upon stimulation. However, in healthy individuals ULVWF multimers do not normally circulate because they are rapidly reduced into smaller multimers soon after their secretion due to cleavage by a plasma metalloprotease, ADAMTS13. Deficiency of ADAMTS13 has been reported consistently in patients with TTP. Such defect may be constitutive, due to homozygous or double heterozygous mutations in the corresponding gene, or acquired, due to the presence of circulating inhibitory antibodies. It follows that in TTP patients, the absent or severely depressed plasma ADAMTS13 activity limits the cleavage of ULVWF multimers, which remain anchored to the endothelial cells in long strings. Particularly under conditions of high shear stress, the multimers may promote the adhesion of circulating platelets, initiating thrombus formation. The clinical implications of these findings to the diagnosis and treatment of TTP are discussed.