Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa
Andexanet alfa is a recombinant factor Xa decoy protein, designed to reverse bleeding associated with oral anti-Xa agents. Andexanet alfa is also reported to neutralize the effects of heparin-related drugs. This study focused on the neutralization profiles of unfractionated heparin (UFH), enoxaparin...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2020-01-01
|
| Series: | Clinical and Applied Thrombosis/Hemostasis |
| Online Access: | https://doi.org/10.1177/1076029619895120 |
| _version_ | 1818530900687716352 |
|---|---|
| author | Fakiha Siddiqui BDS Alfonso Tafur MD Emily Bontekoe BS Omer Iqbal MD Walter Jeske PhD Siddharth Mehrotra Debra Hoppensteadt PhD Eduardo Ramacciotti MD, PhD Jawed Fareed PhD |
| author_facet | Fakiha Siddiqui BDS Alfonso Tafur MD Emily Bontekoe BS Omer Iqbal MD Walter Jeske PhD Siddharth Mehrotra Debra Hoppensteadt PhD Eduardo Ramacciotti MD, PhD Jawed Fareed PhD |
| author_sort | Fakiha Siddiqui BDS |
| collection | DOAJ |
| description | Andexanet alfa is a recombinant factor Xa decoy protein, designed to reverse bleeding associated with oral anti-Xa agents. Andexanet alfa is also reported to neutralize the effects of heparin-related drugs. This study focused on the neutralization profiles of unfractionated heparin (UFH), enoxaparin, and, a chemically synthetic pentasaccharide, fondaparinux by andexanet alfa. Whole blood clotting studies were carried out using thromboelastography (TEG) and activated clotting time (ACT). The anticoagulant profile of UFH, enoxaparin, and fondaparinux was studied using the activated partial thromboplastin time (aPTT), thrombin time (TT), and amidolytic anti-Xa, and anti-IIa methods. Thrombin generation inhibition was studied using the calibrated automated thrombogram system. Reversal of each of these agents was studied by supplementing andexanet alfa at 100 µg/mL. In the TEG, andexanet alfa produced almost a complete reversal of the anticoagulant effects of UFH and enoxaparin; however, it augmented the effects of fondaparinux. In the ACT, aPTT, and TT, UFH produced strong anticoagulant effects that were almost completely neutralized by andexanet alfa. Enoxaparin produced milder anticoagulant responses that were partially neutralized, whereas fondaparinux did not produce any sizeable effects. In the anti-Xa and anti-IIa assays, UFH exhibited partial neutralization whereas enoxaparin and fondaparinux did not show any neutralization. All agents produced varying degrees of the inhibition of thrombin generation, which were differentially neutralized by andexanet alfa. These results indicate that andexanet alfa is capable of differentially neutralizing anticoagulant and antiprotease effects of UFH and enoxaparin in an assay-dependent manner. However, andexanet alfa is incapable of neutralizing the anti-Xa effects of fondaparinux. |
| first_indexed | 2024-12-11T17:25:32Z |
| format | Article |
| id | doaj.art-70da32213e0c4fe3a9ba91f104584129 |
| institution | Directory Open Access Journal |
| issn | 1938-2723 |
| language | English |
| last_indexed | 2024-12-11T17:25:32Z |
| publishDate | 2020-01-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Clinical and Applied Thrombosis/Hemostasis |
| spelling | doaj.art-70da32213e0c4fe3a9ba91f1045841292022-12-22T00:56:59ZengSAGE PublishingClinical and Applied Thrombosis/Hemostasis1938-27232020-01-012610.1177/1076029619895120Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet AlfaFakiha Siddiqui BDS0Alfonso Tafur MD1Emily Bontekoe BS2Omer Iqbal MD3Walter Jeske PhD4Siddharth Mehrotra5Debra Hoppensteadt PhD6Eduardo Ramacciotti MD, PhD7Jawed Fareed PhD8 Cardiovascular Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, IL, USA Northshore Cardiovascular Institute, NorthShore University Health Systems, Skokie, IL, USA Cardiovascular Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, IL, USA Cardiovascular Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, IL, USA Cardiovascular Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, IL, USA Cardiovascular Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, IL, USA Cardiovascular Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, IL, USA Vascular and Endovascular Surgery, Santa Casa School of Medicine, São Paulo, SP, Brazil Cardiovascular Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, IL, USAAndexanet alfa is a recombinant factor Xa decoy protein, designed to reverse bleeding associated with oral anti-Xa agents. Andexanet alfa is also reported to neutralize the effects of heparin-related drugs. This study focused on the neutralization profiles of unfractionated heparin (UFH), enoxaparin, and, a chemically synthetic pentasaccharide, fondaparinux by andexanet alfa. Whole blood clotting studies were carried out using thromboelastography (TEG) and activated clotting time (ACT). The anticoagulant profile of UFH, enoxaparin, and fondaparinux was studied using the activated partial thromboplastin time (aPTT), thrombin time (TT), and amidolytic anti-Xa, and anti-IIa methods. Thrombin generation inhibition was studied using the calibrated automated thrombogram system. Reversal of each of these agents was studied by supplementing andexanet alfa at 100 µg/mL. In the TEG, andexanet alfa produced almost a complete reversal of the anticoagulant effects of UFH and enoxaparin; however, it augmented the effects of fondaparinux. In the ACT, aPTT, and TT, UFH produced strong anticoagulant effects that were almost completely neutralized by andexanet alfa. Enoxaparin produced milder anticoagulant responses that were partially neutralized, whereas fondaparinux did not produce any sizeable effects. In the anti-Xa and anti-IIa assays, UFH exhibited partial neutralization whereas enoxaparin and fondaparinux did not show any neutralization. All agents produced varying degrees of the inhibition of thrombin generation, which were differentially neutralized by andexanet alfa. These results indicate that andexanet alfa is capable of differentially neutralizing anticoagulant and antiprotease effects of UFH and enoxaparin in an assay-dependent manner. However, andexanet alfa is incapable of neutralizing the anti-Xa effects of fondaparinux.https://doi.org/10.1177/1076029619895120 |
| spellingShingle | Fakiha Siddiqui BDS Alfonso Tafur MD Emily Bontekoe BS Omer Iqbal MD Walter Jeske PhD Siddharth Mehrotra Debra Hoppensteadt PhD Eduardo Ramacciotti MD, PhD Jawed Fareed PhD Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa Clinical and Applied Thrombosis/Hemostasis |
| title | Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa |
| title_full | Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa |
| title_fullStr | Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa |
| title_full_unstemmed | Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa |
| title_short | Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa |
| title_sort | assay based differentiation in the neutralization profile of unfractionated heparin enoxaparin and fondaparinux by andexanet alfa |
| url | https://doi.org/10.1177/1076029619895120 |
| work_keys_str_mv | AT fakihasiddiquibds assaybaseddifferentiationintheneutralizationprofileofunfractionatedheparinenoxaparinandfondaparinuxbyandexanetalfa AT alfonsotafurmd assaybaseddifferentiationintheneutralizationprofileofunfractionatedheparinenoxaparinandfondaparinuxbyandexanetalfa AT emilybontekoebs assaybaseddifferentiationintheneutralizationprofileofunfractionatedheparinenoxaparinandfondaparinuxbyandexanetalfa AT omeriqbalmd assaybaseddifferentiationintheneutralizationprofileofunfractionatedheparinenoxaparinandfondaparinuxbyandexanetalfa AT walterjeskephd assaybaseddifferentiationintheneutralizationprofileofunfractionatedheparinenoxaparinandfondaparinuxbyandexanetalfa AT siddharthmehrotra assaybaseddifferentiationintheneutralizationprofileofunfractionatedheparinenoxaparinandfondaparinuxbyandexanetalfa AT debrahoppensteadtphd assaybaseddifferentiationintheneutralizationprofileofunfractionatedheparinenoxaparinandfondaparinuxbyandexanetalfa AT eduardoramacciottimdphd assaybaseddifferentiationintheneutralizationprofileofunfractionatedheparinenoxaparinandfondaparinuxbyandexanetalfa AT jawedfareedphd assaybaseddifferentiationintheneutralizationprofileofunfractionatedheparinenoxaparinandfondaparinuxbyandexanetalfa |