title: Warfarin or low-molecular-weight heparin therapy does not prolong pig-to-primate cardiac xenograft function.
abstract: Microvascular thrombosis is a prominent feature in cardiac delayed xenograft rejection (DXR). We investigated the impact of warfarin or low-molecular-weight heparin (LMWH) anti-coagulation on xenograft function using a heterotopic pig-to-primate model. Donor hearts were from CD46 transgenic pigs and baboon immunosuppression included tacrolimus, sirolimus, anti-CD20 and TPC, an alpha-galactosyl-polyethylene glycol conjugate. Three groups of animals were studied. Group 1 (n = 9) was treated with warfarin, Group 2 (n = 13) with LMWH and Group 3, received no anti-coagulant drugs. The median duration of xenograft function was 20 days (range 3-62 days), 18 days (range 5-109 days) and 15 days (range 4-53 days) in Groups 1 to 3 respectively. Anti-coagulation achieved the targeted international normalized prothrombin ratio (INR) and anti-factor Xa levels consistent with effective in vivo therapy yet, no significant impact on median xenograft function was observed. At rejection, a similar histology of thrombosis and ischemia was apparent in each group and the levels of fibrin deposition and platelet thrombi in rejected tissue was the same. Anti-coagulation with warfarin or LMWH did not have a significant impact on the onset of DXR and microvascular thrombosis. However, a role for specific anti-coagulant strategies to achieve long-term xenograft function cannot be excluded.
authors.affiliation: Mayo Clinic William J von Liebig Transplant Center, Rochester, Minnesota, USA.
authors.forename: Guerard W
authors.initials: GW
authors.lastname: Byrne
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Schirmer
authors.forename: David N
authors.initials: DN
authors.lastname: Fass
authors.forename: Sumeet S
authors.initials: SS
authors.lastname: Teotia
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kremers
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Bashoo
authors.initials: B
authors.lastname: Naziruddin
authors.forename: Henry D
authors.initials: HD
authors.lastname: Tazelaar
authors.forename: John S
authors.initials: JS
authors.lastname: Logan
authors.forename: Christopher G A
authors.initials: CG
authors.lastname: McGregor
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000925:Anticoagulants / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D015951:Factor Xa / Q000737:chemistry; D016027:Heart Transplantation / Q000379:methods*; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000737:chemistry; D007075:Immunoglobulin M / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019934:International Normalized Ratio; D007511:Ischemia; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008833:Microcirculation; D009206:Myocardium / Q000378:metabolism; D010215:Papio; D011323:Primates; D011516:Prothrombin / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013552:Swine; D016559:Tacrolimus / Q000494:pharmacology; D013927:Thrombosis / Q000378:metabolism; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000379:methods*; D016896:Treatment Outcome; D014812:Vitamin K / Q000378:metabolism; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D015703:Antigens, CD; D006495:Heparin, Low-Molecular-Weight; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D014812:Vitamin K; D014859:Warfarin; D011516:Prothrombin; D015951:Factor Xa; D020123:Sirolimus; D016559:Tacrolimus