Targeting factor XI as a compromise between thrombosis and bleeding.

Aleksandra Żuk-Łapan, Olga Jakubik, Michał Pałuchowski, Magdalena Gajewska, Sylwester Rogula, Michał Łomiak, Aleksandra Gąsecka
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Abstract

Thromboembolic diseases have long been a leading cause of morbidity and mortality, necessitating advances in anticoagulant drugs. Heparins, vitamin K inhibitors, and direct oral anticoagulants (DOACs) are well-established drug classes that help prevent thromboembolic complications. While effective, they pose significant risks during long-term therapy, including bleeding, osteoporosis, heparin-induced thrombocytopenia, and the need for frequent monitoring and dose adjustments. Factor XI (FXI) inhibitors represent an innovative approach in anticoagulation therapy, aiming to balance thromboembolic events with the risk of bleeding complications. They include: a) orally administered small molecule inhibitors such as milvexian and asundexian; b) monoclonal antibodies such as abelacimab, osocimab, and xisomab, which specifically bind and inactivate FXI; c) FXI-antisense oligonucleotide (FXI-ASO), which downregulate FXI synthesis at the mRNA level and reduce plasma FXI concentrations. Available data indicate that FXI inhibitors decrease the risk of thromboembolic events and are associated with a lower incidence of major bleeding than current gold standard methods. Hence, FXI inhibitors may become the preferred anticoagulant class, especially for patients with elevated bleeding risk. Their development is an important step in the history of anticoagulant therapy, striving to find a balance between preventing thromboembolism and reducing bleeding risk, ultimately improving patient outcomes. In this context, a discussion on the characteristics of FXI inhibitors, a summary on data regarding the efficacy and safety of FXI inhibitors based on preclinical and clinical studies, and an outline of future perspectives regarding therapeutic strategies of FXI inhibition in venous thrombosis are presented in this study.

靶向因子XI作为血栓和出血之间的折衷。
血栓栓塞性疾病长期以来一直是发病率和死亡率的主要原因,需要抗凝药物的进步。肝素、维生素K抑制剂和直接口服抗凝剂(DOACs)是公认的有助于预防血栓栓塞并发症的药物类别。虽然有效,但在长期治疗过程中存在显著风险,包括出血、骨质疏松、肝素诱发的血小板减少症,需要经常监测和调整剂量。因子XI (FXI)抑制剂代表了抗凝治疗的一种创新方法,旨在平衡血栓栓塞事件与出血并发症的风险。它们包括:a)口服小分子抑制剂,如milvexian和asundexian;b)单克隆抗体,如abelacimab, osociimab和xisomab,特异性结合和灭活FXI;c) FXI-反义寡核苷酸(FXI- aso),在mRNA水平下调FXI合成,降低血浆中FXI浓度。现有数据表明,与目前的金标准方法相比,FXI抑制剂可降低血栓栓塞事件的风险,并与较低的大出血发生率相关。因此,FXI抑制剂可能成为首选的抗凝类药物,特别是对于出血风险升高的患者。它们的发展是抗凝治疗史上的重要一步,努力在预防血栓栓塞和降低出血风险之间找到平衡,最终改善患者的预后。在此背景下,本研究讨论了FXI抑制剂的特点,总结了基于临床前和临床研究的FXI抑制剂的有效性和安全性数据,并概述了FXI抑制静脉血栓形成的治疗策略的未来前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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