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：

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靶向抗凝蛋白 S 改善血友病止血


A 型血友病和 B 型血友病是影响全球 40 万人的出血性疾病，需要改进治疗方法。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的止血。 Protein S (PS) 是一种抗凝剂，充当活化蛋白 C 和组织因子途径抑制剂 (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因子。在这里，我们报告靶向 PS 可重新平衡血友病的凝血。血友病小鼠中的 PS 基因靶向可以保护它们免受出血，特别是在关节内出血时。从机制上讲，这些小鼠表现出凝血酶生成增加、对活化蛋白 C 和 TFPI 的抵抗力以及纤维蛋白网络的改善。阻断血友病患者血浆中的 PS 可以使体外凝血酶的生成正常化。在血友病小鼠关节中均检测到 PS 和 TFPIα。当接受按需治疗时，例如在出血期间，血友病 A 患者的关节中 PS 和 TFPI 的表达强于血友病 B 患者。相反，与骨关节炎患者相比，接受凝血因子浓缩物预防的 A 型血友病患者中 PS 和 TFPI 表达降低。这些结果表明 PS 抑制既是凝血的控制剂，也是血友病的潜在治疗靶点。我们在血友病小鼠身上成功使用的鼠 PS 沉默 RNA 方法可能为血友病患者构成一个新的治疗概念。