ADAMTS13 and microvascular thrombosis

Abstract

Interaction between platelet and von Willebrand factor, a circulating adhesive glycoprotein, is essential for hemostasis under the high shear environments of arterioles and capillaries. If unregulated, this interaction may lead to unwarranted platelet thrombosis. ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, number 13), a plasma zinc metalloprotease synthesized primarily in the stellate cells of the liver, cleaves shear stress-activated von Willebrand factor, thereby preventing the occurrence of von Willebrand factor-platelet interaction in the circulation. A profound deficiency of ADAMTS13, due to genetic mutations or autoimmune inhibition, results in intravascular von Willebrand factor platelet aggregation and widespread microvascular thrombosis characteristic of thrombotic thrombocytopenic purpura. Cloning of ADAMTS13 and structure-function analyses of the enzyme are leading to exciting advances in the diagnosis and therapy of this hitherto mysterious disease.

Figure

A schematic depiction of the domain structure of ADAMTS13. Long vertical lines mark the beginning of each homologous domain sequence. The consensus sequence for zinc binding, potential N- and O-glycosylation sites, and the recombinant fragments exhibiting VWF cleaving activity or interaction with IgG antibodies of TTP are also indicated. TSR: thrombospondin type 1 repeat.