INSERM U1148-LVTS, Université de Paris, Paris, France.
CHU Xavier Bichat, Paris, France.
Thromb Haemost. 2021 Mar;121(3):261-269. doi: 10.1055/s-0040-1716751. Epub 2020 Sep 28.
Hemostasis is a tightly regulated process characterized by a finely tuned balance between procoagulant and anticoagulant systems. Among inherited hemostatic conditions, hemophilia is one of the most well-known bleeding disorders. Hemophilia A (HA) and B (HB) are due to deficiencies in coagulation factor VIII (FVIII) or FIX, respectively, leading to unwanted bleeding. Until recently, hemophilia treatment has consisted of prophylactic replacement therapy using plasma-derived or recombinant FVIII in cases of HA or FIX in cases of HB. Because FVIII and FIX deficiencies lead to an imbalance between procoagulant and anticoagulant systems, a recent upcoming strategy implies blocking of endogenous anticoagulant proteins to compensate for the procoagulant factor deficit, thus restoring hemostatic equilibrium. Important physiological proteins of the anticoagulant pathways belong to the serpin (serine protease inhibitor) family and, recently, different experimental and clinical studies have demonstrated that targeting natural serpins could decrease bleeding in hemophilia. Here, we aim to review the different, recent studies demonstrating that blocking serpins such as antithrombin, protein Z-dependent protease inhibitor, and protease nexin-1 or modifying a serpin like α1-antitrypsin could rebalance coagulation in hemophilia. Furthermore, we underline the potential therapeutic use of serpins for the treatment of hemophilia.
止血是一个受到严格调控的过程，其特征是促凝和抗凝系统之间存在精细的平衡。在遗传性止血条件中，血友病是最著名的出血性疾病之一。血友病 A（HA）和 B（HB）分别是由于凝血因子 VIII（FVIII）或 FIX 的缺乏引起的，导致不必要的出血。直到最近，血友病的治疗一直包括使用血浆衍生或重组 FVIII 进行预防性替代治疗，用于 HA 病例，或 FIX 用于 HB 病例。由于 FVIII 和 FIX 的缺乏导致促凝和抗凝系统之间的失衡，最近出现的一种策略暗示阻断内源性抗凝蛋白以补偿促凝因子的缺乏，从而恢复止血平衡。抗凝途径的重要生理蛋白属于丝氨酸蛋白酶抑制剂（serpin）家族，最近，不同的实验和临床研究表明，靶向天然丝氨酸蛋白酶抑制剂可以减少血友病的出血。在这里，我们旨在综述不同的、最近的研究，这些研究表明阻断抗凝血酶、蛋白 Z 依赖性蛋白酶抑制剂和蛋白酶素-1 等丝氨酸蛋白酶抑制剂，或修饰α1-抗胰蛋白酶等丝氨酸蛋白酶抑制剂，可以使血友病患者的凝血重新达到平衡。此外，我们强调了丝氨酸蛋白酶抑制剂在血友病治疗中的潜在治疗用途。
