Effects of Hirudin and Heparin on the Binding of New Fibrin to the Thrombus in t-PA Treated Rabbits

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Abstract
The aim of this study was to compare the ability of heparin and recombinant hirudin (r-hirudin) in preventing accretion of new fibrin on thrombi during and after treatment with tissue-type plasminogen activator (t-PA) and in enhancing t-PA induced fibrinolysis in a rabbit jugular vein thrombosis model. Heparin and r-hirudin were infused at doses capable of doubling aPTT. In the fibrin accretion inhibition experiments t-PA was infused over 3 h at a dose of 0.2 mg/kg along with saline or heparin, 0.75 mg/ kg or r-hirudin, 1.25 mg/kg. In rabbits treated with t-PA plus saline, heparin or r-hirudin, an accumulation of 125I-fibrinogen on the thrombi of 52.5 ±5.1 εg, 49.5 ± 5.6 εg and 23.5 ± 3.5 εg was observed, respectively, the difference between r-hirudin and both saline and heparin being statistically significant (p <0.01). The inhibition of fibrin accretion on the thrombi induced by r-hirudin persists for at least 9 h after the end of the infusion. By that time r-hirudin has been cleared from the circulation and aPTT has returned to the baseline level for at least 8 h. t-PA, 0.2, 0.4, and 1 mg/kg, infused with saline produced 34 ± 6%, 52 ± 5% and 79 ± 8% lysis of pre-formed thrombi, respectively. The same doses of t-PA infused with heparin, 0.75 mg/kg, produced 32 ± 3%, 54 ± 5% and 78 ± 6% fibrinolysis, respectively and infused with r-hirudin, 1.25 mg/kg, 38 ± 3%, 57 ± 5% and 82 ± 8%, respectively. Thus, no differences in fibrinolysis were observed among the groups of rabbits treated with heparin, r-hirudin and saline receiving the same dose of t-PA. When thrombolysis was assessed by thrombus weight treatment with t-PA and r-hirudin was more effective than treatment with t-PA and saline or heparin. The positive effects of r-hirudin on t-PA induced thrombolysis we observed deserve to be confirmed in clinical settings.