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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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March 23 2017
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Source: Am J Transplant. 17(8):2055-2064
[PDF-593.91 KB]
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Alternative Title:Am J Transplant
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Personal Author:
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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.
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Pubmed ID:28226413
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Pubmed Central ID:PMC5519442
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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 ; ... More +
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Volume:17
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Issue:8
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