Targeting anticoagulant protein S to improve hemostasis in hemophilia

Improved treatments are needed for hemophilia A and B, bleeding disorders affecting 400,000 people worldwide. We investigated whether targeting protein S could promote hemostasis in hemophilia by re-balancing coagulation. Protein S is an anticoagulant acting as cofactor for activated protein C and tissue factor pathway inhibitor (TFPI). This dual role makes PS a key regulator of thrombin generation. Here, we report that targeting protein S rebalances coagulation in hemophilia. Protein S gene targeting in hemophilic mice protected them against bleeding, especially when intra-articular. Mechanistically, these mice displayed increased thrombin generation, resistance to activated protein C and TFPI, and improved fibrin network. Blocking protein S in plasma of hemophilia patients normalized in vitro thrombin generation. Both protein S and TFPIα were detected in hemophilic mice joints. Protein S and TFPI expression was stronger in joints of hemophilia A than hemophilia B patients when receiving on demand therapy, e.g., during a bleeding episode. In contrast, protein S and TFPI expression was decreased in hemophilia A patients receiving prophylaxis with coagulation factor concentrates, and comparable to osteoarthritis patients. These results establish protein S inhibition as both controller of coagulation and potential therapeutic target in hemophilia. The murine protein S silencing RNA approach that we successfully used in hemophilic mice might constitute a new therapeutic concept for hemophilic patients.