Department of Hemotherapy-Hemostasis, Hospital Clinic, Centre de Diagnostic Biomedic, Institut d'Investigacions Biomediques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
PLoS One. 2013 Nov 11;8(11):e78696. doi: 10.1371/journal.pone.0078696. eCollection 2013.
Apixaban is a new oral anticoagulant with a specific inhibitory action on FXa. No information is available on the reversal of the antihemostatic action of apixaban in experimental or clinical settings. We have evaluated the effectiveness of different factor concentrates at reversing modifications of hemostatic mechanisms induced by moderately elevated concentrations of apixaban (200 ng/ml) added in vitro to blood from healthy donors (n = 10). Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were assessed. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with blood circulating through damaged vascular surfaces, at a shear rate of 600 s(-1). The potential of prothrombin complex concentrates (PCCs; 50 IU/kg), activated prothrombin complex concentrates (aPCCs; 75 IU/kg), or activated recombinant factor VII (rFVIIa; 270 μg/kg), at reversing the antihemostatic actions of apixaban, were investigated. Apixaban interfered with TG kinetics. Delayed lag phase, prolonged time to peak and reduced peak values, were improved by the different concentrates, though modifications in TG patterns were diversely affected depending on the activating reagents. Apixaban significantly prolonged clotting times (CTs) in TEM studies. Prolongations in CTs were corrected by the different concentrates with variable efficacies (rFVIIa≥aPCC>PCC). Apixaban significantly reduced fibrin and platelet interactions with damaged vascular surfaces in perfusion studies (p<0.05 and p<0.01, respectively). Impairments in fibrin formation were normalized by the different concentrates. Only rFVIIa significantly restored levels of platelet deposition. Alterations in hemostasis induced by apixaban were variably compensated by the different factor concentrates investigated. However, effects of these concentrates were not homogeneous in all the tests, with PCCs showing more efficacy in TG, and rFVIIa being more effective on TEM and perfusion studies. Our results indicate that rFVIIa, PCCs and aPCCs have the potential to restore platelet and fibrin components of the hemostasis previously altered by apixaban.
阿哌沙班是一种新型的、具有特定 FXa 抑制作用的口服抗凝剂。目前尚无关于在实验或临床环境中逆转阿哌沙班抗止血作用的信息。我们评估了不同因子浓缩物在逆转体外添加到健康供体血液中（n=10）的中等浓度阿哌沙班（200ng/ml）引起的止血机制改变方面的效果。评估了对凝血酶生成（TG）和血栓弹性测定（TEM）参数的影响。在剪切速率为 600s(-1)时，通过循环流经受损血管表面的血液研究，评估了血小板黏附、聚集和促凝活性的改变。研究了凝血酶原复合物浓缩物（PCC；50IU/kg）、活化凝血酶原复合物浓缩物（aPCC；75IU/kg）或重组活化因子 VII（rFVIIa；270μg/kg）逆转阿哌沙班抗止血作用的潜力。阿哌沙班干扰 TG 动力学。不同的浓缩物可改善延迟的潜伏期、延长的达峰时间和降低的达峰值，尽管 TG 模式的改变因激活试剂而异而受到不同影响。阿哌沙班显著延长 TEM 研究中的凝血时间（CT）。不同浓缩物的疗效不同（rFVIIa≥aPCC>PCC），可纠正 CT 延长。阿哌沙班在灌注研究中显著降低纤维蛋白和血小板与受损血管表面的相互作用（分别为 p<0.05 和 p<0.01）。不同的浓缩物可使纤维蛋白形成受损正常化。只有 rFVIIa 可显著恢复血小板沉积水平。不同的因子浓缩物可不同程度地补偿阿哌沙班引起的止血改变。然而，这些浓缩物在所有试验中的效果并不一致，PCC 在 TG 中更有效，rFVIIa 在 TEM 和灌注研究中更有效。我们的结果表明，rFVIIa、PCC 和 aPCC 有潜力恢复阿哌沙班先前改变的止血中的血小板和纤维蛋白成分。
