title: Inhibition of coagulation proteases Xa and IIa decreases ischemia-reperfusion injuries in a preclinical renal transplantation model.
abstract: Coagulation is an important pathway in the pathophysiology of ischemia-reperfusion injuries. In particular, deceased after circulatory death (DCD) donors undergo a no-flow period, a strong activator of coagulation. Hence, therapies influencing the coagulation cascade must be developed. We evaluated the effect of a new highly specific and effective anti-Xa/IIa molecule, with an integrated innovative antidote site (EP217609), in a porcine preclinical model mimicking injuries observed in DCD donor kidney transplantation. Kidneys were clamped for 60 minutes (warm ischemia), then flushed and preserved for 24 hours at 4°C in University of Wisconsin (UW) solution (supplemented or not). EP217609-supplemented UW solution (UW-EP), compared with unfractionated heparin-supplemented UW solution (UW-UFH) or UW alone (UW). A mechanistic investigation was conducted in vitro: addition of EP217609 to endothelial cells during hypoxia at 4°C in the UW solution inhibited thrombin generation during reoxygenation at 37°C in human plasma and reduced tumor necrosis factor alpha, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 messenger RNA cell expressions. In vivo, function recovery was markedly improved in the UW-EP group. Interestingly, levels of thrombin-antithrombin complexes (reflecting thrombin generation) were reduced 60 minutes after reperfusion in the UW-EP group. In addition, 3 months after transplantation, lower fibrosis, epithelial-mesenchymal transition, inflammation, and leukocyte infiltration were observed. Using this new dual anticoagulant, anti-Xa/IIa activity during kidney flush and preservation is protected by reducing thrombin generation at revascularization, improving early function recovery, and decreasing chronic lesions. Such an easy-to-deploy clinical strategy could improve marginal graft outcome.
authors: Inserm U1082 IRTOMIT, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France.
authors: Solenne
authors: S
authors: Tillet
authors: Inserm U1082 IRTOMIT, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France; CHU Poitiers, Service de Biochimie, Poitiers, France.
authors: Sébastien
authors: S
authors: Giraud
authors: Inserm U1082 IRTOMIT, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France; CHU Poitiers, Département d'Anesthésie-Réanimation, Poitiers, France.
authors: Thomas
authors: T
authors: Kerforne
authors: Inserm U1082 IRTOMIT, Poitiers, France; CH d'Angoulème, Service de Chirurgie Urologie, Angoulème, France; CHU de Poitiers, Service d'Urologie, Pôle DUNE, Poitiers, France.
authors: Thibaut
authors: T
authors: Saint-Yves
authors: Inserm U1082 IRTOMIT, Poitiers, France; CHU Poitiers, Service de Biochimie, Poitiers, France.
authors: Sandrine
authors: S
authors: Joffrion
authors: Inserm U1082 IRTOMIT, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France; CHU de Poitiers, Service d'Anapathomopathologie, Poitiers, France.
authors: Jean-Michel
authors: JM
authors: Goujon
authors: Inserm U1082 IRTOMIT, Poitiers, France.
authors: Jerôme
authors: J
authors: Cau
authors: Inserm U1082 IRTOMIT, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France; CHU Poitiers, Service de Biochimie, Poitiers, France.
authors: Gérard
authors: G
authors: Mauco
authors: Inserm U1082 IRTOMIT, Poitiers, France.
authors: Maurice
authors: M
authors: Petitou
authors: Inserm U1082 IRTOMIT, Poitiers, France; Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France; CHU Poitiers, Service de Biochimie, Poitiers, France; IBiSA Plateforme 'plate-forme MOdélisation Préclinique-Innovation Chirurgicale et Technologique (MOPICT), INRA Domaine Expérimental du Magneraud, Surgères, France; FHU SUPORT 'SUrvival oPtimization in ORgan Transplantation', Poitiers, France. Electronic address: thierry.hauet@gmail.com.
authors: Thierry
authors: T
authors: Hauet
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001710:Biotin / Q000031:analogs & derivatives / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D003080:Cold Temperature; D042783:Endothelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors; D005355:Fibrosis; D006801:Humans; D000860:Hypoxia / Q000150:complications; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000187:drug effects; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D023421:Models, Animal; D009844:Oligosaccharides / Q000494:pharmacology; D011516:Prothrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology*; D034421:Sus scrofa; D013917:Thrombin / Q000378:metabolism
chemical_list: D015415:Biomarkers; C547750:EP 217609; D065427:Factor Xa Inhibitors; D009844:Oligosaccharides; D001710:Biotin; D011516:Prothrombin; C025337:Factor IIa; D013917:Thrombin; D015951:Factor Xa