Andexanet versus prothrombin complex concentrates: Differences in reversal of factor Xa inhibitors in in vitro thrombin generation

Abstract

Background Andexanet alfa (andexanet) is a modified human factor Xa (FXa) approved for anticoagulation reversal in patients with life‐threatening bleeding treated with rivaroxaban or apixaban. Four‐factor prothrombin complex concentrates (4F‐PCCs) are approved for reversal of vitamin K antagonist–induced anticoagulation but not FXa inhibitors. The mechanism and effectiveness of 4F‐PCCs for FXa inhibitor reversal are unclear. Objective To investigate the mechanism and impact of 4F‐PCCs on reversal of rivaroxaban and apixaban in vitro compared to andexanet. Methods The effect of 4F‐PCCs (or individual factors) on tissue factor‐initiated thrombin generation (TF‐TG) was evaluated in human plasma, with or without rivaroxaban or apixaban, and compared with andexanet under the same conditions. Results In the TF‐TG assay, 4F‐PCC completely reversed warfarin anticoagulation. Andexanet normalized TF‐TG over a wide range of apixaban and rivaroxaban concentrations tested (19‐2000 ng/mL). However, 4F‐PCC (or individual factors) was unable to normalize endogenous thrombin potential (ETP) or peak thrombin (Peak) in the presence of apixaban or rivaroxaban (75‐500 ng/mL). TF‐TG was only normalized by 4F‐PCC at inhibitor concentrations <75 ng/mL (ETP) or <37.5 ng/mL (Peak). These data can be explained by the estimated thresholds of FXa activity required to support normal TF‐TG based on the inhibitor:FXa ratios and levels of uninhibited FXa. The data are consistent with healthy volunteer studies where TF‐TG is not normalized until inhibitor levels are substantially decreased. Conclusions Both the theoretical calculations and experimental data demonstrated that 4F‐PCCs are only able to normalize TG over a low and narrow range of FXa inhibitor concentrations (<75 ng/mL).

In vitro reversal of direct factor Xa inhibitors: Direct comparison of andexanet alfa and prothrombin complex concentrates Cofact and Beriplex/Kcentra

“…We observed in our in vitro experiments that andexanet alfa increased peak thrombin and velocity index to above normal, irrespective of the presence of FXaI. A similar increase in peak thrombin by andexanet alfa was observed by Lu and coworkers 19 . This increase in peak thrombin and velocity index may be caused by residual thrombin‐generating capacity of the FXa mutant or by neutralizing natural coagulation inhibitors including tissue factor pathway inhibitor (TFPI) 32 .…”

“…This 4F‐PCC is known to contain added heparin. Lu and coworkers treated their PCC with heparinase and reported that similar results were obtained with untreated‐ and heparinase‐treated plasma 19 . Lu and coworkers did not report whether heparin was indeed removed from the PCC by this treatment.…”

“…17,18 Nevertheless, there is still controversy over the usefulness of PCC as a reversal agent for FXaI that originates from in vitro thrombin generation studies. In a recent study by Lu and coworkers, 19 A problem with applying the thrombin generation assay for assessing DOAC reversal is the complexity of this assay system and the lack of standardization. 21 The extent by which thrombin generation is inhibited by FXaI and the dose of PCC needed for subsequent normalization is highly dependent on the TF concentration (thrombin generation reagent).…”

Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy

“…Recent reports have described the use of these agents in patients with ICrH, 25 , 26 , 32 , 33 although the mechanistic basis for their effectiveness is controversial. 34 Furthermore, their efficacy may be restricted in the presence of higher anti-FXa levels, 35 and the reports provide limited or no information regarding baseline anti-FXa activity. Relative to previously available therapies, andexanet represents a therapeutic advance given its specific, rapid, and biologically relevant mechanism of action.…”

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding

“…This may be an important consideration given the results of an in vitro investigation noting insufficient tissue factor initiated thrombin generation with 4F-PCC at apixaban and rivaroxaban concentrations above 75 ng/mL. 51 Similarly, in healthy volunteers with an average rivaroxaban trough concentration of 130 ng/mL, punch biopsy bleeding was not reduced following 4F-PCC (50 units/kg) although endogenous thrombin potential did increase compared to saline controls. 52 Nevertheless, our cohort represents our observations in a real-world setting of FXa-inhibitor-related bleeding.…”