title: Determinants of plasma factor VIIa levels in humans.
abstract: Several enzymes can activate factor VII in vitro, but the protease responsible for generating factor VIIa in vivo has not been determined. Using recombinant tissue factor that has undergone a COOH-terminal truncation, a sensitive functional assay has been established for measuring plasma factor VIIa levels. To evaluate the mechanism responsible for the generation of factor VIIa in vivo, we measured the levels of this enzyme after administering purified concentrates of factor IX and factor VIII to patients with severe deficiencies of these clotting factors. In patients with hemophilia B, factor VIIa levels were initially reduced to 0.5 +/- 0.1 ng/mL and gradually increased to normal after infusing 100 U/kg of body weight (BW) of factor IX. Despite these increases, there were no significant changes in the generation of factor Xa or thrombin. In patients with hemophilia A, only a slight reduction in factor VIIa levels (2.5 +/- 1.3 ng/mL) was observed as compared with controls (3.3 +/- 1.1 ng/mL) and no significant changes were observed after factor VIII levels were normalized. The administration of recombinant factor VIIa (10 micrograms/kg BW) to patients with factor VII deficiency increased the mean circulating level of the enzyme to 118 ng/mL, but this only resulted in normalization of the levels of the activation peptides of factor IX and factor X. The above data indicate that factor IXa is primarily responsible for the basal levels of free factor VIIa generated in vivo (ie, in the absence of thrombosis or provocative stimuli) and that changes in the plasma concentrations of free factor VIIa in the blood do not necessarily lead to alterations in the extent of factor X activation.
authors.affiliation: Department of Medicine, Brockton-West Roxbury Department of Veterans Affairs Medical Center, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Eichinger
authors.forename: P M
authors.initials: PM
authors.lastname: Mannucci
authors.forename: F
authors.initials: F
authors.lastname: Tradati
authors.forename: A A
authors.initials: AA
authors.lastname: Arbini
authors.forename: R D
authors.initials: RD
authors.lastname: Rosenberg
authors.forename: K A
authors.initials: KA
authors.lastname: Bauer
mesh_terms: D000293:Adolescent; D000328:Adult; D004789:Enzyme Activation; D005164:Factor IX / Q000494:pharmacology / Q000627:therapeutic use; D015949:Factor IXa / Q000502:physiology*; D005169:Factor VIII / Q000494:pharmacology / Q000627:therapeutic use; D015942:Factor VIIa / Q000032:analysis / Q000096:biosynthesis* / Q000627:therapeutic use; D015951:Factor Xa / Q000378:metabolism; D006467:Hemophilia A / Q000378:metabolism / Q000628:therapy; D002836:Hemophilia B / Q000378:metabolism / Q000628:therapy; D006801:Humans; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000494:pharmacology
chemical_list: D011994:Recombinant Proteins; D005169:Factor VIII; D005164:Factor IX; D013925:Thromboplastin; D015942:Factor VIIa; D015949:Factor IXa; D013917:Thrombin; D015951:Factor Xa