Degradation of Platelet–von Willebrand Factor Complexes by Plasmin

Abstract

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) is a plasma protease that cleaves von Willebrand factor (VWF) and regulates its thrombogenicity. VWF is a multimeric glycoprotein that plays a key role in hemostasis and thrombosis by stabilizing factor VIII and initiating platelet adhesion and aggregation at sites of vascular injury.1 VWF is stored as ultralarge VWF (ULVWF) multimers in platelet α granules and endothelial storage granules called Weibel-Palade bodies.2 ULVWF multimers, which are considered to be prothrombotic, are not normally present in the plasma of healthy humans but are released into the circulation from Weibel-Palade bodies on endothelial cell activation or injury. During the process of secretion, ULVWF multimers remain transiently bound to the endothelial surface, in which they are cleaved by ADAMTS13 into smaller and less thrombotic VWF multimers that support normal hemostasis.3 The essential role of VWF in hemostasis is evidenced clinically in patients with von Willebrand disease, a bleeding disorder caused by a lack of functional VWF.4 Conversely, deficiency of ADAMTS13 increases plasma levels of prothrombotic ULVWF multimers and causes increased susceptibility to thrombotic thrombocytopenic purpura (TTP), a disorder of thrombotic microangiopathy.5 Interestingly, episodes of TTP occur sporadically in patients with hereditary ADAMTS13 deficiency,6 suggesting the existence of other modifying factors that trigger attack of microvascular thrombosis.7 Moreover, patients with acquired (autoantibody-mediated) ADAMTS13 deficiency can achieve remission of TTP despite the persistence of severe depletion of ADAMTS13,8 …