Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis

T. C. Sarich, J. I. Osende, U. G. Eriksson, G. B. Fager, M. Eriksson-Lepkowska, L. Ohlsson, S. Carlsson, K. Wåhlander, D. Gustafsson, J. J. Badimon

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33 Scopus citations

Abstract

Background: Thrombin plays amajor role in thrombus formation through activation of platelets and conversion of fibrinogen to fibrin. Objectives: To investigate the antithrombotic effects of the oral direct thrombin inhibitor (DTI) ximelagatran and the parenteral DTI r-hirudin in humans. Subjects and methods: Healthy male volunteers randomized into four parallel groups each with 15 subjects received either ximelagatran (20, 40 or 80mg orally) or r-hirudin (0.4mg kg-1 intravenous bolus +infusion of 0.15mgkg-1 h-1 for 2 h and 0.075mgkg-1 h-1 for 3 h). Antithrombotic effects were assessed as changes in total thrombus area (TTA) and total fibrin area (TFA) from baseline, using the Badimon perfusion chamber model at baseline and 2 h and 5 h after drug administration. Results: Two hours postdosing, ximelagatran showed antithrombotic effects at both high and low shear rates (TTA% of mean baseline value ±SEM was 76±13% and 71±17% [both P<0.05] for the 20-mg dose, 85±11% [P>0.05] and 62±15% [P<0.05] for the 40-mg dose and 60±11% and 26±7% [both P<0.05] for the 80-mg dose, respectively). r-Hirudin also showed a significant antithrombotic effect at high and low shear rates (76±11% [P<0.05] and 57±17% [P<0.05] of baseline values, 2 h postdosing, respectively). The inhibitory effects on TFA were similar to those on TTA. Conclusions: The oral DTI ximelagatran shows antithrombotic effects under both high and low shear conditions. The antithrombotic effect of 40-80mg ximelagatran appeared comparable to that of parenterally administered rhirudin, which has been previously demonstrated to be clinically effective in acute coronary syndromes.

Original languageEnglish
Pages (from-to)999-1004
Number of pages6
JournalJournal of Thrombosis and Haemostasis
Volume1
Issue number5
DOIs
StatePublished - May 2003
Externally publishedYes

Keywords

  • Direct thrombin inhibitor
  • R-hirudin
  • Thrombus
  • Ximelagatran

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