新型小分子因子XIa抑制剂milvexian的抗凝作用可通过活化凝血酶原复合物浓缩物和重组因子VIIa在人血浆和体外全血中中和

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis Pub Date : 2024-11-01 DOI:10.1016/j.rpth.2024.102600

Matthew Bunce, Zheng Huang Devine, Madhu Chintala

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引用次数: 0

摘要

开发具有抗血栓疗效而不伴有出血风险的抗凝剂仍然是血栓形成的未满足的临床需求。尽管与华法林相比，直接口服抗凝剂（DOACs）的大出血发生率降低，但仍存在出血风险，导致治疗指数不理想。流行病学数据表明，与当前一代doac相比，抑制活化因子XI （FXIa）在出血风险方面可能提供更高的安全性。此外，milvexian在选择性全膝关节置换术患者中的II期试验显示出强大的剂量依赖性疗效，没有统计学上显著的出血增加。然而，快速有效纠正FXIa抑制剂诱导抗凝的能力在患者出现无法控制的出血或需要紧急手术的情况下仍然是重要的。目的评估新型小分子FXIa抑制剂milvexian （BMS-986177/JNJ-70033093）在体外使用市售的止血前药物的抗凝作用。方法采用活化的部分凝血活素时间凝血试验、血栓弹性成像和高岭土启动的凝血酶生成试验，对smilvexian相关抗凝和校正效果进行评价。结果活化凝血酶原复合物浓缩物（PCCs）和重组因子（rF）VIIa在活化部分凝血酶活时间凝血试验、血栓弹性成像和高岭土启动凝血酶生成试验中纠正了米尔维昔安的抗凝作用。相比之下，其他药物，包括PCCs、rFIX和rFVIII，显示出适度或没有纠正米尔韦昔酮相关抗凝。结论本研究表明，现有的活化PCCs和rFVIIa可使密尔维昔酮诱导的体外抗凝作用正常化。这些药物的临床应用仍有待确定。

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The anticoagulant effects of milvexian, a novel small molecule factor XIa inhibitor, are neutralized by activated prothrombin complex concentrates and recombinant factor VIIa in human plasma and whole blood in vitro

Background

The development of anticoagulants that provide antithrombotic efficacy without a concomitant bleeding risk remains an unmet clinical need in thrombosis. Although direct oral anticoagulants (DOACs) have a reduced incidence of major bleeding compared with warfarin, they still carry a bleeding risk, resulting in a suboptimal therapeutic index. Epidemiologic data suggest that inhibiting activated factor XI (FXIa) may offer an improved safety profile with respect to bleeding risk compared with current-generation DOACs. Additionally, a phase II trial of milvexian in patients undergoing elective total knee replacement demonstrated robust dose-dependent efficacy with no statistically significant increase in bleeding. Nevertheless, the ability to rapidly and effectively correct FXIa inhibitor–induced anticoagulation may still be important in situations where patients experience uncontrolled bleeding or require emergency surgery.

Objectives

We assessed the ability to normalize the anticoagulant effects of the novel small-molecule FXIa inhibitor milvexian (BMS-986177/JNJ-70033093) in vitro using commercially available prohemostatic agents.

Methods

Milvexian-associated anticoagulation and correction was evaluated in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays.

Results

Activated prothrombin complex concentrates (PCCs) and recombinant factor (rF)VIIa corrected the anticoagulant effects of milvexian in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays. In contrast, other agents, including PCCs, rFIX, and rFVIII, demonstrated either modest or no correction of milvexian-associated anticoagulation.

Conclusion

This study demonstrated that currently available activated PCCs and rFVIIa normalize the anticoagulation induced by milvexian in vitro. The clinical utility of these agents remains to be established.

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