title: Plasma elimination kinetics for factor VII are independent of its activation to factor VIIa and complex formation with plasma inhibitors.
abstract: The mechanism for the elimination of factor VII (FVII) from the circulation is unknown, just as it is unclear how activation of FVII to FVIIa and subsequent complex formation with antithrombin III (AT) or alpha2-macroglobulin (alpha2M) affects clearance. The possibility that the clearance mechanism involves activation and inhibitor complex formation as obligatory intermediate reactions is examined in this study. Human and murine sera were spiked with human FVIIa in the absence and presence of heparin and analysed for complex formation. Complex formation in vivo was studied after intravenous injection of (125)I-VIIa in mice; and the pharmacokinetics (PK) of human and murine FVIIa was studied in normal mice. Furthermore, comparative PK studies were performed with FVII, FVIIa, active site blocked FVIIa and a preformed FVIIa-AT complex in normal and alpha2M-deficient mice. The data demonstrated that FVIIa-AT complexes and to a much lesser extent FVIIa-alpha2M-complexes accumulated in vivo after FVIIa administration. FVIIa-AT accounted for about 50% of total FVIIa antigen left in the circulation after 3 hours. All FVII derivatives studied including FVII, FVIIa and FVIIa-AT were cleared with similar rates suggesting an elimination kinetics which is unaffected by FVII activation and subsequent inactivation by plasma inhibitors.
authors.affiliation: Haemostasis Biology, Health Care Discovery, Novo Nordisk, Maalov, Denmark. LCP@novonordisk.com
authors.forename: Lars C
authors.initials: LC
authors.lastname: Petersen
authors.forename: Torben
authors.initials: T
authors.lastname: Elm
authors.forename: Mirella
authors.initials: M
authors.lastname: Ezban
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Krogh
authors.forename: Ditte M
authors.initials: DM
authors.lastname: Karpf
authors.forename: Anne
authors.initials: A
authors.lastname: Steinø
authors.forename: Eva H N
authors.initials: EH
authors.lastname: Olsen
authors.forename: Brit B
authors.initials: BB
authors.lastname: Sørensen
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000378:metabolism*; D005167:Factor VII / Q000493:pharmacokinetics*; D015942:Factor VIIa / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006493:Heparin / Q000097:blood; D006801:Humans; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012712:Serum Globulins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D007457:Iodine Radioisotopes; D012712:Serum Globulins; D000511:alpha-Macroglobulins; C044177:murinoglobulin; D000990:Antithrombin III; D005167:Factor VII; D006493:Heparin; D015942:Factor VIIa