Thrombin inhibition and intracoronary thrombus formation: effect of polyethylene glycol-coupled hirudin in the stenosed, locally injured canine coronary artery.

Abstract

Adhesion and aggregation of platelets at sites of intimal injury are accompanied by local thrombin generation and conversion of fibrinogen to insoluble fibrin. As the long-acting thrombin inhibitor, polyethylene glycol-coupled hirudin (PEG-hirudin), would be expected to interrupt this process by inhibiting the action of thrombin on platelets and fibrinogen, its effect on intracoronary thrombus formation, coagulation, platelet function, and duration and intensity of bleeding events was investigated. Cyclic coronary flow reductions (CFRs) were induced in the left anterior descending coronary artery of 24 anaesthetised mongrel dogs by mechanical injury of the endothelium combined with critical stenosis. There were four treatment regimens (six dogs per group): Control (isotonic saline); PEG 0.08 (0.15 mg/kg bolus + 0.08 mg/kg.h infusion); PEG 0.15 (0.30 mg/kg bolus + 0.15 mg/kg.h infusion); PEG 0.30 (0.60 mg/kg bolus + 0.30 mg/kg.h infusion). A linear increase in steady-state plasma concentrations to 35.4 +/- 1.6 antithrombin units (ATU)/ml, 59.2 +/- 3.0 ATU/ml and 112.7 +/- 8.4 ATU/ml was achieved with the three doses of PEG-hirudin. The activated partial thromboplastin time (APTT) was increased 1.7-fold with PEG 0.08, 1.9-fold with PEG 0.15 and 2.2-fold with PEG 0.30. The frequency of CFRs during the first hour after drug administration was diminished by about 20% with all three doses of PEG. During the second hour, CFRs were decreased by 61% in all treated groups. Thrombin-induced platelet aggregation was completely abolished by all PEG-hirudin regimens. Buccal bleeding time and blood loss were not increased after either treatment. In this canine model of coronary artery stenosis, the thrombin inhibitor, PEG-hirudin, effectively reduces platelet-dependent thrombus formation without interfering with primary haemostasis.