ADAMTS13-mediated modulation of VWF activity limits thrombo-inflammatory ischemia/reperfusion injury in the heart. In the ischemic heart, ultra-large (UL)–VWF released from activated or damaged endothelial cells and platelets promotes neutrophil and platelet recruitment that contribute to tissue damage. UL-VWF is cleaved by ADAMTS13 to smaller VWF multimers that circulate in the plasma and are less potent in recruiting neutrophils and platelets. Infusion of exogenous ADAMTS13 reduces UL-VWF levels and infarct size. Similar results were obtained in VWF-deficient mice or mice treated with anti-VWF antibodies. The exact mechanism of how VWF, platelets, and leukocytes promote these processes to induce tissue damage remains to be determined.