Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers.
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 (i.v.) infusion to achieve steady-state melagatran plasma concentrations of approximately 0.5 micromol/L, with a single i.v. bolus of rFVIIa (90 microg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-anti-thrombin complex, fibrinopeptide A, beta-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-alpha(2)-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.
Wolzt
Michael
M
Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, Vienna, Austria. michael.wolzt@univie.ac.at
Levi
Marcel
M
Sarich
Troy C
TC
Boström
Stig L
SL
Eriksson
Ulf G
UG
Eriksson-Lepkowska
Maria
M
Svensson
Mia
M
Weitz
Jeffrey I
JI
Elg
Margareta
M
Wåhlander
Karin
K
D000328:Adult; D001384:Azetidines; D001596:Benzylamines; D015415:Biomarkers / Q000097:blood; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005167:Factor VII / Q000008:administration & dosage* / Q000494:pharmacology; D015942:Factor VIIa; D005998:Glycine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000187:drug effects*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D016037:Single-Blind Method; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control; D013997:Time Factors
D001384:Azetidines; D001596:Benzylamines; D015415:Biomarkers; D011994:Recombinant Proteins; C109573:melagatran; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa; D005998:Glycine