title: Kinetics of factor IX activity differ from that of factor IX antigen in patients with haemophilia B receiving high-purity factor IX replacement.
abstract: Pharmacokinetic studies in haemophilia B have found in vivo recovery of FIX (FIX) to be uniformly lower than the factor VIII recovery in haemophilia A. We hypothesized that this lower recovery could result from rapid binding to high-affinity receptors on platelets and endothelium. To test this hypothesis, we evaluated the kinetics of FIX activity and protein in haemophilia B patients. Twelve patients were enrolled in a double dosing, crossover study with two high-purity FIX concentrates, AlphaNine SD and MonoNine. Subjects were given 40 U kg-1 of FIX concentrate and blood samples were taken at 15, 30, and 60 min. A second infusion of 40 U kg-1 was given after the 60 min blood sample and further blood samples removed at 15, 60, 120, and 360 min after the second dose. Patients were infused with the alternate concentrate at least 7 days later. Plasma samples were assayed for FIX activity by coagulation assay and antigen by RIA. FIX antigen in the infused concentrates was measured and quantified as microg U-1. There was no difference between the two FIX concentrates (AlphaNine vs. MonoNine) in the initial (15 min) activity (57% +/-1 19% vs. 53% +/-1 12%) and antigen (62% +/-1 16% vs. 55% +/-1 19%) recoveries. Recoveries after the second FIX dose were not statistically different than those observed after the first FIX dose. In one patient, a doubling of the initial infusion dose did not increase FIX recovery after the second FIX dose. However, the recovery of FIX antigen was significantly greater than the recovery of FIX activity and the differences became more significant in the post-15 min samples. We calculated a ratio of plasma FIX antigen to FIX activity in microg U-1. Average antigen to activity ratio increased from 5.8 +/-1 1.9 microg U-1 at 15 min to 7.1 +/-1 2.2 microg U-1 at 60 min. At 420 min the ratio increased to 9.3 +/-1 2.4 microg U-1. Although these studies failed to demonstrate a significant FIX receptor pool, they did demonstrate a phenomenon of progressive loss of biologic activity of the FIX protein after infusion of FIX concentrates.
authors.affiliation: Division of Hematology, Department of Medicine, University of Southern California School of Medicine, Los Angeles, California, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Liebman
authors.forename: T
authors.initials: T
authors.lastname: Rosenwald-Zuckerman
authors.forename: A
authors.initials: A
authors.lastname: Retzios
authors.forename: S
authors.initials: S
authors.lastname: Yasmin
authors.forename: C K
authors.initials: CK
authors.lastname: Kasper
mesh_terms: D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D018592:Cross-Over Studies; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D005164:Factor IX / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D002836:Hemophilia B / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007262:Infusions, Intravenous; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: D000939:Epitopes; D011956:Receptors, Cell Surface; C052276:factor IX-IXa receptor; D005164:Factor IX