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 rebalancing coagulation. Protein S (PS) 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 PS rebalances coagulation in hemophilia. PS 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 PS in plasma of hemophilia patients normalized in vitro thrombin generation. Both PS and TFPIα were detected in hemophilic mice joints. PS and TFPI expression was stronger in the joints of hemophilia A patients than in those of hemophilia B patients when receiving on-demand therapy, for example, during a bleeding episode. In contrast, PS and TFPI expression was decreased in hemophilia A patients receiving prophylaxis with coagulation factor concentrates, comparable to osteoarthritis patients. These results establish PS inhibition as both controller of coagulation and potential therapeutic target in hemophilia. The murine PS silencing RNA approach that we successfully used in hemophilic mice might constitute a new therapeutic concept for hemophilic patients.

中文翻译：

---

靶向抗凝蛋白 S 改善血友病止血

血友病 A 和 B 需要改进的治疗方法，这两种出血性疾病影响着全世界 40 万人。我们研究了靶向蛋白 S 是否可以通过重新平衡凝血来促进血友病患者的止血。蛋白 S (PS) 是一种抗凝血剂，可作为活化蛋白 C 和组织因子通路抑制剂 (TFPI) 的辅助因子。这种双重作用使 PS 成为凝血酶生成的关键调节剂。在这里，我们报告靶向 PS 可重新平衡血友病患者的凝血。血友病小鼠中的 PS 基因靶向可保护它们免于出血，尤其是在关节内时。从机制上讲，这些小鼠表现出增加的凝血酶生成、对活化蛋白 C 和 TFPI 的抗性以及改善的纤维蛋白网络。阻断血友病患者血浆中的 PS 可使体外凝血酶生成正常化。在血友病小鼠关节中检测到 PS 和 TFPIα。当接受按需治疗时，例如，在出血期间，PS 和 TFPI 表达在血友病 A 患者的关节中比在血友病 B 患者的关节中更强。相反，与骨关节炎患者相比，接受凝血因子浓缩物预防的血友病 A 患者的 PS 和 TFPI 表达降低。这些结果确立了 PS 抑制作为血友病中凝血的控制者和潜在的治疗靶点。我们在血友病小鼠中成功使用的小鼠 PS 沉默 RNA 方法可能构成血友病患者的新治疗概念。在出血期间。相反，与骨关节炎患者相比，接受凝血因子浓缩物预防的血友病 A 患者的 PS 和 TFPI 表达降低。这些结果确立了 PS 抑制作为血友病中凝血的控制者和潜在的治疗靶点。我们在血友病小鼠中成功使用的小鼠 PS 沉默 RNA 方法可能构成血友病患者的新治疗概念。在出血期间。相反，与骨关节炎患者相比，接受凝血因子浓缩物预防的血友病 A 患者的 PS 和 TFPI 表达降低。这些结果确立了 PS 抑制作为血友病中凝血的控制者和潜在的治疗靶点。我们在血友病小鼠中成功使用的小鼠 PS 沉默 RNA 方法可能构成血友病患者的新治疗概念。