title: Reduced fibrin deposition and intravascular thrombosis in hDAF transgenic pig hearts perfused with tirofiban.
abstract: BACKGROUND
  Solid organ xenograft rejection is associated with vascular injury resulting at least in part in platelet activation, and rejected xenografts invariably demonstrate intravascular thrombosis and interstitial hemorrhage. Complement activation plays a prominent role in platelet-endothelial interaction. We tested the effects of platelet GPIIb/IIIa inhibitor tirofiban during perfusion of hDAF pig hearts.
  
  
  METHODS
  Using a working-heart model, nontransgenic and hDAF pig hearts were perfused with tirofiban or human blood only. Myocardial damage was determined by hemodynamic parameters (cardiac output, stroke work index) and creatine phosphokinase. Further monitoring included the assessment of complement factors (C3, C4), platelets, fibrinogen, ATIII, and graft histology.
  
  
  RESULTS
  Tirofiban increased cardiac output (CO) and stroke work index (SWI) of nontransgenic pig hearts and improved superior CO and SWI of hDAF pig hearts. Although perfusion time of nontransgenic pig hearts was prolonged by tirofiban (196+/-65 min vs. 162+/-122 min), a similar effect in hDAF pig hearts (218+/-116 min vs. 222+/-30 min) could not be demonstrated. Tirofiban reduced consumption of C3 and C4 independently from hDAF. Depletion of fibrinogen was equally diminished by tirofiban and hDAF; the combination of both agents obtained no further reduction. ATIII consumption was most effectively inhibited by this combination. Intravascular fibrin deposition was reduced by tirofiban and hDAF, but particularly by the combination of the two agents.
  
  
  CONCLUSIONS
  Improvement of heart performance and reduction of myocardial damage and intravascular thrombosis confirm a role of the GPIIb/IIIa inhibitor tirofiban for the prevention of hDAF pig heart rejection and xenograft function.
authors.affiliation: Department of Cardiac Surgery, Ludwig-Maximilians-University, Munich, Germany. ubrandl@med.uni-muenchen.de
authors.forename: Ulrike
authors.initials: U
authors.lastname: Brandl
authors.forename: Hannah
authors.initials: H
authors.lastname: Jöckle
authors.forename: Matthias
authors.initials: M
authors.lastname: Erhardt
authors.forename: Sebastian
authors.initials: S
authors.lastname: Michel
authors.forename: Lars
authors.initials: L
authors.lastname: Burdorf
authors.forename: Paolo
authors.initials: P
authors.lastname: Brenner
authors.forename: Iris
authors.initials: I
authors.lastname: Bittmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Rössle
authors.forename: Volker
authors.initials: V
authors.lastname: Mordstein
authors.forename: Claus
authors.initials: C
authors.lastname: Hammer
authors.forename: Eckart
authors.initials: E
authors.lastname: Thein
authors.forename: Bruno
authors.initials: B
authors.lastname: Reichart
authors.forename: Michael
authors.initials: M
authors.lastname: Schmoeckel
mesh_terms: D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000097:blood; D018958:CD55 Antigens / Q000235:genetics*; D003176:Complement C3 / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D004187:Disaccharides / Q000276:immunology; D005337:Fibrin / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006321:Heart / Q000502:physiology*; D016027:Heart Transplantation / Q000502:physiology; D006801:Humans; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D013552:Swine; D013927:Thrombosis / Q000401:mortality / Q000517:prevention & control*; D000077466:Tirofiban; D014183:Transplantation, Heterologous / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D018958:CD55 Antigens; D003176:Complement C3; D003181:Complement C4; D004187:Disaccharides; D005343:Fibrinolytic Agents; C055075:galactosyl-(1-3)galactose; D014443:Tyrosine; D005337:Fibrin; D003402:Creatine Kinase; D000077466:Tirofiban