The discovery of the plasma protease, ADAMTS13, and its function to cleave the newly synthesized, ultra-large multimers of von Willebrand factor (VWF) changed the landscape of thrombotic thrombocytopenic purpura (TTP), providing insights for etiology and pathogenesis. 1 Severe ADAMTS13 deficiency can be acquired, caused by an autoantibody that inhibits ADAMTS13 function, or very rarely it can be caused by a mutation of the ADAMTS13 gene. A severe deficiency of ADAMTS13 activity, either acquired or congenital, is strongly associated with acute episodes of TTP. However, there are multiple observations that people can have severe ADAMTS13 deficiency, either acquired or congenital, without clinical signs of TTP. Acquired severe ADAMTS13 deficiency can be documented in approximately onethird of patients diagnosed with TTP. 2 Some of these patients may continue to have severe ADAMTS13 deficiency after an apparent complete recovery with no clinical signs of

TTP. Whether persistent ADAMTS13 deficiency during remission predicts a subsequent relapse remains uncertain. 2 In some patients, acute episodes of TTP are apparently preceded (perhaps “triggered”?) by an inflammatory condition (such as pregnancy, pancreatitis, or an infection) but whether “trigger” conditions precede acute episodes of TTP occasionally, often, or always is unknown. The occurrence of acute episodes of TTP in patients with congenital severe ADAMTS13 deficiency may also be unpredictable. Some patients present with manifestations of TTP in infancy while others, even in the same family with the same genetic abnormality, may not have clinical signs of TTP until they are adults, or may never have clinical manifestations of TTP. 3 It was predicted based on clinical observations, that mice with deletions of the ADAMTS13 gene would manifest the clinical features of TTP, but they did not. 4, 5 Additional stresses, such as Shiga toxin, 4 a procoagulant infusion, 5 or use of a mouse strain with