Thrombotic thrombocytopenic purpura (TTP) is caused by inactivation of a von Willebrand factor (VWF)-cleaving enzyme, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), which leads to platelet-rich thrombi comprising unusually large VWF multimers. We have found that ADAMTS13 can bind to the inactivated form of plasmin. In addition, plasmin cleaves purified ADAMTS13 into several fragments and inactivates it. Hence, we hypothesized that activation of plasminogen to plasmin becomes a new-onset factor for TTP due to ADAMTS13 inactivation. Plasmin was added exogenously or activated from plasminogen by streprokinase addition in human plasma (HP). ADAMTS13 digestion and effects of the digestion on ADAMTS13 activity were evaluated. Exogenous plasmin cleaved ADAMTS13 into several fragments, but a portion of ADAMTS13 remained in full-length form. Digestion profile of ADAMTS13 with streprokinase added exogenously in HP was similar to that of ADAMTS13 with exogenous plasmin. ADAMTS13 activity measured using FRETS-VWF73 decreased to ∼40% compared with that for normal plasma. Endogenous VWF multimer-cleaving activity was attenuated more severely (∼10%). These data suggest that endogenous plasmin cleaves ADAMTS13 into fragments and reduces its activity to ∼10%. We suggest that endogenous plasmin activation alone is not sufficient to cause TTP, but plasmin activation with ADAMTS13 deficiency might increase the risk of TTP onset.