THROMBIN GENERATION FOLLOWING ARTERIAL INJURY IS A CRITICAL INITIATING EVENT IN THE PATHOGENESIS OF THE PROLIFERATIVE STAGES OF THE ATHEROSCLEROTIC PROCESS

Vascular injury, activation of the coagulation system and thrombosis a re common initial events in the accelerated atherosclerotic process. T he role of thrombin generated at the site of aortic injury in the subs equent neointimal proliferation was studied in rabbits (n=16) 3 weeks after balloon catheter injury. In half of these animals, potent thromb in antagonists, r-hirudin and P-PACK, were administered to prevent acu te thrombotic events. Compared to aortas with intact endothelium (n=8) , aortas de-endothelialised 21 days earlier showed neointimal hyperpla sia as measured by the intimal/medial ratio (0.68 vs. 0.04, injured vs . normal aortas) and an increase in both total cholesterol(4.08 vs. 3. 31 mg/g, p<0.05) and lipid peroxide content (31.3 vs. 1.1 nmol/g; p<0. 001). Neointimal hyperplasia following endothelial denudation was inhi bited in rabbits treated with thrombin-antagonists (0.27 vs. 0.68, tre ated vs. untreated, p=0.012) and neither total cholesterol (3.48 mg/g) nor lipid peroxide content (1.5 nmol/g) differed significantly from t hat of intact arteries. By demonstrating a strong relationship between thrombin generation following de-endothelialisation and the progressi ve intimal proliferation, this study supports the hypothesis that thro mbin is an important contributor to restenosis after vascular injury. The highly atherogenic lipid peroxidation seems to be linked to the ea rly, thrombin-mediated events, as it was completely prevented by adequ ate thrombin antagonism.