Ali Ahmed E, Becker Richard C
Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
J Thromb Thrombolysis. 2024 Dec;57(8):1315-1328. doi: 10.1007/s11239-024-02972-5. Epub 2024 Apr 16.
Arterial and venous thromboembolism is a major medical concern that requires therapeutic anticoagulation in various medical fields to prevent its drastic consequences. Despite significant advances in anticoagulant therapy, thrombosis remains a leading cause of morbidity and mortality worldwide. Traditional anticoagulants like heparin and vitamin K antagonists (VKAs) have shown efficacy in preventing and treating thrombosis but come with an inherent risk of bleeding due to their non-specific inhibition of multiple coagulation factors. Subsequent direct oral anticoagulants (DOACs), targeting specific factors such as Xa or thrombin, demonstrated improved safety profiles compared to VKAs, yet bleeding remains a concern. Accordingly, research is focused on developing anticoagulants with improved safety profiles. A safer class of anticoagulants would have broad appeal. The intrinsic pathway of coagulation, involving factor XI (FXI), has attracted attention as a potential target for safer anticoagulants. Preclinical studies and epidemiological data indicate that FXI deficiency or inhibition protects against thrombosis with minimal bleeding. Current research involves evaluating various FXI-directed strategies, and phase 2 studies have shown promising results in orthopedic surgery, atrial fibrillation, end-stage renal disease (ESRD), myocardial infarction, and ischemic stroke. Several agents, such as antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers, have been developed to inhibit FXI at different stages, offering potentially safer alternatives to traditional anticoagulants. However, the optimal balance between preventing thrombosis and the risk of bleeding associated with FXI inhibitors requires validation through extensive phase 3 clinical trials using definite clinical endpoints. Several of such trials are currently underway or planned to define the role of FXI inhibitors in clinical practice and determine the most suitable FXI inhibitor for each specific indication. The current review highlights the rationale behind developing FXI inhibitors, presenting the most advanced agents in development, summarizing completed clinical trials, and discussing ongoing research efforts.
动脉和静脉血栓栓塞是一个主要的医学问题，在各个医学领域都需要进行治疗性抗凝以防止其严重后果。尽管抗凝治疗取得了重大进展，但血栓形成仍然是全球发病和死亡的主要原因。传统抗凝剂如肝素和维生素K拮抗剂（VKAs）在预防和治疗血栓形成方面已显示出疗效，但由于它们对多种凝血因子的非特异性抑制，存在出血的固有风险。随后出现的直接口服抗凝剂（DOACs），靶向特定因子如Xa或凝血酶，与VKAs相比显示出更好的安全性，但出血仍然是一个问题。因此，研究集中在开发具有更好安全性的抗凝剂。一类更安全的抗凝剂将具有广泛的吸引力。涉及因子XI（FXI）的内源性凝血途径已成为更安全抗凝剂的潜在靶点而受到关注。临床前研究和流行病学数据表明，FXI缺乏或抑制可预防血栓形成，且出血风险最小。目前的研究包括评估各种针对FXI的策略，2期研究在骨科手术、心房颤动、终末期肾病（ESRD）、心肌梗死和缺血性中风中已显示出有希望的结果。已经开发了几种药物，如反义寡核苷酸、单克隆抗体、小分子合成物、天然肽和适体，以在不同阶段抑制FXI，为传统抗凝剂提供了潜在更安全的替代品。然而，预防血栓形成与FXI抑制剂相关出血风险之间的最佳平衡需要通过使用明确临床终点的广泛3期临床试验来验证。目前正在进行或计划进行几项此类试验，以确定FXI抑制剂在临床实践中的作用，并确定每种特定适应症最合适的FXI抑制剂。本综述强调了开发FXI抑制剂的基本原理，介绍了正在开发的最先进药物，总结了已完成的临床试验，并讨论了正在进行的研究工作。
