Thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) is a disease syndrome, and its history exemplifies how small observational studies lead to hypotheses that spawn randomized control trials (RCTs). Moschowitz's original case report coupled with the case findings of Bukowski and Byrne led to the RCT of Rock and the Canadian Apheresis Group that proved plasma exchange was superior to plasma infusion for the treatment of adults with TTP/HUS. Our single case report of continuous plasma exchange coupled with the observations about the pathogenic role of von Willebrand multimer protease of Tsai and Furlan strengthened by a 25-year observational study of plasma exchange treatment for TTP/HUS has led to a proposal to initiate a new RCT.