Rocca Bianca, Ten Cate Hugo
Department of Medicine and Surgery, LUM University Casamassima, Bari, Italy.
Department of Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center Maastricht, the Netherlands.
Eur Cardiol. 2025 Apr 10;20:e08. doi: 10.15420/ecr.2024.61. eCollection 2025.
Factor XI (FXI) is a liver-produced coagulation zymogen that evolutionarily originated from duplication of the gene encoding for prekallikrein. It circulates in complex with high-molecular-weight kininogen, and consists of two identical subunits that bind thrombin, FXIIa and FIX. Thus, the FXI molecule has features different from other coagulation factors. Pharmacological FXI blockade using small molecules, monoclonal antibodies and antisense oligonucleotides, has been developed, with a hypothesis of a bleeding-free, effective anticoagulation. Dose-finding Phase II trials were performed for thromboprophylaxis in orthopaedic surgery, non-valvular AF and as an add-on strategy to antiplatelet drugs in acute atherothrombosis (stroke or MI). None of those studies were powered for safety or efficacy, but rather, they were used to select the optimal dose for Phase III studies. Nevertheless, their limited results were often (over)interpreted as supporting the hypothesis of the first bleeding-free anticoagulation strategy. The failure of the Phase III OCEANIC-AF trial comparing the FXI inhibitor asundexian to the FXa inhibitor apixaban in AF obliged the scientific community to reconsider the bleeding-free hypothesis and the pathophysiology of FXI. Here, the molecular, disease-related and pharmacological features of FXI were analysed to provide possible explanation(s) and hypotheses for this (temporary) failure of FXI targeting. Specifically, the authors describe the peculiar features of the molecule in the coagulation cascade, the possible mechanisms for the bypassing of FXI activity, the clinical evidence related to FXI congenital deficiency, levels measured in pro-thrombotic settings, the pathophysiology of different thromboembolic disorders and the pharmacodynamics of FXI blockade in Phase I and II studies.
因子 XI（FXI）是一种由肝脏产生的凝血酶原，在进化上起源于编码前激肽释放酶的基因复制。它与高分子量激肽原形成复合物循环，由两个结合凝血酶、FXIIa 和 FIX 的相同亚基组成。因此，FXI 分子具有与其他凝血因子不同的特征。已经开发了使用小分子、单克隆抗体和反义寡核苷酸对 FXI 进行药理学阻断的方法，其假设是实现无出血的有效抗凝。在骨科手术、非瓣膜性房颤中进行了剂量探索性 II 期试验，作为急性动脉粥样硬化血栓形成（中风或心肌梗死）中抗血小板药物的附加策略用于血栓预防。这些研究均未针对安全性或有效性进行足够的样本量设计，而是用于选择 III 期研究的最佳剂量。然而，它们有限的结果常常（过度）被解释为支持首个无出血抗凝策略的假设。III 期 OCEANIC-AF 试验在房颤中将 FXI 抑制剂阿孙西胺与 FXa 抑制剂阿哌沙班进行比较，试验失败迫使科学界重新考虑无出血假设和 FXI 的病理生理学。在此，分析了 FXI 的分子、疾病相关和药理学特征，以对 FXI 靶向治疗的这一（暂时）失败提供可能的解释和假设。具体而言，作者描述了该分子在凝血级联反应中的独特特征、FXI 活性旁路的可能机制、与 FXI 先天性缺乏相关的临床证据、血栓前状态下测得的水平、不同血栓栓塞性疾病的病理生理学以及 I 期和 II 期研究中 FXI 阻断的药效学。
