Antithrombotic Effects of Thrombolytic Agents in a Platelet-Rich Femoral Vein Thrombosis Model in the Hamster

Abstract

The extent and mechanism of the antithrombotic properties of fibrin-selective and non-fibrin-selective thrombolytic agents have not yet been established. The antithrombotic, thrombolytic, fibrinogenolytic, and pharmacokinetic properties of the following substances were determined in hamsters in the absence of conjunctive anticoagulant or antiplatelet therapy: recombinant tissue-type plasminogen activator (rTPA), recombinant single-chain urokinase-type plasminogen activator (rscu-PA), two-chain urokinase-type plasminogen activator (UK), with a rTPA deletion mutant lacking amino acids 6 to 173 and a mutation N184E (K2Pt), a rTPA/rscu-PA chimeric plasminogen activator consisting of amino acids 1 to 3 and 87 to 274 of rTPA and amino acids 138 to 411 of rscu-PA (K1K2Pu), streptokinase (SK), and recombinant staphylokinase (STAR). The anti-thrombotic effect, defined as the intravenous dose required to reduce mural thrombus formation to 50% in a platelet-mediated femoral vein thrombosis model in the hamster, was 6 +/- 1, 5 +/- 2, 1 +/- 0.05, 2.5 +/- 0.2, 0.02 +/- 0.002, 1 +/- 0.09, and 2 +/- 0.3 mg/kg (mean +/- SEM), respectively. The amounts, given as intravenous infusion over 60 minutes that induced 50% clot lysis in a hamster pulmonary embolism model, were 0.18 +/- 0.03, 1.1 +/- 0.05, 0.9 +/- 0.13, 0.34 +/- 0.03, 0.04 +/- 0.003, 0.05 +/- 0.005, and 0.04 +/- 0.001 mg/kg, respectively, indicating that for most thrombolytic agents the antithrombotic dose is much higher than their thrombolytic dose. The fibrinogen levels, measured 40 minutes after bolus injection, were reduced to 50% of baseline with 3.1 +/- 0.2, 2.5 +/- 0.3, 1.2 +/- 0.08, 2.0 +/- 0.14, 1.7 +/- 0.65, 0.54 +/- 0.03, and 1.2 +/- 0.11 mg/kg, respectively. Mean residence times following intravenous bolus injection were: 18 +/- 1, 14 +/- 1, 100 +/- 10, 80 +/- 2, 20 +/- 3, and 34 +/- 5 minutes for rTPA, rscu-PA, K2Pt, K1K2Pu, SK, and STAR, respectively. Regression analysis revealed a significant correlation of the antithrombotic effect with the fibrinogen breakdown (P = .006) but not with the thrombolytic potency or with the mean residence time. These observations support the hypothesis that thrombolytic therapy with fibrinogen-sparing agents requires the conjunctive use of anticoagulant and/or antiplatelet agents.