Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Thromb Res. 2013 Jun;131(6):540-6. doi: 10.1016/j.thromres.2013.04.016. Epub 2013 May 11.
Oral factor Xa (FXa) inhibitors are a novel class of anticoagulants that, unlike heparins, are expected to demonstrate antithrombotic effects independent of plasma antithrombin (AT) concentrations. We utilized heterozygous AT-deficient (AT+/-) mice to determine the impact of AT deficiency on anticoagulant and antithrombotic effects of edoxaban, a direct FXa inhibitor, and compared with heparins (fondaparinux, enoxaparin, and unfractionated heparin [UHF]).
The effects of edoxaban and heparins on in vitro prothrombin time and activated partial thromboplastin time were measured in plasma obtained from wild type (AT+/+) and AT+/- male mice. To assess the antithrombotic effects of these anticoagulants in vivo, venous thrombosis was induced in the inferior vena cava by FeCl3 treatment. Potency ratios of antithrombotic effects in AT+/- compared with AT+/+ mice were analyzed by a parallel line assay.
In vitro studies demonstrated that the clotting-time prolongation effects of edoxaban were not affected by heterozygous AT deficiency whereas those of AT-dependent anticoagulants were attenuated. In AT+/- mice, the antithrombotic effects of AT-dependent anticoagulants were less potent than those in AT+/+ mice. In contrast, edoxaban was equipotent in preventing thrombus formation in both wild-type and AT-deficient mice. The attenuated antithrombotic effects of fondaparinux, enoxaparin, and UFH in AT-deficient mice were restored by AT supplementation. Edoxaban exerts a comparable antithrombotic effect even in mice with low plasma AT antigen and activity to that in wild-type mice.
Edoxaban may potentially be prioritized over AT-dependent anticoagulants in patients with lower plasma AT concentration.
口服因子 Xa（FXa）抑制剂是一类新型抗凝剂，与肝素不同，预计它们具有抗血栓作用，而不依赖于血浆抗凝血酶（AT）浓度。我们利用杂合子 AT 缺陷（AT+/-）小鼠来确定 AT 缺乏对依度沙班（一种直接 FXa 抑制剂）的抗凝和抗血栓作用的影响，并与肝素（磺达肝癸钠、依诺肝素和未分级肝素[UHF]）进行了比较。
在从野生型（AT+/+）和 AT+/-雄性小鼠获得的血浆中测量了依度沙班和肝素对体外凝血酶原时间和激活部分凝血活酶时间的影响。为了评估这些抗凝剂在体内的抗血栓作用，通过 FeCl3 处理在腔静脉中诱导静脉血栓形成。通过平行线分析分析了抗血栓作用在 AT+/-与 AT+/+小鼠中的效价比。
体外研究表明，依度沙班的凝血时间延长作用不受杂合子 AT 缺乏的影响，而 AT 依赖性抗凝剂的作用则减弱。在 AT+/-小鼠中，AT 依赖性抗凝剂的抗血栓作用比 AT+/+小鼠弱。相比之下，依度沙班在野生型和 AT 缺陷型小鼠中均能有效预防血栓形成。在 AT 缺陷型小鼠中，磺达肝癸钠、依诺肝素和 UHF 的抗血栓作用减弱被 AT 补充所恢复。依度沙班在血浆 AT 抗原和活性较低的小鼠中发挥的抗血栓作用与野生型小鼠相当。
在血浆 AT 浓度较低的患者中，依度沙班可能优先于 AT 依赖性抗凝剂。
