ANTITHROMBOTIC EFFECTS OF HIRULOG IN A RAT CAROTID ENDARTERECTOMY MODEL

Although hirulog, a specific, direct inhibitor of thrombin, can preven t thrombosis in unstable angina and angioplasty without inducing exces sive bleeding, it has not been used in a surgical setting. In the pres ent 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 fo llowed by 2.2 mg/kg/hr, n = 7), or saline (n = 6) before endarterectom y and until termination of the protocol 30 min later. Platelet deposit ion, as measured by scanning electron microscopy, in rats receiving th is high dose of hirulog was reduced by 63% (+/-14%, SE) compared to co ntrols (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 w as reduced by only 16% (+/-27%, P = 0.30), although I-125-fibrin depos ition was reduced by 64% (+/-11%, P = 0.004). In the high-dose hirulog group, plasma hirulog levels, as determined with a quantitative throm bin 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) mu g/ml vs 3 .9 +/- 0.6 mu g/ml, P = 0.0022]. However, the mean activated partial t hrombo plastin time with the higher dose was similar to that of the lo wer dose (110 +/- 4 vs 90 +/- 13 sec, P = 0.09). The antithrombotic ac tivity of hirulog can be maximized by titrating the dose, monitoring p lasma drug levels, and possibly administering the drug after surgery t o avoid prolonged bleeding.