Human monocytes support factor X activation by factor VIIa, independent of tissue factor: implications for the therapeutic mechanism of high-dose factor VIIa in hemophilia.
High doses of recombinant factor VIIa are useful in managing bleeding in hemophiliacs with inhibitors. Whether this therapeutic effect of factor VIIa is dependent on tissue factor (TF) is a matter of debate. We examined the ability of freshly isolated human monocytes (which lack TF) to support the activation of coagulation-factor X by factor VIIa. The rate of factor-X activation by factor VIIa was accelerated in the presence of monocytes compared with the rate of X activation in solution. This activation of factor X on monocytes was saturable with a K1/2 of about 400 to 600 pmol/L factor VIIa. The rate of activation was not inhibited by an excess of inhibitory anti-TF antibody or a Gla-containing fragment of prothrombin. In contrast to monocytes, an endothelial cell line did not support activation of factor X by factor VIIa. Our findings suggest that at least one cell type can accelerate activation for factor X by factor VIIa in the absence of TF. This activity requires higher concentrations of factor VIIa than does the TF mechanism. The concentrations of VIIa required are of a similar order of magnitude to those required for a therapeutic effect of VIIa in bleeding hemophiliacs with inhibitors.
Hoffman
M
M
Department of Pathology, Durham Veterans Affairs Medical Center, NC 27705.
Monroe
D M
DM
Roberts
H R
HR
D002478:Cells, Cultured; D015942:Factor VIIa / Q000494:pharmacology* / Q000627:therapeutic use; D005170:Factor X / Q000378:metabolism*; D006467:Hemophilia A / Q000628:therapy*; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D013925:Thromboplastin / Q000502:physiology*
D005170:Factor X; D013925:Thromboplastin; D015942:Factor VIIa