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Published Online: 1 June 2022

Combining Heparin and a FX/Xa Aptamer to Reduce Thrombin Generation in Cardiopulmonary Bypass and COVID-19

Publication: nucleic acid therapeutics
Volume 32, Issue Number 3

Abstract

Known limitations of unfractionated heparin (UFH) have encouraged the evaluation of anticoagulant aptamers as alternatives to UFH in highly procoagulant settings such as cardiopulmonary bypass (CPB). Despite progress, these efforts have not been totally successful. We take a different approach and explore whether properties of an anticoagulant aptamer can complement UFH, rather than replace it, to address shortcomings with UFH use. Combining RNA aptamer 11F7t, which targets factor X/Xa, with UFH (or low molecular weight heparin) yields a significantly enhanced anticoagulant cocktail effective in normal and COVID-19 patient blood. This aptamer-UFH combination (1) supports continuous circulation of human blood through an ex vivo membrane oxygenation circuit, as is required for patients undergoing CPB and COVID-19 patients requiring extracorporeal membrane oxygenation, (2) allows for a reduced level of UFH to be employed, (3) more effectively limits thrombin generation compared to UFH alone, and (4) is rapidly reversed by the administration of protamine sulfate, the standard treatment for reversing UFH clinically following CPB. Thus, the combination of factor X/Xa aptamer and UFH has significantly improved anticoagulant properties compared to UFH alone and underscores the potential of RNA aptamers to improve medical management of acute care patients requiring potent yet rapidly reversible anticoagulation.

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Information & Authors

Information

Published In

cover image Nucleic Acid Therapeutics
nucleic acid therapeutics
Volume 32Issue Number 3June 2022
Pages: 139 - 150
PubMed: 35021888

History

Published in print: June 2022
Published online: 1 June 2022
Published ahead of print: 12 January 2022
Accepted: 10 November 2021
Received: 7 September 2021

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Authors

Affiliations

Department of Surgery, Department of Medicine, Duke University Medical Centre, Durham, North Carolina, USA.
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
James W. Frederiksen
Department of Surgery, Department of Medicine, Duke University Medical Centre, Durham, North Carolina, USA.
Lyra B. Olson
Department of Surgery, Department of Medicine, Duke University Medical Centre, Durham, North Carolina, USA.
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
Medical Scientist Training Program, Duke University, Durham, North Carolina, USA.
Ibtehaj A. Naqvi
Department of Surgery, Department of Medicine, Duke University Medical Centre, Durham, North Carolina, USA.
Department of Anesthesiology, Department of Medicine, Duke University Medical Centre, Durham, North Carolina, USA.
Sharon E. Hall
Division of Hematology, Department of Medicine, Duke University Medical Centre, Durham, North Carolina, USA.
Ruwan Gunaratne
Department of Medicine, Stanford University Medical Center, Stanford, California, USA.
Bryan D. Kraft
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
Loretta G. Que
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
Lingye Chen
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
Bruce A. Sullenger [email protected]
Department of Surgery, Department of Medicine, Duke University Medical Centre, Durham, North Carolina, USA.
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.

Notes

Address correspondence to: Bruce A. Sullenger, PhD, Department of Surgery, Duke University Medical Centre, Box 103035, Durham, NC 27710, USA [email protected]

Author Disclosure Statement

Duke has submitted patent applications on the factor X/Xa anticoagulant aptamer(s) and combinations of the aptamer with other anticoagulants. Dr. Sullenger and Dr. Frederiksen are inventors on such Duke Intellectual Property.

Funding Information

This work was supported by a US National Institutes of Health grant (Grant No. P01-HL139420).

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