Andexanet-Alfa-Associated Heparin Resistance in the Context of Hemorrhagic Stroke

Abstract

Background: With a growing number of patients on new oral anticoagulants, interest in reversal agents is rising. Andexanet alfa is used for reversal of factor Xa inhibitors in intracranial hemorrhage.

Methods: We provide a brief review on andexanet-alfa-associated heparin resistance and discuss potentially critical situations from different clinical perspectives.

Results: Case reports point out that andexanet alfa can cause unresponsiveness to heparin, leading to catastrophic events. As a result, regulatory bodies have issued warning notices to avoid heparinization parallel to the use of andexanet alfa.

Conclusions: Although well known to hematologists, the phenomenon is underrecognized among stroke clinicians. However, patients with intracranial hemorrhage frequently undergo endovascular or surgical interventions that require periprocedural administration of heparin.

Keywords: Anticoagulants; Factor Xa inhibitors; Hemorrhagic stroke; Heparin; PRT064445.

Fig. 1

Simplified schematic outline of andexanet-alfa-associated heparin resistance. Rivaroxaban and apixaban inhibit factor Xa (FXa), which normally catalyzes the formation of thrombin (dotted line). Andexanet alfa reverses the effects of apixaban and rivaroxaban by binding with higher affinity to these molecules compared with endogenous FXa (dotted line). Unfractionated heparin (UFH) potentiates the antithrombin (AT)-mediated inhibition of FXa. Andexanet alfa also binds to heparin-activated AT and thereby neutralizes the effect of heparin (intersected line)

Fig. 2

Institutional decision management algorithm for patients with potentially life-threatening intracranial hemorrhage under rivaroxaban or apixaban. PCC, prothrombin complex concentrate