PB0984 - Direct comparison of Andexanet alfa and prothrombin complex concentrates in the reversal of direct factor Xa inhibitors – An in vitro study

Background: Both Andexanet alfa and 4-factor prothrombin complex concentrate (4F-PCC) are clinically applied reversal agents for direct factor Xa inhibitors (FXaI) in emergency situations. Andexanet alfa is a recombinant modified human factor Xa. 4F-PCC is a human plasma-derived mixture of partially purified vitamin K-dependent coagulation factors and may contain added heparin. Controversy exists whether Andexanet alfa is preferred over 4F-PCC in correcting FXaI anticoagulation.

Aims: This in vitro study was designed to directly compare Andexanet alfa with two different 4F-PCCs, one with and the other without added heparin, in their ability to correct FXaI anticoagulation.

Methods: Normal plasma was spiked with Apixaban or Rivaroxaban. Reversal of anticoagulation by the reversal agents 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 also corrected over the full range of applied FXaI (0-800 ng/ml). 4F-PCC in increasing dose (0.625, 1.25 and 2 IU/ml; ~25, 50 and 80 IU/kg) only partially restored thrombin generation lag time and clotting time. Partial correction to over-normalization 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. 4F-PCC with added heparin was consistently less effective than 4F-PCC without added heparin.

Conclusion(s): Both Andexanet alfa and 4F-PCC improved coagulation in the presence of FXaI. While Andexanet alfa corrected all thrombin generation parameters, 4F-PCC predominantly increased peak thrombin and ETP. Especially 4F-PCC without added also improved clot stability against fibrinolytic breakdown. Whether heparin supplement to 4F-PCC counteracts its prohemostatic effectivity in bleeding patients on FXaI remains to be investigated.