title: Increased immunosuppression, not anticoagulation, extends cardiac xenograft survival.
abstract: BACKGROUND
  Cardiac xenograft function is lost due to delayed xenograft rejection (DXR) characterized by microvascular thrombosis and myocardial necrosis. The cause of DXR is unknown but may result from thrombosis induced by antibody-mediated activation of endothelial cells and/or by incompatibilities in thromboregulatory interactions.
  
  
  METHODS
  To examine these issues, a series (Groups 1-6) of previous transgenic CD46 pig-to-baboon heterotopic cardiac transplants were reanalyzed for baseline immunosuppressive levels, graft survival and infectious complications with and without systemic anticoagulation. Groups 1-4 received low dose tacrolimus and sirolimus maintenance therapy, with splenectomy, anti-CD20 and daily alpha-Gal polymer. Group 1 recipients received no anticoagulation. Groups 2-4 were anticoagulated with aspirin and Plavix, Lovenox, or Coumadin, respectively. Group 5 was treated with Lovenox and high dose tacrolimus and sirolimus maintenance therapy. Group 6 recipients received no postoperative anticoagulation but the same immunosuppression as group 5.
  
  
  RESULTS
  Median survival (15-22 days) within groups 1-4 was not significantly different. At rejection all tissues exhibited microvascular thrombosis, coagulative necrosis and similar levels of platelet and fibrin deposition. Groups 5 and 6 median survival (76 days) was significantly increased compared to groups 1-4. There was no significant difference in median survival between Lovenox treated recipients (68 days) and anticoagulant free recipients (96 days). Rejected tissues showed vascular antibody deposition, microvascular thrombosis, and myocyte necrosis.
  
  
  CONCLUSIONS
  Significant prolongation in xenograft survival is achieved by improved immunosuppression. These results suggest that ongoing immune responses remain the major stimulus for DXR.
authors.affiliation: William J. von Liebig Transplant Center, Mayo Clinic-Rochester, Rochester, MN 55905, USA. byrne.guerard@mayo.edu
authors.forename: Guerard W
authors.initials: GW
authors.lastname: Byrne
authors.forename: William R
authors.initials: WR
authors.lastname: Davies
authors.forename: Keiji
authors.initials: K
authors.lastname: Oi
authors.forename: Vinay P
authors.initials: VP
authors.lastname: Rao
authors.forename: Sumeet S
authors.initials: SS
authors.lastname: Teotia
authors.forename: David
authors.initials: D
authors.lastname: Ricci
authors.forename: Henry D
authors.initials: HD
authors.lastname: Tazelaar
authors.forename: Randall C
authors.initials: RC
authors.lastname: Walker
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; D000925:Anticoagulants / Q000008:administration & dosage; D001777:Blood Coagulation / Q000187:drug effects; D017984:Enoxaparin / Q000008:administration & dosage; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D010215:Papio; D013156:Splenectomy; D013552:Swine / Q000276:immunology; D013927:Thrombosis / Q000276:immunology / Q000517:prevention & control*; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; D007166:Immunosuppressive Agents