Procoagulant off-target effect of the direct oral anticoagulant reversal agent Andexanet alfa

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2025-08-04 DOI:10.1016/j.bvth.2025.100100

Ischa M. S. Hoornstra , Junxiong Zhao , Harmen Middelveld , Siyu Sun , Claudia Schönichen , Johan W. M. Heemskerk , Hendrik Stragier , René Heylen , Bas de Laat , Mark Roest

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Abstract

Patients with hemorrhage after treatment with direct oral anticoagulants (DOACs) are saved from hematoma expansion by administration of Andexanet alfa, a modified factor Xa analog. A recent clinical trial points to incidental prothrombotic effects after Andexanet alfa treatment. We investigated mechanisms explaining the thrombogenic side effect. Calibrated automated thrombin generation was employed to assess the effect of Andexanet alfa on the coagulant potential of DOAC-treated plasma and whole blood. The study examined anticoagulant inhibition pathways involving tissue factor pathway inhibitor (TFPI), antithrombin, and endothelial cell components. Treatment of control plasmas with rivaroxaban, apixaban, or edoxaban resulted in an impaired thrombin generation, exemplified by a prolonged lag time and reduced thrombin peak height. Andexanet alfa over-converted this anticoagulant activity into a procoagulant effect. Plasma treatment with Andexanet alfa similarly increased thrombin generation in the absence of DOACs, even at 8 nM far below the therapeutic dose. The enhancement was abrogated in the absence or by blocking of TFPI. The Andexanet alfa effect was enhanced in the presence of heparin, thereby reversing the antithrombin protection. In the presence of endothelial cells, Andexanet alfa stimulated coagulation via TFPI and heparin inhibition. Andexanet alfa overconverts the anticoagulant effect of rivaroxaban, apixaban, and edoxaban to achieve a hypercoagulable plasma state. The action mechanism involves TFPI inhibition and neutralization of antithrombin-heparin complexes. This may account for the incidence of thrombosis observed in patients treated with Andexanet alfa.

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直接口服抗凝逆转剂安德沙奈的促凝脱靶效应

摘要直接口服抗凝剂（DOACs）治疗后出血的患者可通过给予改良Xa因子类似物安德沙奈（Andexanet alfa）来避免血肿扩大。最近的一项临床试验指出，anddexanet α治疗后附带的血栓前作用。我们研究了解释血栓性副作用的机制。采用校准的自动凝血酶生成来评估anddexanet alfa对doac处理的血浆和全血凝血电位的影响。该研究检测了抗凝血抑制途径，包括组织因子途径抑制剂（TFPI）、抗凝血酶和内皮细胞成分。用利伐沙班、阿哌沙班或依多沙班治疗对照血浆导致凝血酶生成受损，表现为延迟时间延长和凝血酶峰高度降低。anddexanet α将这种抗凝活性过度转化为促凝作用。在没有doac的情况下，Andexanet α α血浆治疗同样增加凝血酶的产生，即使在远低于治疗剂量的8 nM时也是如此。在缺乏或阻断TFPI的情况下，这种增强被取消。在肝素的存在下，Andexanet α - fa的作用增强，从而逆转了抗凝血酶的保护作用。在内皮细胞存在的情况下，anddexanet通过TFPI和肝素抑制刺激凝血。anddexanet alfa过度转换利伐沙班、阿哌沙班和依多沙班的抗凝作用，达到高凝血浆状态。其作用机制涉及TFPI抑制和中和抗凝血素-肝素复合物。这可能解释了在接受安德沙奈治疗的患者中观察到的血栓发生率。

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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Blood Vessels, Thrombosis & Hemostasis

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