Background: Andexanet alfa (AnXa) is an inactive variant of factor Xa (FXa) that functions as a stoichiometric drug-sequestering antidote for direct FXa inhibitors. Case reports suggest that AnXa administration prior to administration of unfractionated heparin (UFH) for cardiopulmonary bypass (CPB) may result in inadequate anticoagulation.

Aims: We set out to determine whether AnXa interferes with the effects of UFH in point-of-care assays, and, if so, whether this effect resulted in inadequate anticoagulation on artificial surfaces. Further, we attempted to elucidate the mechanism of AnXa-associated heparin resistance and identify clinical countermeasures should it occur.

Methods: We measured the activated clotting time (ACT) in human whole blood supplemented with varying amounts of AnXa and UFH. Further, we flowed AnXa and UFH-supplemented human whole blood in an extracorporeal oxygenator membrane model to assess whether administration of UFH following AnXa provided adequate anticoagulation. Finally, we supplemented plasma with AT in thrombin generation (TG) studies to determine if additional AT could overcome AnXa-associated heparin resistance.

Results: Both low and high dose AnXa prevented the expected ACT prolongation after usual cardiopulmonary bypass (CPB) doses of UFH (4 U/mL). AnXa also prevented high doses (16 U/mL) of UFH from prolonging the ACT beyond 400 seconds. In an extracorporeal model, concomitant administration of AnXa and 4 U/mL UFH resulted rapid circuit thrombosis not seen with UFH alone (Figure 1), suggesting that AnXa-associated heparin resistance is not simply an in vitro effect. In TG studies, excess UFH restored anticoagulation when low-dose AnXa was used, but at high AnXa doses, AT supplementation in addition to excess UFH was needed to restore anticoagulation.Administration of Andexanet alfa to an adequately heparinized (4 U/mL) extracorporeal circuit results in rapid circuit thrombosis as evidenced by an abrupt decrease in circuit flow (A) and increase in circuit pressure (B)

Conclusions: AnXa produces heparin resistance that results in insufficient anticoagulation for cardiopulmonary bypass due to binding to UFH-AT complexes. Depending on the dose of AnXa used, extreme doses of UFH and sometimes AT supplementation may be necessary to achieve adequate anticoagulation with UFH.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/characterization-of-andexanet-alfa-associated-heparin-resistance-implications-for-management/