title: 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.
abstract: 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.
authors.affiliation: Department of Pathology, Durham Veterans Affairs Medical Center, NC 27705.
authors.forename: M
authors.initials: M
authors.lastname: Hoffman
authors.forename: D M
authors.initials: DM
authors.lastname: Monroe
authors.forename: H R
authors.initials: HR
authors.lastname: Roberts
mesh_terms: 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*
chemical_list: D005170:Factor X; D013925:Thromboplastin; D015942:Factor VIIa