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. 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.