Elsevier

Thrombosis Research

Volume 94, Issue 3, 1 May 1999, Pages 187-197
Thrombosis Research

Regular article
Antithrombotic Effects and Bleeding Time of Thrombin Inhibitors and Warfarin in the Rat

https://doi.org/10.1016/S0049-3848(98)00213-8Get rights and content

Abstract

Warfarin limits the synthesis of γ-glutamyl carboxylated forms of coagulation factors, factor II, factor VII, factor IX, and factor X, protein C, and protein S and as a result impairs the function of these proteins. In contrast, direct inhibitors of throm- bin only affect one enzyme in the coagulation cascade. The aim of this study was to investigate the antithrombotic effect and the slope of the dose- response curves of the multifactorial coagulation inhibitor warfarin in comparison with the single factor low-molecular-weight thrombin inhibitors melagatran and inogatran. An arterial thrombosis model in rats was used, and vessel damage was induced by topical application of ferric chloride to the carotid artery. The slopes of the dose-response curves were 3.6, 1.8, 1.1, and 1.2, for warfarin, heparin, inogatran, and melagatran, respectively. For warfarin the antithrombotic effect increased from 23% to 81% when the dose was doubled. In contrast, 10-fold increases in the doses of inogatran and melagatran were necessary to obtain a similar increase in antithrombotic effect. The doses needed to obtain 80% antithrombotic effect for heparin, warfarin, and melagatran were investigated in a tail transection bleeding model. For heparin, this dose significantly prolonged the bleeding time and the blood loss; for warfarin, only the total bleeding time was increased while for melagatran there was no increase in bleeding. We conclude that, thrombin inhibitors affecting only one enzyme in the coagulation cascade seem preferable to inhibitors affecting multiple enzymes, such as warfarin, due to shallower dose-response curves and a wider therapeutic interval.

Section snippets

Materials and Methods

Male Sprague-Dawley rats (body weight 350–425 g; Møllegaard Breeding Centre, Skensved, Denmark) were used in this study. The animal care and use was approved by Gothenburg Local Ethical Committee on Animal Experiments, a body within The National Board for Laboratory Animals, Sweden. The animals were anaesthetized with an intraperitoneal injection of sodium pentobarbital (80 mg/kg; NordVacc, Malmö, Sweden) followed by a continuous infusion (12 mg/kg per hour) throughout the experiment. The body

Antithrombotic Effect versus Dose and Plasma Concentration

The doses and the mean plasma concentrations are summarized in Table 1. In rats, given vehicle (group 1) the thrombus size was 18.8±1.2 in AU. Figure 2 shows the antithrombotic effects of warfarin, inogatran, melagatran, and heparin. A 50% antithrombotic effect for warfarin was obtained with 0.40 μmol/kg per day for 4 days and for inogatran and melagatran at a dose of 0.92 and 0.13 μmol/kg per hour when given as a continuous infusion during the experiment. The slopes of the dose-response curves

Discussion

The arterial thrombosis model used in this study, where application of ferric chloride to the carotid artery was used as a thrombogenic stimulus, was slightly modified from that used previously [15]. In that study, a 50% antithrombotic effect was obtained at a plasma concentration of 0.14–0.12 μmol l−1 for hirudin and melagatran, respectively. In the present study, the plasma concentration at 50% antithrombotic effect was 0.15 μmol/l for melagatran.

The turnover for the individual coagulation

Acknowledgements

The authors acknowledge Therese Hultstrand for technical assistance with the bleeding time experiments.

References (27)

  • S.E Lind et al.

    Plasma levels of factors II, VII and X and their relationship to the international normalised ratio during chronic warfarin therapy

    Blood Coagul Fibrinolysis

    (1997)
  • M.L Brigden

    Oral anticoagulant therapyPractical aspects of management

    Postgrad Med

    (1996)
  • L.R Bush

    Argatroban, a selective, potent thrombin inhibitor

    Cardiovasc Drug Rev

    (1991)
  • Cited by (0)

    View full text