Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions

von Willebrand factor (VWF) is a critical ligand for platelet adhesion and aggregation. It is synthesized and released as multimers composed of various numbers of monomers. When first released from the storage granules of endothelial cells, VWF multimers are rich in the ultra-large (UL) forms that spontaneously bind the GP Ib-IX complex and aggregate platelets. These prothrombotic ULVWF multimers are rapidly cleaved by the metalloprotease ADAMTS-13 (A Disintegrin and Metalloprotease with ThromboSpondin motif) to smaller and much less active forms. Recently, several methods have been developed to measure ADAMTS-13 activity in vitro and to link its deficiency to thrombotic thrombocytopenic purpura. Correlations between the structure and functions of the metalloprotease have also been extensively studied using recombinant technologies. However, questions remain regarding the proper substrate for the metalloprotease, the time and location of ULVWF proteolysis, and the role of fluid shear stress. In this brief review, we have discussed a potential model for ULVWF proteolysis by ADAMTS-13 in vivo. In this model, ULVWF is anchored to the surface of endothelial cells to form string-like structures under fluid shear stress. Such an elongated conformation facilitates ULVWF cleavage by exposing either the cleavage or binding sites for the metalloprotease. When ADAMTS-13 is deficient, the uncleaved ULVWF accumulates in plasma and on endothelial cells to capture platelets. This leads to platelet aggregation and thromboembolism. Dissecting the process of ULVWF proteolysis is important for not only understanding the pathophysiology of thrombotic microangiopathies, but also developing more effective means to treat these deadly diseases.