title: Prevention of hyperacute xenograft rejection through direct thrombin inhibition with hirudin.
abstract: BACKGROUND
  Hyperacute xenograft rejection (HXR) is characterized by complement activation and intravascular thrombosis. The pathogenesis of HXR is attributed to antibodies binding to α-Gal-epitopes on the endothelial cells (EC) of the xenograft, activating complement and thrombin-mediated coagulation mechanisms. Our aim was to evaluate the influence of thrombin inhibition upon HXR and tissue integrity in an ex-vivo working heart model.
  
  
  METHODS
  Eighteen isolated porcine hearts were perfused with human whole blood in a working heart model. The blood was treated with heparin (n=9) in group G-I and with heparin and additionally recombinant hirudin (0.012 mg/ml bolus, afterwards 4.5 µg/ml/h continuously) in group G-II (n=9). The experiments were terminated at end of cardiac output. Histological analysis was performed after the experiments.
  
  
  RESULTS
  Working heart time of G-II was significantly longer (712.0±37.8 vs. 125.0±31.4 min, p<0.01). Heart weight increase in G-II was lower (0.05±0.01 vs. 0.30±0.06%/min, p<0.01). Stroke work index and specific coronary flow improved significantly in G-II after 120 minutes. Histological analysis revealed increased tissue damage and thrombosis phenomena in G-I. Moreover, immunohistochemistry showed increased C3 and C5b-C9 upon EC of G-I.
  
  
  CONCLUSIONS
  Direct thrombin inhibition with Hirudin could be a successful strategy in primate xenotransplantation experiments to prevent tissue damage thus improving the graft survival.
authors.affiliation: Department of Cardiac Surgery, Ludwig-Maximilians-University Hospital, Munich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Brenner
authors.forename: Miriam
authors.initials: M
authors.lastname: Keller
authors.forename: Andres
authors.initials: A
authors.lastname: Beiras-Fernandez
authors.forename: Sunji
authors.initials: S
authors.lastname: Uchita
authors.forename: Felix
authors.initials: F
authors.lastname: Kur
authors.forename: Eckart
authors.initials: E
authors.lastname: Thein
authors.forename: Cosmas
authors.initials: C
authors.lastname: Wimmer
authors.forename: Claus
authors.initials: C
authors.lastname: Hammer
authors.forename: Michael
authors.initials: M
authors.lastname: Schmoeckel
authors.forename: Bruno
authors.initials: B
authors.lastname: Reichart
mesh_terms: D000208:Acute Disease; D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D006321:Heart / Q000503:physiopathology; D016027:Heart Transplantation / Q000276:immunology*; D024764:Hirudin Therapy; D006801:Humans; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D013552:Swine; D013997:Time Factors; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D000991:Antithrombins