Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab
Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab
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DOI：
10.1160/th14-08-0712
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发表时间：
2015-04-01
影响因子：
6.7
通讯作者：
Grottke, Oliver
中科院分区：
文献类型：
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作者：
Honickel, Markus;Treutler, Stefanie;Grottke, Oliver
紧急手术或危及生命的出血需要迅速逆转达比加群的抗凝作用。本研究评估了三因子和四因子凝血酶原复合物浓缩物（PCC）和依达赛珠单抗（达比加群的特异性解毒剂）在猪创伤模型中逆转达比加群抗凝作用的能力。在造成创伤前，对12只动物经口给予达比加群酯（DE）并静脉给予达比加群。6只动物在损伤后12分钟接受氨甲环酸加纤维蛋白原浓缩物。向离体血样中加入6个PCC（各30和60 U/kg）和依达赛珠单抗（30和60 mg/kg）。通过几种凝血试验评估凝血。达比加群输注后，所有凝血参数均发生改变（血浆水平：442 +/- 138 ng/ml）。三因素和四因素PCC均大部分或完全逆转了达比加群对血栓弹性测定变量和PT的影响，但未逆转对aPTT的影响。Idarucizumab中和了达比加群的血浆浓度，并逆转了药物对凝血变量的影响。凝血酶生成在添加PCC后显示出剂量依赖性过度校正，这意味着需要升高的凝血酶水平来克服达比加群诱导的凝血病。相比之下，依达赛珠单抗治疗使凝血酶生成恢复至基线水平。创伤后，氨甲环酸加纤维蛋白原治疗改善了PCC凝血参数和依达赛珠单抗血栓弹性测定参数的校正。所有研究的PCC改善达比加群和创伤诱导的凝血功能障碍的程度相似。总之，本研究表明，三因素和四因素PCC对达比加群逆转的有效性相似。Idarucizumab还逆转了达比加群的作用，与PCC不同，Idarucizumab与凝血酶生成的过度校正无关。
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.