Inhibition of intimal hyperplasia by direct thrombin inhibitors in an animal vein bypass model

Many functions of the coagulation system have nonthrombotic effects. The indirect thrombin inhibitor heparin has been previously shown to be effective in limiting intimal hyperplasia (IH). We sought to study the effect of thrombin on IH by using two direct thrombin inhibitors (DTIs), argatroban and lepirudin. Sprague-Dawley rats underwent interposition vein grafting to the carotid artery. Vein grafts were treated with either saline (n = 6) or one of the two DTIs (n = 6 for both). At 30 days, the rats were sacrificed and vessels were perfusion fixed. Sections of the proximal carotid artery, graft, and both anastomoses were stained with both hematoxlyin/eosin and von Gieson's elastin stain. Sections were examined and compared for luminal area and intima-to-media (IM) ratio. The vessels treated with DTIs had less (p < 0.05) IH (IM ratio for proximal anastomosis: control 1.036 &PLUSMN; 0.857, lepirudin 0.373 &PLUSMN; 0.21, argatroban 0.182 &PLUSMN; 0.118) and better lumen preservation than the control vessels (lumen area of proximal anastomosis: control 1.69 &PLUSMN; 0.9, lepirudin 2.45 &PLUSMN; 0.74, argatroban 2.81 &PLUSMN; 0.78). There were no thromboses in the DTI-treated vessels. Dilatation of the graft segment was noted in the argatroban group. Thus, DTIs are effective at reducing IH in a small-animal model, suggesting that inhibition of thrombin has a protective role in IH. In addition, a difference of action between DTIs is suggested by the dilatation seen only in the argatroban-treated graft sections.