Additive effect of the combined administration of low molecular weight heparin and recombinant hirudin on thrombus growth in a rabbit jugular vein thrombosis model
Biemond, B.J.; Levi, M.; Nurmohamed, M.T.; Büller, H.R.; ten Cate, J.W.
Thrombosis and Haemostasis 72(3): 377-380
1994
ISSN/ISBN: 0340-6245 PMID: 7855787 Document Number: 424173
Recombinant Hirudin (r-Hirudin) is a new anticoagulant with specific antithrombin activity independently of antithrombin III. Low molecular weight heparins (LMWH) exert predominantly anti-Xa activity. Therefore, 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 125I-labeled fibrinogen onto autologous non-radioactive thrombi preformed in the jugular veins of rabbits. The rabbits received unfractionated heparin (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 dependent fashion. The combined administration of 80 anti-Xa U LMWH and r-Hirudin at a dose of 0.3 mg/kg resulted in a stronger antithrombotic effect 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 LMWH versus unfractionated heparin on r-Hirudin was also observed when LMWH was combined with 5.0 mg/kg and 10.0 mg/kg r-Hirudin versus unfractionated 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 antithrombotic 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 anticoagulant effect when combined with LMWH.