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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
1   Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, Austria
,
Marcel Levi
2   Academic Medical Centre, University of Amsterdam, The Netherlands
,
Troy C. Sarich
3   AstraZeneca LP, Wilmington, Delaware, USA
,
Stig L. Boström
4   AstraZeneca R&D Mölndal, Sweden
,
Ulf G. Eriksson
4   AstraZeneca R&D Mölndal, Sweden
,
Maria Eriksson-Lepkowska
4   AstraZeneca R&D Mölndal, Sweden
,
Mia Svensson
4   AstraZeneca R&D Mölndal, Sweden
,
Jeffrey I. Weitz
5   Henderson Research Centre and McMaster University, Hamilton, Canada
,
Margareta Elg
4   AstraZeneca R&D Mölndal, Sweden
,
Karin Wåhlander
4   AstraZeneca R&D Mölndal, Sweden
6   Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Hospital, Göteborg University, Sweden
› Author AffiliationsFinancial support: This study was funded by AstraZeneca.
Further Information

Publication History

Received 29 September 2003

Accepted after revision 09 March 2004

Publication Date:
02 December 2017 (online)

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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

Melagatran - ximelagatran - shed blood - FVIIa - anticoagulant
 

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