A new drug for an old concept: aptamer to von Willebrand factor for prevention of arterial and microvascular thrombosis

Authors: Veyradier, A.

Publication: Haematologica; 105,11: November 2020

Affiliations: Hematology department, French National Reference Centre for Thrombotic Microangiopathies and von Willebrand disease, Hospital Lariboisière, AP-HP.Nord; EA3518 Saint-Louis Research Institute, Paris University, Paris, France

Abstract: Von Willebrand factor (VWF) is a large and complex multimeric glycoprotein essential for initiation of hemostasis after vascular injury. VWF is the mediator of platelet adhesion to the subendothelial collagen matrix and of platelet aggregation, especially at high shear rates of blood flow present in the microcirculation and stenotic arteries.1 Platelet adhesion involves specific sequences of the A1 domain of VWF (VWF-A1) and the platelet receptor glycoprotein Ib (GPIb).1 The adhesive properties of VWF are proportional to both the size of its multimers and their shear-induced unfolding, which respectively determine the number of available VWF-A1 and their swift from a cryptic to an exposed status able to bind platelet GPIb.2 Physiologically, in order to prevent the spontaneous binding of VWF to platelets, VWF multimeric distribution is regulated by a specific-cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13).3 A defect in VWF (related to genetic mutations of VWF) causes a bleeding disorder named von Willebrand disease (VWD) while an excess of ultralarge multimers of VWF (UL VWF) (due to a severe deficiency in ADAMTS13 mostly mediated by specific auto-antibodies) causes a thrombotic microangiopathy called thrombotic thrombocytopenic purpura (TTP).4 In addition, the interaction of VWF-A1 with platelet GPIb also contributes to arterial thrombosis present in atherosclerotic cardiovascular disease (ACD).5 Consequently, inhibiting the binding of VWF to GPIb by specifically targeting VWF-A1, is a rational approach to decrease both arterial and microvascular thrombosis by preventing the formation of further VWF- and platelet-rich thrombi2 in both acute ACD5 and acute TTP3, respectively.