From the Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland.
Anesth Analg. 2020 Feb;130(2):535-541. doi: 10.1213/ANE.0000000000004419.
Incomplete reversal with a recommended 5-g dose of idarucizumab has been reported in patients with excessively high dabigatran concentrations. A timely detection of reversal failure after idarucizumab using whole blood (WB) coagulation testing is clinically useful. The aims of this study were to determine residual dabigatran activity after idarucizumab on thrombin generation (TG) using in vitro supratherapeutic dabigatran models and to compare 4 WB point-of-care tests (activated partial thromboplastin time [aPTT], prothrombin time [PT], and 2 thromboelastometry tests) with the TG results.
Blood samples from 12 healthy volunteers were spiked in vitro with 0-5000 ng/mL of dabigatran. Dabigatran reversal was evaluated by adding 1000 μg/mL of idarucizumab (Praxbind) to dabigatran-spiked samples, which reflect the administration of 5-g idarucizumab to a 70-kg patient. Residual dabigatran activity was assessed using the calibrated automated TG (Thrombinoscope) in platelet-poor plasma samples. The TG results were compared with WB aPTT (DRIHEMATO APTT-S) and PT (DRIHEMATO PT-S) using CG02N analyzer, thromboelastometry (ROTEM) triggered by ellagic acid (INTEM) and tissue factor (EXTEM).
At a therapeutic concentration of dabigatran (200 ng/mL), the lag time was prolonged, and peak TG was decreased. The effects of dabigatran on TG were increased up to 1000 ng/mL, and TG was obliterated at higher supratherapeutic dabigatran levels (P < .001 versus control, respectively). TG was fully restored with idarucizumab when dabigatran was ≤2000 ng/mL, but residual anticoagulant activity was observed at higher dabigatran levels. Dabigatran prolonged WB aPTT and PT concentration dependently, and residual prolongations were observed when idarucizumab was added to 3000 or 5000 ng/mL of dabigatran (P < .001 versus control, respectively). In contrast, both INTEM and EXTEM clotting times were reversed toward reference ranges at all dabigatran concentrations when idarucizumab was added.
Our data indicate that the recommended dose of idarucizumab may not restore TG completely with excessively elevated concentrations of dabigatran. All WB measurements with aPTT, PT, and thromboelastometry predicted supratherapeutic dabigatran concentrations, whereas those tests varied in sensitivity to residual anticoagulant activity after reversal. WB aPTT corresponded well with plasma TG changes among those measurements, but the use of thromboelastometry may overestimate the effect of idarucizumab. Caution should be exercised before extrapolating in vitro point-of-care data to the clinical monitoring of dabigatran reversal.
曾有报道称，在达比加群酯浓度过高的患者中，使用推荐剂量（5g）的依达鲁单抗进行逆转后，仍存在部分逆转不完全的情况。因此，在使用依达鲁单抗后，通过全血（WB）凝血检测及时发现逆转失败具有重要的临床意义。本研究旨在使用体外超治疗浓度达比加群酯模型来确定依达鲁单抗逆转后达比加群酯的残留活性，并比较 4 种 WB 即时检验（活化部分凝血活酶时间[aPTT]、凝血酶原时间[PT]和 2 种血栓弹力图试验）与血栓生成试验（TG）的结果。
将 12 名健康志愿者的血液样本在体外分别用 0-5000ng/ml 的达比加群酯进行加标。向达比加群酯加标样本中加入 1000μg/ml 的依达鲁单抗（Praxbind），以评估达比加群酯的逆转效果，这相当于给 70kg 的患者使用 5g 依达鲁单抗。使用血小板缺乏血浆样本中的校准自动 TG（血栓酶谱仪）评估达比加群酯的残留活性。通过 CG02N 分析仪比较 TG 结果与 WB aPTT（DRIHEMATO APTT-S）和 PT（DRIHEMATO PT-S），通过鞣花酸（INTEM）和组织因子（EXTEM）触发血栓弹力图（ROTEM）。
在达比加群酯的治疗浓度（200ng/ml）下，凝血酶原时间延长，最大 TG 降低。达比加群酯对 TG 的影响在 1000ng/ml 时增加，在更高的超治疗浓度达比加群酯水平时 TG 完全被抑制（分别与对照组相比，P<0.001）。当达比加群酯浓度≤2000ng/ml 时，依达鲁单抗可完全恢复 TG，但在更高的达比加群酯浓度下仍观察到残留的抗凝活性。达比加群酯浓度依赖性地延长 WB aPTT 和 PT，当向 3000 或 5000ng/ml 的达比加群酯中加入依达鲁单抗时，仍观察到残留的延长（分别与对照组相比，P<0.001）。相反，当加入依达鲁单抗时，所有的 INTEM 和 EXTEM 凝血时间都恢复到参考范围。
我们的数据表明，推荐剂量的依达鲁单抗可能无法完全恢复因达比加群酯浓度过高而导致的 TG 水平。所有 WB 检测，包括 aPTT、PT 和血栓弹力图，都能预测超治疗浓度的达比加群酯，但这些检测在敏感性方面存在差异，可检测到逆转后残留的抗凝活性。在这些检测中，WB aPTT 与血浆 TG 变化具有良好的相关性，但血栓弹力图的使用可能会高估依达鲁单抗的效果。在将体外即时检验数据外推到达比加群酯逆转的临床监测之前，应谨慎行事。
