Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux.
BACKGROUND
Fondaparinux is a synthetic pentasaccharide, which selectively inhibits coagulation factor (F) Xa, and is registered for prevention of venous thromboembolism following hip fracture, hip replacement, and knee replacement surgery. Recently, it was shown that recombinant FVIIa (rFVIIa) reverses anticoagulant effects of fondaparinux in healthy volunteers.


OBJECTIVE
In this study, we have explored the in vitro and ex vivo effects of rFVIIa on clot formation and thrombin-activatable fibrinolysis inhibitor (TAFI)-mediated down-regulation of fibrinolysis after fondaparinux administration.


METHODS
In vitro clot lysis assays were performed in pooled normal plasma from healthy volunteers to which fondaparinux was added, and in serial samples from healthy volunteers who received a single bolus dose of fondaparinux, a single bolus dose of rFVIIa, or both.


CONCLUSIONS
Fondaparinux significantly delayed clot formation, and clot lysis was significantly increased due to decreased activation of TAFI. Addition of recombinant FVIIa corrected the inhibited clot formation induced by fondaparinux, and the acceleration of clot lysis was partially reversed. In vivo administration of fondaparinux (10 mg) to healthy volunteers similarly resulted in accelerated plasma clot lysis. Subsequent administration of rFVIIa (90 microg kg(-1)) normalized the clot lysis time up to 6 h postadministration. rFVIIa might be a good therapeutic option in patients treated with fondaparinux who develop bleeding complications, since both clot formation as well as fibrinolytic resistance are improved.
Lisman
T
T
Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center, Utrecht, The Netherlands. j.a.lisman@azu.nl
Bijsterveld
N R
NR
Adelmeijer
J
J
Meijers
J C M
JC
Levi
M
M
Nieuwenhuis
H K
HK
De Groot
P G
PG
D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D025901:Carboxypeptidase B2 / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D005167:Factor VII / Q000008:administration & dosage / Q000494:pharmacology*; D015942:Factor VIIa; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000077425:Fondaparinux; D006801:Humans; D007700:Kinetics; D011134:Polysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D011134:Polysaccharides; D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D025901:Carboxypeptidase B2; D015942:Factor VIIa; D000077425:Fondaparinux