TY - JOUR
T1 - In vitro reversal of direct factor Xa inhibitors
T2 - Direct comparison of andexanet alfa and prothrombin complex concentrates Cofact and Beriplex/Kcentra
AU - Brinkman, Herm Jan M.
AU - Zuurveld, Marleen
AU - Meijers, Joost C. M.
N1 - Funding Information: This study was funded in part by Prothya Biosolutions, Amsterdam, The Netherlands. Prothya Biosolutions is manufacturer of Cofact, one of the PCCs tested in this study. Prothya Biosolutions was not involved in design of the study, data analysis or interpretation, writing of the manuscript, and the decision to submit the manuscript. Publisher Copyright: © 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Background: 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. Objective: 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. Method: 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. Results: 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. Conclusion: 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.
AB - Background: 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. Objective: 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. Method: 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. Results: 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. Conclusion: 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.
KW - PRT064445
KW - anticoagulation reversal
KW - apixaban
KW - prothrombin complex concentrates
KW - rivaroxaban
UR - http://www.scopus.com/inward/record.url?scp=85135846868&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/rth2.12775
DO - https://doi.org/10.1002/rth2.12775
M3 - Article
C2 - 35928523
SN - 2475-0379
VL - 6
JO - Research and practice in thrombosis and haemostasis
JF - Research and practice in thrombosis and haemostasis
IS - 5
M1 - e12775
ER -