凝血因子Ⅺ——靶向抗凝治疗新策略

Blood coagulation factor XI:new strategy of targeted anticoagulant therapy

血栓性疾病是全球发病率和病死率的主要原因。尽管近十年抗凝治疗取得了突破性进展,传统的维生素K拮抗剂被选择性靶向凝血因子Ⅹa或Ⅱa的直接口服抗凝剂(DOACs)所取代。然而,对于伴发疾病不断增长的人群而言,仍然缺乏令人满意的治疗方案。凝血靶向治疗是一项具有挑战性的任务,因为它干扰了促凝和抗凝活性之间的微妙平衡。流行病学和动物研究已将因子Ⅺ确定为更安全的抗凝潜在靶点,因为因子Ⅺ缺乏或抑制可预防血栓形成,且与少量或无出血相关。基于接触性止血概念,回顾凝血因子Ⅺ抑制剂开发基本原理、阐述现有FXI抑制剂药理学特征、总结临床试验研究现状,以期为新型抗凝药物研发及临床抗凝治疗提供思路。

Thrombotic disease remains a leading cause of morbidity and mortality worldwide.Despite breakthroughs in anticoagulant therapy over the past decade,traditional vitamin K antagonists have been replaced by direct oral anticoagulants(DOACs)that selectively target coagulation factor Xa or IIa.However,for the growing population with concomitant diseases,there is still a lack of satisfactory treatment options.Coagulationtargeted therapy is a challenging task because it interferes with the delicate balance between procoagulant and anticoagulant activities.Epidemiological and animal studies have identified factor XI as a potential target for anticoagulation,because factor XI deficiency or inhibition can prevent thrombosis and is associated with little or no bleeding.Based on the concept of contact hemostasis,this review describes the basic principles of the development of coagulation factor XI inhibitors,elaborates on the pharmacological characteristics of existing factor XI inhibitors,and summarizes the current situation of clinical trial research,to provide some insight for the development of new anticoagulant drugs and clinical anticoagulant treatment.