Hirudin reduces tissue factor expression and attenuates graft arteriosclerosis in rat cardiac allografts

Background-Intravascular clotting has been implicated in the pathogenesis o f cardiac allograft vasculopathy (CAV). We previously identified the expres sion of tissue factor (TF), the primary cellular initiator of blood coagula tion, within the coronary intima, which was associated with neointimal thic kening. In the present study, the effect of recombinant hirudin on CAV was assessed in Lewis to Fisher rat heterotopic cardiac allografts. Methods and Results-Transplant recipients were randomized to a control grou p (n = 10) and a hirudin-treated group (n = 12; 2 mg kg(-1) d(-1) SC). Hist ological evaluations of rejection, CAV, and TF staining were performed 120 days after transplantation. No significant differences were observed betwee n the 2 groups with respect to the degree of rejection. Hirudin significant ly (P < 0.05) suppressed the development of CAV in the graft microvessels, but it was less effective in large coronary arteries. Graft intimal cells, isolated by laser-assisted cell picking, showed a marked upregulation of TF gene transcription, which was prevented by hirudin (P < 0.01). As demonstr ated by immunohistochemistry and quantitative analyses of TF mRNA levels by real-time polymerase chain reaction, hirudin treatment resulted in a signi ficant reduction of TF protein and mRNA expression (P < 0.001). Conclusions-Treatment with hirudin in this rat cardiac transplant model inh ibited TF expression and decreased neointimal hyperplasia. These results su ggest that TF inhibition by hirudin, in addition to its direct effect on th rombin, may attenuate the hypercoagulable state and prevent the development of CAV at least in restricted sites of the graft coronary vasculature.