Why Do We Need ADAMTS13?

Abstract

ADAMTS13 is a member of a newly recognized zinc metalloprotease family that has been the subject of intense interest in recent years. Cleavage of von Willebrand factor by this protease is essential for preventing the development of thrombotic thrombocytopenic purpura (TTP) Von Willebrand factor (VWF), synthesized in vascular endothelial cells and megakaryocytes, supports platelet adhesion and aggregation at sites of vessel injury under high shear stress conditions. VWF exists in the circulation as a series of multimers, which were once believed to be released directly from vascular endothelial cells. By late 1980’s, much was known about the physiology and genetics of VWF. Nevertheless, three characteristics of VWF-platelet interaction in hemostasis had resisted efforts to unravel their molecular mechanisms (Table 1). First, VWF-platelet binding occurs only at sites of vessel injury but not in the circulation. There are two receptors on platelet surface that are engaged in VWF binding: glycoproteins αIIbβ3 and Ib/IX/V. Much is known about the regulation of VWF–αIIbβ3: αIIbβ3, normally in an inactive conformation, is transformed upon platelet activation to a competent form for ligand binding. In contrast, the regulation of VWF–Ib/IX/V remained mostly unclear. There is no definitive evidence that Ib/IX/V requires activation. What processes prevent VWF-platelet binding in the circulation but allows it to occur at sites of vessel injury? Second, several lines of evidence suggest that the large VWF multimers arc hemostatically more effective than small multimers. What is the molecular basis of this size dependence? Third, in experimental models, high levels of shear stress enhance the VWF-mediated platelet aggregation. What are the molecular features of VWF that enable VWF to become more effective under high shear stress conditions? Table 1 Characteristics of VWF-platelel interaction and their causes