von Willebrand Factor Proteolysis by ADAMTS13

Revew Article

von Willebrand Factor Proteolysis by ADAMTS13

J Derrick Bowen
Affiliation: Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK

Submission date: 27th July 2009, Revision date: 1st September 2009, Acceptance date: 5th September 2009


ABSTRACT

The plasma glycoprotein von Willebrand factor (VWF) is essential for effective hemostasis. It mediates platelet adhesion and aggregation at a site of vascular damage. Additionally, it transports coagulation factor VIII (an important protein of the clotting cascade) in the blood, shielding the coagulation factor from inactivation. VWF is found in plasma, platelets, vascular subendothelium and endothelial cells; its presence throughout the vasculature reflects its fundamental role in blood clot formation. Plasma VWF circulates as homopolymers (multimers) of different lengths, with the size differences arising principally through cleavage by the metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin repeats). ADAMTS13‐mediated VWF proteolysis contributes to the regulation of VWF bioactivity: newly synthesized ultralarge multimers are highly thrombogenic in comparison to smaller proteolysed forms. The regulation of VWF multimer size by ADAMTS13 is essential for normal hemostatic function, as evidenced by the pathological states that occur when proteolysis is deficient or excessive: ADAMTS13 deficiency is the basis for the life‐threatening disorder thrombotic thrombocytopenic purpura (TTP), in which ultralarge VWF multimers in the circulation predispose to the spontaneous formation of platelet aggregates, with potentially fatal consequences; conversely, too much proteolysis of VWF underlies one form of the hemorrhagic disorder von Willebrand disease (VWD): hemostasis is severely compromised by the absence of large (and sometimes intermediate) multimers in the circulation due to their rapid breakdown by ADAMTS13. This review aims to provide the clinician or scientist new to this subject area with an overview of ADAMTS13‐mediated VWF proteolysis and the known key factors that can affect this important biochemical process in health and disease.

Keywords: von Willebrand factor, von Willebrand disease, ADAMTS13, proteolysis, thrombotic thrombocytopenic purpura (TTP)
Correspondence: Derrick J Bowen, Department of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK