The first case of TTP was described by Dr. Moschowitz (8) who, in 1924, reported a case of a previously healthy 16-year-old girl with a pentad of symptoms comprising anemia, thrombocytopenia, fever, focal alteration in the central nervous system and in the kidney. The patient died after two weeks and post-mortem examination showed widespread thrombi in the terminal circulation of several organs, composed mainly by platelets.

It was clear from the start that the anemia and thrombocytopenia were direct consequences of the mechanical destruction of red blood cells and of platelet consumption in the microcirculation: thrombocytopenia was caused by massive intravascular platelet aggregation while anemia was caused by the passage of red blood cells through small vessels partially obstructed by thrombi, leading to their fragmentation and development of intravascular hemolysis.

However the pathogenesis of the main feature of TTP, the microvascular thrombosis due to increased platelet aggregation, remained unknown until the beginning of the 1980s. In 1982 Joel Moake (9) observed that the plasma of patients with chronic relapsing TTP contained very high molecular weight, so-called ultralarge (UL), multimers of von Willebrand factor (VWF), a multimeric adhesive glycoprotein contained in endothelial cells, platelets and plasma. These ULVWF multimers promote platelet aggregation and platelet-dependent microvascular thrombosis, suggesting that patients lacked a VWF protease able to reduce the size of VWF multimers by cleavage.

The next key step was the discovery made in 1996, by Furlan, Tsai and their colleagues (10,11), who isolated a von Willebrand factor-cleaving protease that had properties consistent with the activity that had been postulated to be absent in patients with TTP. These two groups subsequently published evidence that very low or undetectable plasma levels of this protease were specifically indicative of TTP (12,13)

The von Willebrand factor-cleaving protease is now known as ADAMTS13, a member of the ADAMTS metalloprotease family (A Disintegrin And Metalloprotease with Thrombospondin-1 repeats), thanks to its identification and purification by Fujikawa et al. (14), Gerritsen et al. (15) and Zheng et al. (16) in 2001. In the same year Levy et al. identified the ADAMTS13 gene and described in seven unrelated families 12 distinct mutations, underlying the molecular mechanism responsible for the very rare congenital TTP (17). The great majority of cases of TTP is due to acquired formation of autoantibodies that inactivate ADAMTS13 or cause its removal from the circulation.