HIRUDIN REDUCES TISSUE FACTOR EXPRESSION IN NEOINTIMA AFTER BALLOON INJURY IN RABBIT FEMORAL AND PORCINE CORONARY-ARTERIES

Background-Tissue factor (TF) is a transmembrane glycoprotein that, af ter binding to factor VII/VIIa, initiates the extrinsic coagulation pa thway, resulting in thrombin generation and its sequelae. Thrombin has been shown to induce TF mRNA in endothelium, monocytes, and smooth mu scle cells, further perpetuating the thrombogenic cycle. This study wa s designed to determine the effect of specific inhibition of thrombin by recombinant hirudin (r-hirudin) on TF distribution after balloon an gioplasty in the cholesterol-fed rabbit femoral artery and porcine cor onary artery models. Methods and Results-Thirty-five femoral arteries from 32 cholesterol-fed New Zealand White rabbits and 84 coronary arte ries from 55 Yorkshire-Albino swine were studied by use of a recently developed in situ method of TF localization based on digoxigenin label ing of recombinant factor VIIa (Dig-VIIa), with correlative studies of TF immunoreactivity by use of anti-rabbit (AP-1) or anti-human (sTF) antibodies. At sites of balloon angioplasty in rabbit femoral or pig c oronary arteries (double or single injury), TF-antibody and Dig-VIIa s taining were noted in association with endothelial cells, smooth muscl e cells, and foam cells and within the fibrous tissue matrix primarily of the adventitia and neointima. Staining was significantly greater a fter balloon angioplasty than in vessels that had not undergone angiop lasty but was similar after single and double balloon injury. Animals treated with r-hirudin (rabbits, 1 mg/kg bolus plus 2-hour infusion; p igs, 1 mg/kg bolus plus 0.7 mg.kg(-1).d(-1) infusion for 14 days with implantable pump) had diminished TF-antibody and Dig-VIIa staining 28 days after balloon angioplasty compared with controls (bolus heparin o nly), This effect was more prominent on the neointima and was more str iking in the porcine than the rabbit model. Conclusions-TF expression, persistent 1 month after balloon angioplasty in rabbit femoral arteri es and porcine coronary arteries, is attenuated by specific thrombin i nhibition with hirudin. These results suggest that thrombin inhibition , in addition to its effect on acute thrombus formation and its effect on luminal narrowing by plaque in experimental animals, may result in a prolonged reduction in thrombogenicity of the restenotic plaque thr ough this effect on TF expression.