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 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Center for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Center, Amsterdam, The Netherlands.
B J
BJ
Biemond
M
M
Levi
M T
MT
Nurmohamed
H R
HR
Büller
J W
JW
ten Cate
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D024764:Hirudin Therapy; D006629:Hirudins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007262:Infusions, Intravenous; D007601:Jugular Veins; D017762:Nadroparin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control*
D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D006629:Hirudins; D017762:Nadroparin; D011994:Recombinant Proteins; D013917:Thrombin; C060225:desirudin