Reduced fibrin deposition and intravascular thrombosis in hDAF transgenic pig hearts perfused with tirofiban.
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.
Brandl
Ulrike
U
Department of Cardiac Surgery, Ludwig-Maximilians-University, Munich, Germany. ubrandl@med.uni-muenchen.de
Jöckle
Hannah
H
Erhardt
Matthias
M
Michel
Sebastian
S
Burdorf
Lars
L
Brenner
Paolo
P
Bittmann
Iris
I
Rössle
Matthias
M
Mordstein
Volker
V
Hammer
Claus
C
Thein
Eckart
E
Reichart
Bruno
B
Schmoeckel
Michael
M
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
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