Targeting anticoagulant protein S to improve hemostasis in hemophilia

Raja Prince, Luca Bologna, Mirko Manetti, Daniela Melchiorre, Irene Rosa, Natacha Dewarrat, Silvia Suardi, Poorya Amini, José A. Fernández, Laurent Burnier, Claudia Quarroz, Maria Desiré Reina Caro, Yasuhiro Matsumura, Johanna A. Kremer Hovinga, John H. Griffin, Hans-Uwe Simon, Lidia Ibba-Manneschi, François Saller, Sara Calzavarini and Anne Angelillo-Scherrer

Key points

  • Targeting anticoagulant protein S rebalances coagulation in hemophilia.

  • Protein S in joints is a novel pathophysiological contributor to hemarthrosis and a potential therapeutic target 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.

  • Submitted September 18, 2017.
  • Accepted January 3, 2018.