Haematology Department, Hôtel-Dieu University Hospital, Paris, France.
Thromb Res. 2012 Apr;129(4):e77-82. doi: 10.1016/j.thromres.2011.07.026. Epub 2011 Aug 17.
Edoxaban, an oral direct factor Xa (FXa) inhibitor, is in Phase III development for prevention and treatment of thromboembolic disorders. Fondaparinux is an approved indirect FXa inhibitor. This study compared the effects of edoxaban and fondaparinux on thrombin generation (TG) using the calibrated automated thrombogram (CAT). Secondary objectives included evaluation of edoxaban and inhibition of coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [aPTT]), anti-FXa activity and clotting times.
Pooled citrated platelet-poor plasma from healthy subjects was spiked with edoxaban (0.02-3.65 μM) or fondaparinux (0.15-1.18 μM). Parameters of TG were calculated using Thrombinoscope software. PT ratios and aPTT were measured in the presence of different thromboplastin reagents. Exogenous anti-FXa was measured using Rotachrom HBPM (Stago) and a specific assay developed for direct FXa inhibitors (Hyphen BioMed).
Edoxaban exhibited a 3-fold greater concentration-dependent effect than fondaparinux across TG parameters (except endogenous thrombin potential). Edoxaban also produced a concentration-dependent prolongation of PT ratio and aPTT. The magnitude of concentration-dependent increase was related to thromboplastin reagent. In contrast to edoxaban, fondaparinux was inactive on these clotting tests. Linear correlations were observed between plasma concentration of edoxaban and anti-FXa activity and results of clotting time assays.
TG evaluation by the CAT method, coagulation tests, and anti-FXa and clotting assays demonstrated concentration-dependent effects of edoxaban. The PT and aPTT prolongation are reagent dependent; correction of PT ratio by international normalized ratio does not reduce variability in response. The greater effect of edoxaban vs. fondaparinux may be related to the broader activity of direct FXa inhibitors compared with indirect FXa inhibitors.
依度沙班是一种口服直接因子 Xa（FXa）抑制剂，目前处于预防和治疗血栓栓塞性疾病的 III 期开发阶段。磺达肝癸钠是一种已批准的间接 FXa 抑制剂。本研究使用校准的自动化血栓图（CAT）比较了依度沙班和磺达肝癸钠对凝血酶生成（TG）的影响。次要目标包括评估依度沙班和对凝血参数（凝血酶原时间[PT]、活化部分凝血活酶时间[aPTT]）、抗 FXa 活性和凝血时间的抑制作用。
将来自健康受试者的混合柠檬酸血小板少血浆与依度沙班（0.02-3.65 μM）或磺达肝癸钠（0.15-1.18 μM）混合。使用凝血酶谱软件计算 TG 参数。在不同的凝血活酶试剂存在下测量 PT 比值和 aPTT。使用 Rotachrom HBPM（Stago）和专门为直接 FXa 抑制剂开发的特定测定法（Hyphen BioMed）测量外源性抗 FXa。
依度沙班在 TG 参数（除内源性凝血酶潜能外）上表现出比磺达肝癸钠强 3 倍的浓度依赖性效应。依度沙班还导致 PT 比值和 aPTT 浓度依赖性延长。浓度依赖性增加的幅度与凝血活酶试剂有关。与依度沙班相反，磺达肝癸钠在这些凝血试验中没有活性。在依度沙班的血浆浓度与抗 FXa 活性和凝血时间测定结果之间观察到线性相关性。
通过 CAT 方法、凝血试验以及抗 FXa 和凝血试验评估 TG 表明，依度沙班具有浓度依赖性作用。PT 和 aPTT 的延长与试剂有关；通过国际标准化比值校正 PT 比值并不能降低反应的变异性。依度沙班与磺达肝癸钠相比，其效果更强，这可能与直接 FXa 抑制剂与间接 FXa 抑制剂相比具有更广泛的活性有关。
