Towards a perfect balance: therapeutic silencing of von Willebrand factor in bleeding and thrombosis

Abstract

Coagulation, the process of blood clot formation, has two stages: primary and secondary hemostasis. In primary hemostasis, platelets form a plug, while in secondary hemostasis, coagulation factors create a stable fibrin clot. Von Willebrand factor (VWF) protein plays an essential role in the primary hemostasis, initiating platelet adhesion. Abnormal VWF levels can cause hemostatic disorders, with low levels leading to von Willebrand disease (VWD), the most common inherited bleeding disorder, and high levels raising the risk of (arterial) thrombosis. Treatments for thrombosis traditionally inhibit platelet aggregation, but disadvantages include resistance or bleeding complications. While there are inhibitors of VWF function to reduce thrombosis risk, in this thesis we explore the feasibility of inhibiting the production of VWF. Here, we performed allele-selective silencing of murine endothelial Vwf in mice using siRNAs. We demonstrated that a 50% VWF reduction lowers thrombus formation without increasing bleeding times. Murine-specific siRNAs encapsulated in lipid nanoparticles showed successful delivery to the endothelium, both under normal and diseased conditions. All in all, our suggest that siRNA-mediated Vwf-silencing could offer a new therapeutic approach for both VWD and thrombotic disorders. These findings support further exploration of allele-selective VWF silencing for clinical applications in hemostatic management.