ADDITIVE EFFECT OF THE COMBINED ADMINISTRATION OF LOW-MOLECULAR-WEIGHT HEPARIN AND RECOMBINANT HIRUDIN ON THROMBUS GROWTH IN A RABBIT JUGULAR-VEIN THROMBOSIS MODEL

Recombinant Hirudin (r-Hirudin) is a new anticoagulant with specific a ntithrombin activity independently of antithrombin III. Low molecular weight heparins. (LMWH) exert predominantly anti-Xa activity. Therefor e, we hypothesized that combined administration of r-Hirudin and LMWH would induce a stronger antithrombotic effect as compared to r-Hirudin administered alone or combined with unfractionated heparin. To assess the effect on thrombus growth, we determined the accretion of I-125-l abeled fibrinogen onto autologous non-radioactive thrombi preformed in the jugular veins of rabbits. The rabbits received unfractionated hep arin (80 anti-factor Xa U), LMWH (80 anti-factor Xa U) or r-Hirudin (0 .3, 5.0 and 10.0 mg/kg) either separately or by combined infusion for a 3 h period. R-Hirudin reduced the thrombus growth in a dose dependen t fashion. The combined administration of 80 anti-Xa U LMWH and r-Hiru din at a dose of 0.3 mg/kg resulted in a stronger antithrombotic effec t as compared to the combined infusion of unfractionated heparin and r -Hirudin (thrombus growth: 14.3% +/- 6.0 vs 28.9% +/- 6.5; p = 0.001). This difference in additive antithrombotic effect of 80 anti-Xa U LMW H versus unfractionated heparin on r-Hirudin was also observed when LM WH was combined with 5.0 mg/kg and 10.0 mg/kg r-Hirudin versus unfract ionated heparin combined with r-Hirudin (thrombus growth: 16.4% +/- 1. 6 vs 29.1% +/- 3.9; p = 0.01 and 10.1% +/- 1.8 vs 20.4% +/- 4.5; p = 0 .001, respectively). In conclusion, this study showed an additive anti thrombotic effect of LMWH on the thrombus growth reducing effect of r- Hirudin. This may potentially be of clinical interest, i.e. much lower doses of r-Hirudin may be used to achieve a similar effective anticoa gulant effect when combined with LMWH.