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Thrombalexin: use of a cytotopic anticoagulant to reduce thrombotic microangiopathy in a highly sensitized model of kidney transplantation

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Miriam Manook, Jean Kwun, Christian Burghuber, Kannan Samy, Michael Mulvihill, Janghoon Yoon, He Xu, Andrea L MacDonald, Kyle Freischlag, Verna Curfman, Evelyn Branum, David Howell, Alton Brad Farris, R. A. Smith, S. Sacks, A. Dorling, N. Mamode, S. J. Knechtle

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Abstract

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anti-coagulation is difficult due to bleeding. A novel 'cytotopic' agent, 'Thrombalexin', (TLN) combines a cell-membrane bound (mirystoyl tail) anti-thrombin (HLL peptide) which can be perfused directly to the donor organ or cells.. Thromboelastography (TEG) was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN vs. HLL (without cytotopic tail) vs. negative-control. Both TLN and HLL treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells (EC) and neonatal porcine islets (NPI) prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and FACS. In vivo, perfusion of a NHP kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to four days after transplantation. There was no platelet deposition and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis) were less in the TLN treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated. This article is protected by copyright. All rights reserved.

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