History of Thrombotic Thrombocytopenic Purpura and the von Willebrand Factor–Cleaving Protease, ADAMTS13

Abstract

We first summarize the course from the initial description of a patient with thrombotic thrombocytopenic purpura (TTP) and the creation of the disease’s name to the diagnostic criteria proposed in 1966. A disease variant, obviously a constitutional form of a TTP-like disease responding to plasma infusions, is presented next. The many pathophysiological hypotheses put forward over the years are outlined with a focus on the detection of von Willebrand factor–cleaving protease, later identified as the metalloprotease ADAMTS13, and its severe deficiency as an important pathogenetic factor for TTP. A more common autoantibody-mediated acquired ADAMTS13 deficiency leading to acquired TTP should be distinguished from the rare hereditary form of the disease which is caused by homozygous or double heterozygous ADAMTS13 mutations. Then, the empirically introduced plasma therapy is reviewed, and the rationale for plasma exchange with fresh frozen plasma replacement in acquired TTP and plasma infusion in hereditary TTP is summarized. Finally, the differential diagnosis between the closely similar diseases TTP and (atypical) hemolytic uremic syndrome is discussed, and the sensitivity and specificity of a severe deficiency of ADAMTS13 activity for diagnosing TTP is evaluated. We conclude that some rare patients with “true” TTP may not be severely deficient in ADAMTS13 activity as measured with currently available methods. However, a severe deficiency of ADAMTS13 is a specific feature for a thrombotic microangiopathy that most clinicians diagnose as TTP.