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

Details

• Journal Article:
  Am J Transplant
• Personal Author:
  Manook, Miriam ; Kwun, Jean ; Burghuber, Christian ; Samy, Kannan ; Mulvihill, Michael ; Yoon, Janghoon ; Xu, He ; MacDonald, Andrea L. ; Freischlag, Kyle ; Curfman, Verna ; Branum, Evelyn ; Howell, David ; Farris, Alton Brad ; Smith, Richard A ; Sacks, Stephen ; Dorling, Anthony ; Mamode, Nizam ; Knechtle, Stuart
• Description:
  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.
• Subjects:
  Animals Anticoagulants Article Blood Coagulation Humans Kidney Transplantation Macaca Mulatta Male Peptides Perfusion Thrombotic Microangiopathies

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• Source:
  Am J Transplant. 17(8):2055-2064
• DOI:
  http://dx.doi.org/10.1111/ajt.14234
• Pubmed ID:
  28226413
• Pubmed Central ID:
  PMC5519442
• Document Type:
  Text ; Journal Article
• Funding:
  TL1 TR002555/NCATS NIH HHS/National Center for Advancing Translational Sciences/United States ; G0401591/Medical Research Council/United Kingdom ; U24 AI126683/NIAID NIH HHS/National Institute of Allergy and Infectious Diseases Extramural Activities/United States ; MR/J006742/1/Medical Research Council/United Kingdom ; U19 AI051731/NIAID NIH HHS/National Institute of Allergy and Infectious Diseases Extramural Activities/United States ; G1001197/Medical Research Council/United Kingdom ; R24 OD010976/ODCDC CDC HHS/Office of the Director/United States ; G0600892/Medical Research Council/United Kingdom
• Genre:
  Journal Article
• Volume:
  17
• Issue:
  8
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:e3d6070eed4920363db9da274a513247eee0aafaa26a158418f08725be477a58f1e185a588f45df6ba0db8c352311a78eb9027a35f5c67cc9a889323f3f39495
• Download URL:
  https://stacks.cdc.gov/view/cdc/80351/cdc_80351_DS1.pdf
• File Type:
  [PDF - 593.91 KB ]