title: Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation.
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.
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.|Renal and Transplant Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Manook
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: J
authors.initials: J
authors.lastname: Kwun
authors.affiliation: Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Burghuber
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: K
authors.initials: K
authors.lastname: Samy
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: M
authors.initials: M
authors.lastname: Mulvihill
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: J
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: A L
authors.initials: AL
authors.lastname: MacDonald
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: K
authors.identifier: http://orcid.org/0000-0002-0234-5235
authors.initials: K
authors.lastname: Freischlag
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: V
authors.initials: V
authors.lastname: Curfman
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: E
authors.initials: E
authors.lastname: Branum
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: D
authors.initials: D
authors.lastname: Howell
authors.affiliation: Department of Pathology, Emory University Hospital, Atlanta, GA.
authors.forename: A B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: MRC Centre for Transplantation, King's College, London, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Smith
authors.affiliation: MRC Centre for Transplantation, King's College, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Sacks
authors.affiliation: MRC Centre for Transplantation, King's College, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dorling
authors.affiliation: Renal and Transplant Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Mamode
authors.affiliation: Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
authors.forename: S J
authors.initials: SJ
authors.lastname: Knechtle
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects*; D008253:Macaca mulatta; D008297:Male; D010455:Peptides / Q000097:blood / Q000494:pharmacology*; D010477:Perfusion; D057049:Thrombotic Microangiopathies / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D010455:Peptides; C000619912:thrombalexin
keywords: alloantibody; animal models: nonhuman primate; basic (laboratory) research/science; coagulation and hemostasis; islet transplantation; organ perfusion and preservation; organ transplantation in general; thrombosis and thromboembolism