Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A.
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 (C(lys 1/2)-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 (C(clot 1/2)-VIIa) was approximately 10-fold lower than the C(lys 1/2)-VIIa value (median, 8.4 U/mL; range, 1.7-22.5 U/mL). Inhibition of TFPI with a polyclonal antibody significantly decreased C(lys 1/2)-VIIa values (median, 2.6 U/mL; range, 0-86.9 U/mL), whereas C(clot 1/2)-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 C(lys 1/2)-VIIa values was observed (median, 119.2 U/mL; range, 12.3-375.0 U/mL), whereas C(clot 1/2)-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.
Lisman
Ton
T
Thrombosis and Haemostasis Laboratory, Department of Haematology, Institute of Biomembranes, Van Creveldkliniek, University Medical Centre, Utrecht University, The Netherlands. j.a.lisman@lab.azu.nl
Mosnier
Laurent O
LO
Lambert
Thierry
T
Mauser-Bunschoten
Evelien P
EP
Meijers
Joost C M
JC
Nieuwenhuis
H Karel
HK
de Groot
Philip G
PG
D000906:Antibodies / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D001798:Blood Proteins / Q000032:analysis; D025901:Carboxypeptidase B2 / Q000502:physiology; D005169:Factor VIII / Q000502:physiology; D015942:Factor VIIa / Q000008:administration & dosage / Q000494:pharmacology*; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents; D006467:Hemophilia A / Q000097:blood*; D006801:Humans; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000502:physiology; D013997:Time Factors
D000906:Antibodies; D001798:Blood Proteins; D005343:Fibrinolytic Agents; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D005169:Factor VIII; D013925:Thromboplastin; D025901:Carboxypeptidase B2; D015942:Factor VIIa