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Blood, 1 January 2002, Vol. 99, No. 1, pp. 175-179
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Inhibition of fibrinolysis by recombinant factor VIIa in plasma
from patients with severe hemophilia A
Ton Lisman,
Laurent O. Mosnier,
Thierry Lambert,
Evelien P. Mauser-Bunschoten,
Joost C. M. Meijers,
H. Karel Nieuwenhuis, and
Philip G. de
Groot
From the Thrombosis and Haemostasis Laboratory,
Department of Haematology, Institute of Biomembranes, Van
Creveldkliniek, University Medical Centre, Utrecht University, The
Netherlands; Centre de Traitement des Hémophiles, Hôpital
de Bicêtre, Le Kremlin Bicêtre, France; and Department of
Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Recombinant factor VIIa (rFVIIa) is a novel prohemostatic drug for
patients with hemophilia who have developed inhibitory antibodies. The
postulation has been made that hemophilia is not only a disorder of
coagulation, but that hyperfibrinolysis due to a defective activation
of thrombin activatable fibrinolysis inhibitor (TAFI) might also play a
role. In this in vitro study, the potential of rFVIIa to down-regulate
fibrinolysis via activation of TAFI was investigated. rFVIIa was able
to prolong clot lysis time in plasmas from 17 patients with severe
hemophilia A. The prolongation of clot lysis time by rFVIIa was
completely abolished by addition of an inhibitor of activated TAFI. The
concentration of rFVIIa required for half maximal prolongation of clot
lysis time (Clys1/2-VIIa) varied widely between patients
(median, 73.0 U/mL; range, 10.8-250 U/mL). The concentration of rFVIIa required for half maximal reduction of clotting time
(Cclot1/2-VIIa) was approximately 10-fold lower
than the Clys1/2-VIIa value (median, 8.4 U/mL; range,
1.7-22.5 U/mL). Inhibition of TFPI with a polyclonal antibody
significantly decreased Clys1/2-VIIa values (median, 2.6 U/mL; range, 0-86.9 U/mL), whereas Cclot1/2-VIIa values did
not change (median, 7.2 U/mL; range, 2.2-22.5 U/mL). On addition of 100 ng/mL recombinant full-length TFPI, a nonsignificant increase of
Clys1/2-VIIa values was observed (median, 119.2 U/mL;
range, 12.3-375.0 U/mL), whereas Cclot1/2-VIIa values did
not change (median, 8.8 U/mL; range, 2.6-34.6 U/mL). In conclusion, this study shows that rFVIIa both accelerates clot formation and inhibits fibrinolysis by activation of TAFI in factor VIII-deficient plasma. However, a large variability in antifibrinolytic potential of
rFVIIa exists between patients.
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