Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation

• Type of Material: Article
• Authors: Miriam Manook, Duke University; Jean Kwun, Duke University; Christian Burghuber, Medical University of Vienna; Kannan Samy, Duke University; Michael Mulvihill, Duke University; Janghoon Yoon, Duke University; He Xu, Duke University; Andrea L. MacDonald, Duke University; Kyle Freischlag, Duke University; Verna Curfman, Duke University; Evelyn Branum, Duke University; David Howell, Duke University; Alton B Farris III, Emory University; Richard A. Smith, Kings College London; Stephen Sacks, Kings College London; Anthony Dorling, Kings College London; Nizam Mamode, Guy’s and St Thomas’ NHS Foundation Trust; Stuart Knechtle, Duke University
• Language: English
• Date: 2017-08-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons
• Final Published Version (URL): http://dx.doi.org/10.1111/ajt.14234
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 17
• Issue: 8
• Start Page: 2055
• End Page: 2064
• Grant/Funding Information: The authors acknowledge the support of the Medical Research Council (MRC) Centre for Transplantation, King’s College London, UK – MRC grant no. MR/J006742/1.; MM was supported by a St John’s Ambulance Air Wing Fellowship.; This work was supported by NIH grant U19AI051731 and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London.
• Keywords: RECIPIENTS; COAGULATION; DIAGNOSIS; Transplantation; Surgery; ANTIBODY-MEDIATED REJECTION; Life Sciences & Biomedicine; INHIBITION; ECULIZUMAB; MANAGEMENT; HUMAN THROMBOMODULIN; Science & Technology; COMPLEMENT ACTIVATION PATHWAY
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel “cytotopic” agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus 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 and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate 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 4 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.