title: Parameters influencing FVIII pharmacokinetics in patients with severe and moderate haemophilia A.
abstract: In haemophilia A patients factor VIII (FVIII) recovery and half-life can vary substantially. There are parameters known to modulate FVIII pharmacokinetics (PK), but they explain only about 34% of the variability. The aim of this study was to identify new parameters that influence FVIII PK and thus to expand the current knowledge. FVIII PK were determined in 42 haemophilia A patients (37 severe, 5 moderate) without inhibitor. Patients' characteristics and laboratory parameters were evaluated for an association with FVIII PK. We analysed plasma levels of low-density lipoprotein receptor-related protein 1 (LRP1) and protein C (PC) activity, which had been hypothesized to influence FVIII activity. Furthermore, four variations in intron 6 of the LRP1 gene, which had been shown to influence LRP1, were investigated. FVIII half-life differed widely from 6.2 to 20.7 h, with a median of 10.0 h. Patients with blood group O had shorter FVIII half-life compared to patients with non-O blood group (median FVIII half-life 9.0 h vs. 10.4 h, P = 0.018). Age was significantly associated with FVIII half-life (r = 0.32, P = 0.035). Besides age, also VWF antigen (r = 0.52, P < 0.001) and blood group (r = -0.37, P = 0.015) was associated with FVIII half-life. No correlation was found with FVIII- or LRP1-genotype, LRP1 or PC concentrations. Our data showed large differences in FVIII PK between individual patients and revealed age, blood group and VWF levels as important determining factors for FVIII half-life. FVIII genotype or levels of LRP1 or PC had no influence on FVIII PK.
authors.affiliation: Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Kepa
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Horvath
authors.affiliation: Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Reitter-Pfoertner
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Schemper
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Quehenberger
authors.affiliation: Division of Haematology and Oncology, Department of Internal Medicine III, Medical University of Salzburg, Salzburg, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Grundbichler
authors.affiliation: Department of Internal Medicine I, Clinical Centre of Klagenfurt am Woerthersee, Klagenfurt am Woerthersee, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Heistinger
authors.affiliation: Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Neumeister
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Mannhalter
authors.affiliation: Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Pabinger
mesh_terms: D000017:ABO Blood-Group System; D000328:Adult; D000367:Age Factors; D001777:Blood Coagulation; D015992:Body Mass Index; D005169:Factor VIII / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult; D014841:von Willebrand Factor
chemical_list: D000017:ABO Blood-Group System; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005169:Factor VIII
keywords: Haemophilia A; LRP1; LRP1 polymorphisms; Protein C; influences on FVIII pharmacokinetics