Vascular injury, activation of the coagulation system and
thrombosis are common initial events in the accelerated atherosclerotic process. The role of
thrombin generated at the site of aortic injury in the subsequent neointimal proliferation was studied in rabbits (n = 16) 3 weeks after balloon
catheter injury. In half of these animals, potent
thrombin antagonists, r-
hirudin and P-PACK, were administered to prevent acute thrombotic events. Compared to aortas with intact endothelium (n = 8), aortas de-endothelialised 21 days earlier showed neointimal
hyperplasia 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 inhibited in rabbits treated with
thrombin-antagonists (0.27 vs. 0.68, treated vs. untreated, p = 0.012) and neither total
cholesterol (3.48 mg/g) nor
lipid peroxide content (1.5 nmol/g) differed significantly from that of intact arteries. By demonstrating a strong relationship between
thrombin generation following de-endothelialisation and the progressive intimal proliferation, this study supports the hypothesis that
thrombin is an important contributor to restenosis after
vascular injury. The highly atherogenic lipid peroxidation seems to be linked to the early,
thrombin-mediated events, as it was completely prevented by adequate
thrombin antagonism.