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22 December 2010

Prevention of hyperacute xenograft rejection through direct thrombin inhibition with hirudin

Paolo Brenner, Miriam Keller, Andres Beiras-Fernandez, Sunji Uchita, Felix Kur, Eckart Thein, Cosmas Wimmer, Claus Hammer, Michael Schmoeckel, Bruno Reichart

Ann Transplant 2010; 15(4): 30-37 :: ID: 881349

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.
Material/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.

Keywords: hyperacute rejection, Thrombin, Xenotransplantation, anticoagulation, hirudin

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Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358