Antithrombotic effects of hirulog in a rat carotid endarterectomy model

Although hirulog, a specific, direct inhibitor of thrombin, can prevent thrombosis in unstable angina and angioplasty without inducing excessive bleeding, it has not been used in a surgical setting. In the present study, the antithrombotic activity of hirulog was assessed in rats undergoing carotid endarterectomy. Three groups of anesthetized male Sprague-Dawley rats received either intravenous heparin (10 U/kg bolus followed by 90 U/kg/hr, n = 4), high-dose hirulog (0.8 mg/kg bolus followed by 2.2 mg/kg/hr, n = 7), or saline (n = 6) before endarterectomy and until termination of the protocol 30 min later. Platelet deposition, as measured by scanning electron microscopy, in rats receiving this high dose of hirulog was reduced by 63% (+/- 14%, SE) compared to controls (P = 0.004) and by 36% (+/- 16%) in heparinized rats (P - 0.07). Both groups had prolonged postsurgical bleeding. Infusion of hirulog at a lower dose (0.4 mg/kg bolus followed by 1.0 mg/kg/hr, n = 8) was not associated with prolonged bleeding; however, platelet deposition was reduced by only 16% (+/- 27%, P = 0.30), although 125I-fibrin deposition was reduced by 64% (+/- 11%, P = 0.004). In the high-dose hirulog group, plasma hirulog levels, as determined with a quantitative thrombin time, were three times higher (95% CI: 1.5-4.5 times) than in the group receiving the lower hirulog dose [11.6 +/- 2.3 (SE) micrograms/ml vs 3.9 +/- 0.6 micrograms/ml; P = 0.0022]. However, the mean activated partial thromboplastin time with the higher dose was similar to that of the lower dose (110 +/- 4 vs 90 +/- 13 sec, P - 0.09). The antithrombotic activity of hirulog can be maximized by titrating the dose, monitoring plasma drug levels, and possibly administering the drug after surgery to avoid prolonged bleeding.