Brinkman Herm Jan M, Zuurveld Marleen, Meijers Joost C M
Department of Molecular Hematology Sanquin Research Amsterdam The Netherlands.
Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences Amsterdam UMC, University of Amsterdam Amsterdam The Netherlands.
Res Pract Thromb Haemost. 2022 Aug 1;6(5):e12775. doi: 10.1002/rth2.12775. eCollection 2022 Jul.
Both andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) are clinically applied reversal agents for direct factor Xa inhibitors (FXaIs) in emergency situations. Controversy exists whether 4F-PCC is as effective as andexanet alfa in correcting FXaI anticoagulation.
This in vitro study was designed to directly compare andexanet alfa with two different 4F-PCCs (Cofact and Beriplex/Kcentra) in their ability to correct FXaI anticoagulation.
Normal plasma was spiked with apixaban or rivaroxaban. Reversal of anticoagulation was assessed using a thrombin generation assay and a fibrin generation-clot lysis test.
Andexanet alfa, applied at clinically recommended doses, was effective in restoring thrombin generation as evidenced by correction of thrombin generation lag time, peak thrombin, and endogenous thrombin potential (ETP). Clotting time and clot resistance to fibrinolytic breakdown was corrected over the full range of applied FXaI (0-800 ng/ml). 4F-PCC in increasing doses (0.625, 1.25 and 2 IU/ml; approximately 25, 50, and 80 IU/kg) only partially restored thrombin generation lag time and clotting time. Partial correction to overnormalization of peak thrombin and ETP was observed, depending on FXaI concentration and PCC dose. Clot resistance to fibrinolytic breakdown was dose-dependently improved to above normal. Beriplex/Kcentra was consistently less effective than Cofact.
Both andexanet alfa and 4F-PCC improved coagulation that is hampered by FXaIs. While andexanet alfa corrected all thrombin generation parameters, 4F-PCC predominantly increased peak thrombin and ETP. Especially heparin-free 4F-PCC also improved clot stability against fibrinolytic breakdown. Beriplex/Kcentra contains heparin, and this may have caused reduced effectivity compared to Cofact.
在紧急情况下，andexanet alfa和四因子凝血酶原复合物浓缩剂（4F-PCC）均为临床上用于直接因子Xa抑制剂（FXaIs）的逆转剂。关于4F-PCC在纠正FXaI抗凝作用方面是否与andexanet alfa一样有效，存在争议。
本体外研究旨在直接比较andexanet alfa与两种不同的4F-PCC（Cofact和Beriplex/Kcentra）纠正FXaI抗凝作用的能力。
将阿哌沙班或利伐沙班加入正常血浆中。使用凝血酶生成试验和纤维蛋白生成-凝块溶解试验评估抗凝作用的逆转情况。
以临床推荐剂量应用的andexanet alfa可有效恢复凝血酶生成，凝血酶生成滞后时间、凝血酶峰值和内源性凝血酶潜力（ETP）的纠正证明了这一点。在应用的FXaI的整个范围内（0 - 800 ng/ml），凝血时间和凝块对纤维蛋白溶解破坏的抵抗力均得到纠正。4F-PCC剂量增加（0.625、1.25和2 IU/ml；约25、50和80 IU/kg）仅部分恢复了凝血酶生成滞后时间和凝血时间。根据FXaI浓度和PCC剂量，观察到凝血酶峰值和ETP部分纠正至超正常水平。凝块对纤维蛋白溶解破坏的抵抗力呈剂量依赖性改善至高于正常水平。Beriplex/Kcentra始终比Cofact效果差。
andexanet alfa和4F-PCC均可改善受FXaIs阻碍的凝血功能。虽然andexanet alfa纠正了所有凝血酶生成参数，但4F-PCC主要增加了凝血酶峰值和ETP。尤其是不含肝素的4F-PCC还提高了凝块对纤维蛋白溶解破坏的稳定性。Beriplex/Kcentra含有肝素，与Cofact相比，这可能导致其有效性降低。
