Normal cleavage of von Willebrand factor by ADAMTS‐13 in the absence of factor VIII in patients with severe hemophilia A

Abstract

Von Willebrand factor (VWF) is required for hemostasis, recruiting platelets from rapidly flowing blood to sites of vessel injury and protecting factor VIII (FVIII) from degradation. The adhesive activity of VWF correlates with its size: large VWF multimers bind more avidly to platelets [1]. VWF multimer distribution is regulated by the metalloprotease ADAMTS13 in plasma [2,3]. In the absence of ADAMTS13 activity, ultra-large VWF (ULVWF) multimers accumulate and induce spontaneous platelet clumping [4] and cause the life-threatening disease thrombotic thrombocytopenia purpura [5]. Recent studies by Cao et al. [6] showed that under shear stress in a system using purified proteins, exogenous FVIII enhanced the cleavage of high-molecular-weight VWF multimers by ADAMTS13. Based on this result, the authors proposed that FVIII is a cofactor for ADAMTS13, suggesting that reduced VWF processing and increased platelet adhesion could represent a form of hemostatic compensation in patients with severe hemophilia A. This finding predicts that absence of FVIII in hemophilia A patients would reduce VWF proteolysis, which would be normalized by infusion of FVIII. Here, we assessed VWF multimer distribution, VWF antigen levels, and ADAMTS13 activity in the plasmas of seven patients with severe hemophilia A before recombinant FVIII infusion. In two patients, we also examined the VWF cleavage by endogenous ADAMTS13 before and after FVIII infusion.