Oliver Grottke, MD PhD, Department of Anaesthesiology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany, Tel.: +49 241 8080972, Fax: +49 241 8082406, E-mail:
Thromb Haemost. 2015 Apr;113(4):728-40. doi: 10.1160/TH14-08-0712. Epub 2015 Jan 8.
Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of dabigatran. This study assessed the ability of three- and four-factor prothrombin complex concentrate (PCC) and idarucizumab (specific antidote for dabigatran) to reverse the anticoagulant effects of dabigatran in a porcine model of trauma. Twelve animals were given dabigatran etexilate (DE) orally and dabigatran intravenously, before infliction of trauma. Six animals received tranexamic acid plus fibrinogen concentrate 12 minutes post-injury. Six PCCs (each 30 and 60 U/kg) and idarucizumab (30 and 60 mg/kg) were added to blood samples ex vivo. Coagulation was assessed by several coagulation assays. All coagulation parameters were altered after dabigatran infusion (plasma level: 442 ± 138 ng/ml). Both three- and four-factor PCCs mostly or completely reversed the effects of dabigatran on thromboelastometry variables and PT but not on aPTT. Idarucizumab neutralised plasma concentrations of dabigatran, and reversed the effects of the drug on coagulation variables. Thrombin generation showed dose-dependent over-correction following the addition of PCC, implying that elevated levels of thrombin are required to overcome dabigatran-induced coagulopathy. In contrast, treatment with idarucizumab returned thrombin generation to baseline levels. Following trauma, therapy with tranexamic acid plus fibrinogen improved correction of coagulation parameters by PCC, and thromboelastometry parameters by idarucizumab. All investigated PCCs improved dabigatran- and trauma-induced coagulopathy to a similar degree. In conclusion, this study shows that three- and four-factor PCCs are similarly effective for dabigatran reversal. Idarucizumab also reversed the effects of dabigatran and, unlike PCCs, was not associated with over-correction of thrombin generation.
紧急手术或有生命威胁的出血需要迅速逆转达比加群的抗凝作用。本研究评估了三种和四种因子的凝血酶原复合物浓缩物（PCC）和依达鲁单抗（达比加群的特异性解毒剂）在创伤猪模型中逆转达比加群抗凝作用的能力。12 只动物口服给予达比加群乙酯（DE）并静脉给予达比加群，然后造成创伤。6 只动物在受伤后 12 分钟给予氨甲环酸加纤维蛋白原浓缩物。将三种和四种 PCC（每种 30 和 60 U/kg）和依达鲁单抗（30 和 60 mg/kg）添加到离体血液样本中。通过几种凝血检测评估凝血。达比加群输注后所有凝血参数均发生改变（血浆水平：442±138ng/ml）。三种和四种因子 PCC 主要或完全逆转了达比加群对血栓弹性描记变量和 PT 的作用，但对 aPTT 无作用。依达鲁单抗中和达比加群的血浆浓度，并逆转药物对凝血变量的作用。凝血酶生成显示，添加 PCC 后呈剂量依赖性过度校正，表明需要升高的凝血酶水平来克服达比加群诱导的凝血障碍。相比之下，依达鲁单抗治疗使凝血酶生成恢复到基线水平。创伤后，氨甲环酸加纤维蛋白原治疗可改善 PCC 对凝血参数的校正，并改善依达鲁单抗对血栓弹性描记参数的校正。所有研究的 PCC 对达比加群和创伤引起的凝血障碍均有相似程度的改善。总之，本研究表明，三种和四种因子的 PCC 对达比加群的逆转效果相似。依达鲁单抗也逆转了达比加群的作用，与 PCC 不同，不会引起凝血酶生成的过度校正。
