title: Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations.
abstract: Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter-individual variation in factor VIII levels. Intra-individual variation accounted for 45% of the variation in the three largest mutation groups.
  
  
  
  Background The bleeding phenotype in patients with mild/moderate hemophilia A (MHA) is inversely associated with the residual plasma concentration of factor VIII (FVIII:C). Within a group of patients with the same F8 missense mutation, baseline FVIII:C may vary, because, in healthy individuals, von Willebrand factor (VWF) levels, ABO blood group and age are also known to influence baseline FVIII:C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII:C in MHA patients is still limited. Objectives To estimate the variation and determinants of baseline FVIII:C among MHA patients with the same F8 missense mutation. Methods Three hundred and forty-six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHA patients from Europe, Canada, and Australia. Baseline FVIII:C was measured with a one-stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed-model analyses. Results For 59% of patients, the observed variation in baseline FVIII:C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra-individual variation explained 45% of the observed variance in baseline FVIII:C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII:C levels are not exclusively determined by F8 genotype in MHA patients. Insights into other factors may provide potential novel targets for the treatment of MHA.
authors.affiliation: Department of Pediatric Hematology, Emma Children's Hospital, Amsterdam, the Netherlands.
authors.forename: J I
authors.initials: JI
authors.lastname: Loomans
authors.affiliation: Department of Pediatric Hematology, Emma Children's Hospital, Amsterdam, the Netherlands.
authors.forename: A S
authors.initials: AS
authors.lastname: van Velzen
authors.affiliation: Department of Pediatric Hematology, Emma Children's Hospital, Amsterdam, the Netherlands.|Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: C L
authors.initials: CL
authors.lastname: Eckhardt
authors.affiliation: Department of Pediatric Hematology, Emma Children's Hospital, Amsterdam, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Peters
authors.affiliation: Children's Hospital and Hematology, Comprehensive Cancer Center, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Mäkipernaa
authors.affiliation: Coagulation Unit, Hematology Center, Karolinska University Hospital and Department of Medicine Karolinska Inisitutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Holmstrom
authors.affiliation: Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: P P
authors.initials: PP
authors.lastname: Brons
authors.affiliation: Catharina Hospital, Eindhoven, the Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Dors
authors.affiliation: University Hospital la Fe, Valencia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Haya
authors.affiliation: Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory, Amsterdam, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Voorberg
authors.affiliation: Leiden University Hospital, Leiden, the Netherlands.|Sanquin Research, Leiden, the Netherlands.
authors.forename: J G
authors.initials: JG
authors.lastname: van der Bom
authors.affiliation: Department of Pediatric Hematology, Emma Children's Hospital, Amsterdam, the Netherlands.|Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory, Amsterdam, the Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Fijnvandraat
mesh_terms: D000017:ABO Blood-Group System; D000328:Adult; D001777:Blood Coagulation; D003894:Deamino Arginine Vasopressin / Q000737:chemistry; D005169:Factor VIII / Q000032:analysis* / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006467:Hemophilia A / Q000235:genetics* / Q000378:metabolism*; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D020125:Mutation, Missense; D015588:Observer Variation; D010641:Phenotype; D011487:Protein Conformation; D012189:Retrospective Studies; D055815:Young Adult; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D000017:ABO Blood-Group System; D014841:von Willebrand Factor; D005169:Factor VIII; D003894:Deamino Arginine Vasopressin
keywords: 
  FVIII
  ; cohort study; determinants; hemophilia A; mutation