Aptamer-based factor IXa inhibition preserves hemostasis and prevents thrombosis in a piglet model of ECMO.

Autor:	Reed CR; Department of Surgery, Duke University Medical Center and Health System, 2301 Erwin Road, Box 3443, Durham, NC 27710, USA., Bonadonna D; Extracorporeal Life Support, Duke University Medical Center, Durham, NC 27710, USA., Otto JC; Department of Surgery, Duke University Medical Center and Health System, 2301 Erwin Road, Box 3443, Durham, NC 27710, USA., McDaniel CG; Duke University, Durham, NC 27710, USA., Chabata CV; Departments of Surgery; and Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA., Kuchibhatla M; Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA., Frederiksen J; Department of Surgery, Duke University Medical Center and Health System, 2301 Erwin Road, Box 3443, Durham, NC 27710, USA., Layzer JM; Duke University Clinical and Translational Science Institute, Durham, NC 27710, USA., Arepally GM; Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA., Sullenger BA; Department of Surgery, Duke University Medical Center and Health System, 2301 Erwin Road, Box 3443, Durham, NC 27710, USA., Tracy ET; Department of Surgery, Duke University Medical Center and Health System, 2301 Erwin Road, Box 3443, Durham, NC 27710, USA.; Division of Pediatric Surgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2021 Dec 11; Vol. 27, pp. 524-534. Date of Electronic Publication: 2021 Dec 11 (Print Publication: 2022).
DOI:	10.1016/j.omtn.2021.12.011
Abstrakt:	Extracorporeal membrane oxygenation (ECMO) requires anticoagulation to prevent clotting when the patient's blood contacts the circuit. Unfractionated heparin (UFH) usually prevents clotting but can cause life-threatening bleeding. An anticoagulant that selectively inhibits the contact activation (intrinsic) pathway while sparing the tissue factor (extrinsic) pathway of coagulation might prevent clotting triggered by the circuit while permitting physiologic coagulation at surgical sites. DTRI-178 is an RNA anticoagulant aptamer conjugated to polyethylene glycol that increases its half-life in circulation. This aptamer is based on a previously described molecule (9.3t) that inhibits intrinsic tenase activity by binding to factor IXa on an exosite. Using a piglet model of pediatric venoarterial (VA) ECMO, we compared thromboprevention and blood loss using a single dose of DTRI-178 versus UFH. In each of five experiments, we subjected two litter-matched piglets, one anticoagulated with DTRI-178 and the other with UFH, to simultaneous 12-h periods of VA ECMO. Both anticoagulants achieved satisfactory and comparable thromboprotection. However, UFH piglets had increased surgical site bleeding and required significantly greater blood transfusion volumes than piglets anticoagulated with DTRI-178. Our results indicate that DTRI-178, an aptamer against factor IXa, may be feasible, safer, and result in fewer transfusions and clinical bleeding events in ECMO. Competing Interests: Duke University has issued patents on the anti-FIXa aptamer used in the manuscript, DTRI-178. Dr. Sullenger is listed as an inventor on these patents. Duke University has applied for a use patent for DTRI-178 in extracorporeal circulation. Drs. Reed, Tracy, and Sullenger are listed as inventors on this application. None of the authors have otherwise commercialized or monetized this experimental oligonucleotide. (© 2021 The Authors.)
Databáze:	MEDLINE
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