The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor.
The human coagulation system continuously generates very small quantities of Factor Xa and thrombin. Current evidence suggests that basal level activation of the hemostatic mechanism occurs via Factor VIIa-dependent activation of Factor X, but direct proof has not been available for the participation of tissue factor in this pathway. To examine this issue, we infused relatively high concentrations of recombinant Factor VIIa (approximately 50 micrograms/kg body wt) into normal chimpanzees and observed significant increases in the plasma levels of Factor IX activation peptide, Factor X activation peptide, and prothrombin activation fragment F1+2. Metabolic turnover studies with radiolabeled Factor IX activation peptide, Factor X activation peptide, and F1+2 indicate that elevated levels of the activation peptides are due to accelerated conversion of the three coagulation system zymogens into serine proteases. The administration of a potent monoclonal antibody to tissue factor, which immediately neutralizes function of the Factor VIIa-tissue factor complex in vitro, abolishes the activation of Factor X and prothrombin mediated by the infused recombinant protein, and also suppresses basal level activation of Factor IX and Factor X. The above results suggest that recombinant Factor VIIa functions as a prohemostatic agent by interacting with endogenous tissue factor sites, but definitive proof will require studies in hemophilic animals using relevant hemostatic endpoints.
Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands.
H
H
ten Cate
K A
KA
Bauer
M
M
Levi
T S
TS
Edgington
R D
RD
Sublett
S
S
Barzegar
B L
BL
Kass
R D
RD
Rosenberg
D000818:Animals; D001777:Blood Coagulation; D004789:Enzyme Activation; D005164:Factor IX / Q000378:metabolism; D015942:Factor VIIa / Q000378:metabolism*; D005170:Factor X / Q000378:metabolism*; D008297:Male; D002679:Pan troglodytes; D011516:Prothrombin / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism*
D011516:Prothrombin; D005164:Factor IX; D005170:Factor X; D013925:Thromboplastin; D015942:Factor VIIa