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Inhibition of coagulation proteases Xa and IIa decreases ischemia-reperfusion injuries in a preclinical renal transplantation model.

Solenne Tillet 1 Sébastien Giraud 2, 1 Thomas Kerforne 3, 1 Thibaut Saint-Yves 4, 1, 5 Sandrine Joffrion 1, 2 Jean-Michel Goujon 6, 1 Jérôme Cau 1 Gérard Mauco 1, 2 Maurice Petitou 1 Thierry Hauet 1, 2, 7, 8, *
* Corresponding author
8 FHU SUPORT - Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation
IRTOMIT - Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques, RESINFIT - Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques, Cellules Dendritiques, Immunomodulation et Greffes, CHU Poitiers - Centre hospitalier universitaire de Poitiers , CHU Limoges, CHRU TOURS - Centre Hospitalier Régional Universitaire de Tours, IPPRITT - Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation
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.
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Solenne Tillet, Sébastien Giraud, Thomas Kerforne, Thibaut Saint-Yves, Sandrine Joffrion, et al.. Inhibition of coagulation proteases Xa and IIa decreases ischemia-reperfusion injuries in a preclinical renal transplantation model.. Translational Research, The Journal of Laboratory and Clinical Medicine, Elsevier, 2016, 178, pp.95-106. ⟨10.1016/j.trsl.2016.07.014⟩. ⟨inserm-01376194⟩

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