Thrombotic thrombocytopenic purpura and anti-thrombotic therapy targeted to von Willebrand factor

Resting endothelial cells lining the inner surface of blood vessels have anti-thrombotic and anti-inflammatory actions, critical for maintaining normal vascular homeostasis. Upon localized or systemic stimulation, endothelial cells are activated to secrete bioactive molecules; among them is von Willebrand factor (VWF). Freshly secreted VWF is enriched in ultra-large (UL) forms that are anchored to endothelial cells to form long string-like structures, to which platelets tether and aggregate. This prothrombotic event is normally prevented by proteolytic cleavage of ULVWF multimers by ADAMTS-13 at a single peptide bond of Tyr1605-Met1606 in the A2 domain. The cleavage reduces the size and adhesion activity of (UL)VWF multimers. Lacking this cleaving activity due to mutations in the ADAMTS13 gene or autoantibodies against the metalloprotease is associated with systemic microvascular thrombosis found in patients with thrombotic thrombocytopenic purpura (TTP). Recombinant ADAMTS-13 has the potential to be a therapeutic agent to reduce prothrombotic activity of ULVWF multimers. Alternatively, blocking an interaction between ULVWF and its platelet receptor could achieve the same therapeutic goal. This review discusses potentials of using recombinant ADAMTS-13 and VWF-blocking agents as therapeutics for TTP and other acquired ADAMTS-13 deficiencies.