The von Willebrand Factor-Cleaving Protease (ADAMTS-13) and the Diagnosis of Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is a life threatening disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia as a result of microvascular platelet clumping often accompanied by ischemic organ dysfunctions such as neurological abnormalities or renal insufficiency, and fever. Until the sixties of the 20th century TTP remained an almost universally fatal disorder. The introduction of plasma exchange therapy (PE) with replacement of fresh frozen plasma has dramatically improved the survival of patients with acute TTP from less than 10% to about 80-90% and is now considered the therapy of choice. Severe deficiency of the von Willebrand factor (VWF)-cleaving protease, now denoted as ADAMTS-13, prevents normal processing of unusually large VWF multimers released from endothelial cells and it is assumed that their persistence is responsible for the formation of platelet thrombi in the microvasculature, a pathophysiological hallmark of acute TTP. An ADAMTS-13 activity of <5% of the normal is a specific finding for acute classical TTP. However, the sensitivity of this finding for the clinical diagnosis of TTP is equivocal with reported prevalences ranging from 33 -100%. Today, two forms of classical TTP are distinguished. Hereditary TTP, also known as Upshaw-Schulman syndrome, is caused by severe constitutionalADAMTS-13 deficiency due to compound heterozygous or homozygous mutations of theADAMTS13 gene and patients often present with a chronic relapsing course. The acquired or sporadic form of TTP is caused by circulating autoantibodies inhibiting ADAMTS-13 activity. Relapses are also frequent in acquired TTP occurring in about 35-50% of survivors of a first bout. Despite improved treatment modalities, patients suffering from acute bouts of TTP constitute a challenge for any clinician as mortality and morbidity rates are still considerably high.