Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(06): 1090-1096
DOI: 10.1160/TH03-09-0605

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers

Michael Wolzt

¹Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, Austria

,

Marcel Levi

²Academic Medical Centre, University of Amsterdam, The Netherlands

,

Troy C. Sarich

³AstraZeneca LP, Wilmington, Delaware, USA

,

Stig L. Boström

⁴AstraZeneca R&D Mölndal, Sweden

,

Ulf G. Eriksson

⁴AstraZeneca R&D Mölndal, Sweden

,

Maria Eriksson-Lepkowska

⁴AstraZeneca R&D Mölndal, Sweden

,

Mia Svensson

⁴AstraZeneca R&D Mölndal, Sweden

,

Jeffrey I. Weitz

⁵Henderson Research Centre and McMaster University, Hamilton, Canada

,

Margareta Elg

⁴AstraZeneca R&D Mölndal, Sweden

,

Karin Wåhlander

⁴AstraZeneca R&D Mölndal, Sweden

⁶Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Hospital, Göteborg University, Sweden

› Author Affiliations

Summary

The objectives were to investigate whether activation of the extrinsic coagulation cascade by recombinant factor VIIa (rFVIIa) reverses the inhibition of thrombin generation and platelet activation by melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. In a single-blind, randomized, parallel-group study, volunteers (20 per group) received a 5-hour intravenous (iv) infusion to achieve steadystate melagatran plasma concentrations of approximately 0.5 µmol/L, with a single iv bolus of rFVIIa (90 µg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-antithrombin complex, fibrinopeptide A, β-thromboglobulin, and thrombin-activatable fibrinolysis inhibitor were quantified for venous and shed blood. Activated partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin potential, thrombus precursor protein (TpP), and plasmin-α₂-antiplasmin complex concentrations were determined in venous blood. Shed blood volume was measured. Melagatran reduced markers of thrombin generation and platelet activation in shed blood and prolonged APTT. rFVIIa increased FVIIa activity, PT, and TpP in venous blood. All other parameters were unaffected. In conclusion, rFVIIa did not reverse the anticoagulant effects of high constant concentrations of melagatran. However, the potential value of higher, continuous or repeated doses of rFVIIa or its use with lower melagatran concentrations has not been excluded.

Keywords

Keywords

Melagatran - ximelagatran - shed blood - FVIIa - anticoagulant

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