Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan-Dec:30:10760296241247558.
doi: 10.1177/10760296241247558.

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

Fakiha Siddiqui  1   2 , Debra Hoppensteadt  1 , Walter Jeske  1 , Eduardo Ramacciotti  1   3   4 , Alfonso Tafur  5   6 , Jawed Fareed  1
Affiliations

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

Fakiha Siddiqui et al. Clin Appl Thromb Hemost. 2024 Jan-Dec.

Abstract

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.

Keywords: andexanet alfa; chromogenic assays; clot-based assays; heparin; protamine sulfate; thrombin generation assay.

PubMed Disclaimer

Conflict of interest statement

Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
A comparison of bovine, ovine and porcine UFH's and their neutralization by andexanet alfa and protamine sulfate in whole blood activated clotting time (ACT). Graph representing neutralization of UFH's at a final concentration of 2.5 μg/ml by (A) andexanet alfa and (B) protamine sulfate.
Figure 2.
Figure 2.
A comparison of bovine, ovine and porcine UFH's and their relative neutralization by andexanet alfa and protamine sulfate in activated partial thromboplastin time (aPTT). Graph representing neutralization of UFH's by (A) andexanet alfa and (B) protamine sulfate.
Figure 3.
Figure 3.
A comparison of bovine, ovine and porcine UFH's and their relative neutralization by andexanet alfa and protamine sulfate in amidolytic anti-Xa assay. Graph representing neutralization of UFH's by (A) andexanet alfa and (B) protamine sulfate.
Figure 4.
Figure 4.
A comparison of bovine, ovine and porcine UFH's and their relative neutralization by andexanet alfa and protamine sulfate in amidolytic anti-IIa assay. Graph representing neutralization of UFH's by (A) andexanet alfa and (B) protamine sulfate.
Figure 5.
Figure 5.
Effect of bovine, ovine and porcine UFH's on inhibition of thrombin generation (TG) and their neutralization by andexanet alfa. Graph representing neutralization effect of andexanet alfa on (A) control, (B) bovine UFH, (C) ovine UFH and (D) porcine UFH.
Figure 6.
Figure 6.
Effect of bovine, ovine and porcine UFH's on inhibition of thrombin generation (TG) and their neutralization by protamine sulfate. Graph representing neutralization effect of protamine sulfate on (A) control, (B) bovine UFH, (C) ovine UFH and (D) porcine UFH.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Oduah EI, Linhardt RJ, Sharfstein ST. Heparin: Past, present, and future. Pharmaceuticals (Basel). 2016;9(3):38. doi: 10.3390/ph9030038 - DOI - PMC - PubMed
    1. Danek BA, Kearney KE, Chung CJet al. et al. The contemporary role of protamine in the cardiac catheterization laboratory. Catheter Cardiovasc Interv. 2023;102(1):111-120. doi: 10.1002/ccd.30679 - DOI - PubMed
    1. Carr JA, Silverman N. The heparin-protamine interaction. A review. J Cardiovasc Surg (Torino). 1999;40(4):659-666. - PubMed
    1. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446-451. doi: 10.1038/nm.3102 - DOI - PubMed
    1. Pharmaceuticals. P. U.S. FDA approves Portola Pharmaceuticals Andexxa®, the first and only antidote for the reversal of factor Xa inhibitors. In; 2018.