Department of Hemoterapy and Hemostasis, ICMHO, Hospital Clinic of Barcelona, Barcelona, Spain.
Department of Hematopathology, CDB, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain.
Transfusion. 2019 Jul;59(7):2436-2445. doi: 10.1111/trf.15259. Epub 2019 Apr 4.
Comparative studies on the restoration of hemostasis with different reversal agents after dabigatran therapy have not been performed. We compared the efficacy and prothrombotic potential of the specific antidote idarucizumab with that of previously recommended non-specific procoagulant concentrates.
We explored the in vitro effects of dabigatran (184 ng/mL) on fibrin and platelet-aggregate formation onto a damaged vessel under flow conditions (600 s ). The reversal mechanisms and efficacy of idarucizumab (0.3-3 mg/mL) were compared with that of the non-specific procoagulant concentrates aPCC (25-75 U/Kg), PCC (70 U/Kg), or rFVIIa (120 μg/Kg). Generation of thrombin and prothrombin fragment (F1 + 2), and thromboelastometry parameters of clot formation were measured.
Dabigatran caused pronounced reductions in fibrin (87%) and platelet interactions (36%) with damaged vessels (p < 0.01) and significantly impaired thrombin generation and thromboelastometric parameters (delayed dynamics and reduced firmness). Idarucizumab completely normalized rates of fibrin and platelet coverage to baseline values in flow studies; and reversed the alterations in thrombin generation, F1 + 2 and thromboelastometry parameters produced by dabigatran. In comparison, aPCC and PCC only partially compensated for the dabigatran-induced alterations in fibrin deposition, but were unable to fully restore them to baseline values. Reversal with aPCC or PCC improved the majority of alterations in coagulation-related tests, but tended to overcompensate thrombin generation kinetics and significantly increased F1 + 2 levels.
Idarucizumab antagonizes alterations of direct and indirect biomarkers of hemostasis caused by dabigatran. In our studies, idarucizumab was clearly more efficacious than strategies with non-specific procoagulant concentrates and devoid of the excessive procoagulant tendency observed with the latter.
针对达比加群治疗后不同逆转剂对止血作用的比较研究尚未进行。我们比较了特异性拮抗剂依达鲁单抗与先前推荐的非特异性促凝血剂浓缩物的疗效和促血栓形成潜力。
我们在 600 秒的流动条件下，研究了达比加群（184ng/ml）对纤维蛋白和血小板聚集体在受损血管上形成的体外影响。比较了依达鲁单抗（0.3-3mg/ml）与非特异性促凝血剂浓缩物 aPCC（25-75U/kg）、PCC（70U/kg）或 rFVIIa（120μg/kg）的逆转机制和疗效。测量了凝血酶和凝血酶原片段（F1+2）的产生以及血栓弹性描记术参数的凝血。
达比加群显著降低了纤维蛋白（87%）和血小板相互作用（36%）与受损血管（p<0.01），并显著抑制了凝血酶生成和血栓弹性描记术参数（动力学延迟和坚固性降低）。依达鲁单抗在流动研究中完全将纤维蛋白和血小板覆盖的速度恢复到基线值；并逆转了达比加群引起的凝血酶生成、F1+2 和血栓弹性描记术参数的改变。相比之下，aPCC 和 PCC 仅部分补偿了达比加群引起的纤维蛋白沉积改变，但无法将其完全恢复到基线值。用 aPCC 或 PCC 逆转改善了大多数与凝血相关的测试改变，但倾向于过度补偿凝血酶生成动力学，并显著增加 F1+2 水平。
依达鲁单抗拮抗达比加群引起的直接和间接止血生物标志物的改变。在我们的研究中，依达鲁单抗明显比非特异性促凝血剂浓缩物的策略更有效，并且没有后者观察到的过度促凝血倾向。
