Andexanet Alfa, the Possible Alternative to Protamine for Reversal of Unfractionated Heparin

Abstract

The recent shortage of protamine prompted an investigation of alternatives for reversal of unfractionated heparin. Heparin is an anticoagulant utilized in the hospital setting. Available options for anticoagulation include direct oral anticoagulants, vitamin K antagonists, thrombin inhibitors, low-molecular-weight heparins, and heparin. Protamine is the approved reversal agent for heparin with few alternatives under investigation. Although andexanet was designed as an antidote for apixaban and rivaroxaban, in vitro studies show that in a dose-dependent technique, andexanet had near full reversal of heparin, reversed anti–factor Xa activity, and neutralized anticoagulant effects of activated partial thromboplastin time and thrombin time induced by heparin.

Pharmacology of Heparin and Related Drugs: An Update

“…New heparin-neutralizing agents are in development at various preclinical and clinical stages (Sokolowska et al, 2016) (see Section VI. A.1), in part attempting to address the recent difficulties encountered due to protamine shortages (Maneno and Ness, 2021).…”

“…For example, a recombinant inactive AT was as efficient as protamine at neutralizing heparin after cardiopulmonary bypass in rats (Bianchini et al, 2018). A similar strategy has been adopted in the design of andaxanet, a recombinant inactivated factor Xa (FXa) already approved as an antagonist to the Xa inhibitors apixaban and rivaroxaban and shown to also neutralize the activity of heparin (Maneno and Ness, 2021). These inactivated proteins of the coagulation system act as decoy molecules, binding either to the high affinity motif in heparin (for inactivated AT) or to heparin-activated AT (for andaxanet).…”

“…This effect has been reported to be managed by administration of exogenous AT (Apostel et al, 2021), although the consideration of alternative reversal approaches to andexanet has been suggested for management of DOAC-induced bleeding in situations where subsequent anticoagulation with heparin may be required (Levy and Connors, 2021)-while andexanet is currently approved for reversal of rivaroxaban or apixaban activity in the event of life-threatening bleeding, there are reports of off-license preoperative use with unclear benefit (Levy and Connors, 2021). Nonetheless, andexanet presents as a plausible future alternative to protamine for reversal of the anti-FXamediated effects of heparin therapy (Maneno and Ness, 2021).…”

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

“…1 ). These findings even led to the conclusion that AA may be suitable as an alternative to protamine in reversal of UFH [ 8 ].

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In vitro and in vivo safety studies indicate that R15, a synthetic polyarginine peptide, could safely reverse the effects of unfractionated heparin

“…The properties of PS that may induce adverse reactions are as follows: (a) highly cationic charges that may interact with cells or proteins in the blood system [8,9]; (b) antigenicity derived from heterogeneous species, which may lead to anaphylaxis [10,11]; and (c) influences of UFH-PS complex, a polyelectrolyte with a tendency to coacervate and precipitate, on the blood system [12][13][14]. Currently, the most advanced clinical heparin antagonist is andexanet alfa (not approved for UFH reversal) [15] or preclinically cationically modified dextrans [16], and universal heparin reversal agents (UHRAs) [17]. Other candidates, including recombinant inactive antithrombin, poly-llysine, and low-molecular-weight protamine, exhibit the ability to reverse UFH in animals [18][19][20].…”