Mechanism of antithrombotic effect of heparin and antithrombin in balloon-injured arteries

The mechanism of the antithrombotic effects of heparin and the synthetic antithrombin agent argatroban was evaluated in a dog model. Thrombus formation following balloon injury was evaluated by angioscopy in the right iliac arteries of 20 dogs to serve as a control. After the evaluation of the growth of thrombus on the control side, heparin (200 U/kg) or argatroban (0.2 mg/kg) was infused intravenously, and the distal site of the contralateral left iliac artery was injured in the same manner. At 30 to 120 min before the final examination, the proximal site of the left iliac artery also was injured. After antithrombotic drug infusion, the percent angioscopic stenosis at the distal site was much lower (P < 0.0001) than that of the control site (mean stenosis index: 0.67 in heparin vs. 3.8 in control, and 0.25 in argatroban vs. 4.3 in control); however, thrombus formation was observed at the proximal site. With local delivery of a low dose of either antithrombotic drug (n = 10), an antithrombotic effect was maintained until 4 h after the infusion. A very weak fluorescence of FITC–heparin was detected at the injured artery 2 h after infusion. In a shunt experiment involving 5 dogs, carotid arteries were injured and incubated in oxygenated Krebs–Henseleit solution before auto grafting into the femoral artery. At 2 h after the grafting, no thrombus was formed in the grafted vessels incubated for 4 h, but was formed in those incubated for 10 min. These results indicate that the relatively long antithrombotic effect of these drugs may be due to a local drug effect at the injured artery, as well as the recovery of the antithrombogenicity of the injured artery.