title: FVIII-binding IgG modulates FVIII half-life in patients with severe and moderate hemophilia A without inhibitors.
abstract: The substantial variability in pharmacokinetic parameters in hemophilia patients A poses a challenge for optimal treatment with factor VIII (FVIII) products. We investigated the effect of FVIII-specific immunoglobulin G (IgG) on FVIII half-life in a cohort of 42 adult patients with severe and moderate hemophilia A without inhibitors. Fifteen (35.7%) of 42 patients tested positive for FVIII-binding IgG with titers ≥1:20 in the initial antibody screen, 9 of these 15 patients had FVIII-specific antibodies with titers ≥1:40, mostly low-to-moderate-affinity IgG1 and IgG3, and 1 had high-affinity IgG4 and later developed low-titer FVIII inhibitors. His brother with low-to-moderate-affinity IgG1 and IgG3 also later developed low-titer FVIII inhibitors. The presence of FVIII-specific IgG subclass titer ≥1:40 antibodies was significantly associated with shorter FVIII half-life (median, 7.8 hours [interquartile range, 6.6-9.2 hours]) vs 10.4 hours [interquartile range, 8.9-13.8 hours]); the regression coefficient adjusted for log age and log von Willebrand factor (VWF) antigen was -0.32 (P = .004), accounting for 16.9% of the observed variability of FVIII half-life in our cohort. Our data indicate a significant contribution of non-neutralizing FVIII-specific IgG to FVIII half-life reduction in hemophilia A patients. Thus, screening for FVIII-specific IgG could be beneficial in tailoring FVIII prophylactic regimens.
authors.affiliation: Department of Immunology, Research & Innovation, Baxalta, Vienna, Austria;
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Hofbauer
authors.affiliation: Clinical Division of Haematology and Haemostaseology, Department of Medicine I.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kepa
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Schemper
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Quehenberger
authors.affiliation: Clinical Division of Haematology and Haemostaseology, Department of Medicine I.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Reitter-Pfoertner
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
authors.affiliation: Department of Immunology, Research & Innovation, Baxalta, Vienna, Austria;
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Reipert
authors.affiliation: Clinical Division of Haematology and Haemostaseology, Department of Medicine I.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pabinger
mesh_terms: D000328:Adult; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood*; D005169:Factor VIII / Q000008:administration & dosage / Q000493:pharmacokinetics; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D008297:Male
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D007074:Immunoglobulin G; C078147:F8 protein, human; D005169:Factor VIII