1 Cardiovascular Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, IL, USA.
2 Northshore Cardiovascular Institute, NorthShore University HealthSystem, Skokie, IL, USA.
Clin Appl Thromb Hemost. 2019 Jan-Dec;25:1076029619863493. doi: 10.1177/1076029619863493.
Recombinant coagulation factor Xa (FXa), inactivated Zh-zo, also known as andexanet alfa (AA), is a modified version of human FXa that has been developed to neutralize FXa inhibitors. We studied the reversal effect of AA for these inhibitors in various anticoagulant and thrombin generation (TG) assays. Individual aliquots of normal human plasma containing 1 µg/mL of apixaban, betrixaban, edoxaban, and rivaroxaban, were supplemented with saline or AA at a concentration of 100 µg/mL. Clotting profiles include prothrombinase-induced clotting time, activated partial thromboplastin time, and prothrombin time. Factor Xa activity was measured using an amidolytic method. Thrombin generation was measured using a calibrated automated thrombogram. Differential neutralization of all 4 anticoagulants was noted in the activated clotting time and other clotting tests. The FXa activity reversal profile varied with an observed decrease in apixaban (22%), betrixaban (56%), edoxaban (28%), and rivaroxaban (49%). Andexanet alfa also led to an increased TG in comparison to saline. The peak thrombin was higher (40%), area under the curve (AUC) increased (15%), whereas the lag time (LT) decreased (17%). Andexanet alfa added at 100 µg/mL to various FXa supplemented systems resulted in reversal of the inhibitory effects, restoring the TG profile; AUC, LT, and peak thrombin levels were comparable to those of unsupplemented samples. Andexanet alfa is capable of reversing anti-Xa activity of different oral FXa inhibitors but overshoots thrombogenesis in both the saline and FXa inhibitor supplemented systems. The degree of neutralization of Xa inhibitor is specific to each agent.
重组凝血因子 Xa（FXa），失活的 Zh-zo，也称为andexanet alfa（AA），是一种经过修饰的人 FXa，旨在中和 FXa 抑制剂。我们研究了 AA 对这些抑制剂在各种抗凝和凝血酶生成（TG）测定中的逆转作用。含有 1µg/mL 阿哌沙班、贝曲沙班、依度沙班和利伐沙班的正常人血浆的单独等分试样，用生理盐水或浓度为 100µg/mL 的 AA 补充。凝血曲线包括凝血酶原酶诱导的凝血时间、活化部分凝血活酶时间和凝血酶时间。使用酶解方法测量 FXa 活性。使用校准的自动血栓图测量凝血酶生成。在激活的凝血时间和其他凝血试验中注意到所有 4 种抗凝剂的差异中和。FXa 活性逆转谱因观察到阿哌沙班（22%）、贝曲沙班（56%）、依度沙班（28%）和利伐沙班（49%）的减少而变化。与生理盐水相比，andexanet alfa 还导致 TG 增加。最大凝血酶升高（40%），曲线下面积（AUC）增加（15%），而滞后时间（LT）减少（17%）。在各种添加 FXa 的系统中添加 100µg/mL 的 andexanet alfa 导致抑制作用的逆转，恢复 TG 谱；AUC、LT 和最大凝血酶水平与未添加样本相当。Andexanet alfa 能够逆转不同口服 FXa 抑制剂的抗-Xa 活性，但在生理盐水和 FXa 抑制剂补充系统中均过度引发血栓形成。Xa 抑制剂的中和程度对每种药物都是特异性的。
