Differential Neutralization of Unfractionated Heparin and Enoxaparin by Andexanet Alfa

Lewis, J. M.; Iqbal, Omer; Jeske, Walter; Hoppensteadt, Debra; Siddiqui, Fakiha; Fareed, Jawed

doi:10.1177/10760296221099934

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…In our previous work, andexanet alfa partially neutralized UFH and enoxaparin in several TEG parameters, but it was not as effective as PrSO 4 in any of the assays used. 15 Consistent with our previous observation in the current study, PrSO 4 was more effective than AA in reversing Xa and IIa. Still, andexanet alfa also showed some reversal of such parameters in an UFH concentration-dependent inverse manner.…”

Section: Discussionsupporting

confidence: 93%

Andexanet Alfa Neutralizes the Anticoagulant Effects of Unfractionated Heparin of Bovine, Ovine and Porcine Origin Almost as Protamine Sulfate

Siddiqui,

Hoppensteadt,

Jeske

et al. 2024

Clin Appl Thromb Hemost

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Introduction Andexanet alfa (AA) - zhzo, recombinant coagulation factor Xa, is an approved antidote for oral Xa inhibitors (apixaban and rivaroxaban). Unfractionated heparin (UFH) is commonly used for therapeutic, interventional, and surgical indications. Protamine sulfate (PrSO4) is frequently used to neutralize UFH. This study aimed to investigate the comparative neutralization profiles of AA and PrSO4 for heparins of bovine, ovine, and porcine origin. Materials and Methods The neutralization effect of PrSO4 at 25 µg/ml and AA at 100 µg/ml was studied on an approximate surgical/interventional concentration of heparin by supplementing whole blood with each of the heparins at 25 µg/ml. For the clotting profile (activated partial thromboplastin time: aPTT), amidolytic (anti-Xa and anti-IIa), and thrombin generation assay each of the heparin were supplemented from –10–0.62 µg/ml. Results In the whole blood ACT studies, all three heparins produced strong anti-coagulant effects (400–450 seconds) compared to saline (130–150 seconds). Both AA and PrSO4 almost fully neutralized the anti-coagulant effects of heparins (140–160 seconds). Both antidotes completely reversed the anticoagulant effects of all three heparins in the aPTT and thrombin generation assay. However, PrSO4 was more effective in neutralizing the anti-Xa, and anti-IIa effects than AA, which only partially neutralized these effects. Conclusion Andexanet alfa at 100 µg/ml effectively neutralizes the therapeutic and surgical/interventional concentrations of heparins in in-vitro settings. While differences in the anti-Xa, and anti-IIa effects between heparins were noted, anti-coagulant effect of these agents in the aPTT assay were comparable. A similar neutralization profile was observed in the ACT and thrombin generation assays by both agents.

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Section: Discussionsupporting

confidence: 93%

Andexanet Alfa Neutralizes the Anticoagulant Effects of Unfractionated Heparin of Bovine, Ovine and Porcine Origin Almost as Protamine Sulfate

Siddiqui,

Hoppensteadt,

Jeske

et al. 2024

Clin Appl Thromb Hemost

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“… 13 – 15 Studies have also suggested Andexanet Alfa can partially neutralize heparin-related drugs through assays such as ACT. 16 Heparin resistance has been reported in patients where the effect of direct oral anti-Xa agents is fully neutralized. 17 It is quite clear that in some of the assays, even at concentrations between 50–100 μg/mL, measurable biological activity persists.…”

Section: Discussionmentioning

confidence: 99%

Differential Neutralization of Apixaban, Betrixaban, Edoxaban, and Rivaroxaban by Andexanet Alfa as Measured by Whole Blood Thromboelastographic Analysis

Mehrotra

Hoppensteadt

Jeske

et al. 2022

Clin Appl Thromb Hemost

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Introduction The available oral anti-Xa agents are routinely used for the management of thrombotic disorders. A molecularly modified recombinant coagulation FXa, also known as Andexanet Alfa (AA), that has been developed as an antidote to neutralize the bleeding effects of oral FXa inhibitors, such as Apixaban and Rivaroxaban. Materials and Methods This study utilized thromboelastography (TEG 5000 Hemostasis System), to investigate the neutralizing effects of AA at different concentrations of oral FXa inhibitors measuring such parameters as R-Time, K-Time, Angle, and Max Amplitude (MA). Apixaban, Betrixaban, Edoxaban, and Rivaroxaban were obtained commercially in powdered form. Each of these drugs was supplemented with freshly drawn whole citrated blood at a concentration of 1 μg/mL. And subsequently mixed with AA at 50 or 100 μg/mL. Results At a concentration of 1 μg/mL, all FXa inhibitors produced variable anticoagulant effects in the order of Edoxaban > Betrixaban > Rivaroxaban > Apixaban. AA at 100 μg/mL produced a complete neutralization of these inhibitors whereas at 50 μg/mL relatively weaker neutralization as measured by various parameters. Conclusion These results suggest that regardless of the variable anticoagulant effects exhibited by the FXa Inhibitors, AA at FC = 100 μg/mL fully neutralized these agents as measured by the TEG parameters. AA was shown to be more effective in neutralizing Betrixaban and least effective in Apixaban. The neutralization of various FXa inhibitors was dose and donor-dependent warranting dosage adjustment for optimal outcomes.

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“…The use of andexanet before a vascular surgery requiring the administration of unfractionated heparin (UFH) remains controversial. Indeed, andexanet partially neutralizes UFH and induces heparin resistance [18,19]. After potentially hemorrhagic vascular surgery, therapeutic anticoagulation may be delayed until 48-72 h after surgery because the hemorrhagic risk of resuming full-dose anticoagulation exceeds the thromboembolic risk.…”

Section: Doacs During the Perioperative Period Of Vascular Surgerymentioning

confidence: 99%

Clinical Use of Direct Oral Anticoagulants and Reversal: Consideration for Vascular Surgeons

Houben¹,

Bonhomme

Sénard³

2023

JVD

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Since their first approval in 2010, direct oral anticoagulants (DOACs) have become attractive for anticoagulant treatment. DOACs are indicated for the prevention and treatment of several cardiovascular conditions and have now emerged as leading therapeutic options. Every year, large number of patients receiving DOACs routinely are scheduled for invasive surgical procedures and need specific perioperative management. Moreover, recently published trials have provided arguments for a larger future use of DOACs, including during the postoperative period after vascular surgery and for high-risk cardiovascular patients. In this communication, we discuss the perioperative management of DOACs for patients undergoing vascular surgery.

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Differential Neutralization of Unfractionated Heparin and Enoxaparin by Andexanet Alfa

Cited by 4 publications

References 26 publications

Andexanet Alfa Neutralizes the Anticoagulant Effects of Unfractionated Heparin of Bovine, Ovine and Porcine Origin Almost as Protamine Sulfate

Andexanet Alfa Neutralizes the Anticoagulant Effects of Unfractionated Heparin of Bovine, Ovine and Porcine Origin Almost as Protamine Sulfate

Differential Neutralization of Apixaban, Betrixaban, Edoxaban, and Rivaroxaban by Andexanet Alfa as Measured by Whole Blood Thromboelastographic Analysis

Clinical Use of Direct Oral Anticoagulants and Reversal: Consideration for Vascular Surgeons

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