title: Prevalence, biological phenotype and genotype in moderate/mild hemophilia A with discrepancy between one-stage and chromogenic factor VIII activity.
abstract: BACKGROUND
  In most laboratories, the severity of hemophilia A is assessed by the factor VIII activity (FVIII:C) one-stage assay. However, comparisons of these results with those of two-stage assays can reveal discrepancies and suggest misdiagnosis.
  
  
  METHODS
  In this monocentric study, we measured FVIII:C with two methods (one-stage chronometric and chromogenic assays) in 307 (173 families) patients with moderate/mild hemophilia A. To compare results, we used a chronometric/chromogenic ratio. Discrepancy was defined as a ratio < 0.5 or > 1.5. We studied their putative involvement at known FVIII functional sites, their interspecies conservation status, and their spatial position within the FVIII structure.
  
  
  RESULTS
  Thirty-six patients from 17 families exhibited a discrepancy between the two assays: 12 (6.9%) families had a low ratio (< 0.5), and five (2.9%) families had a high ratio (> 1.5). Qualitative deficiency was diagnosed in about 16% of the families. Molecular studies were performed in 15 of these 17 families, resulting in each case in the identification of missense mutations, including three novel mutations. We were further able to propose a pathophysiologic explanation.
  
  
  CONCLUSIONS
  In this monocentric study, we have demonstrated a discrepancy between FVIII:C assay results in 10% of families with moderate/mild hemophilia A. The prevalence of 'inverse' discrepancy (i.e. low chronometric/chromogenic ratio) is high as compared with previous reports. We suggest that both FVIII:C assays are recommended in patients with moderate/mild hemophilia A for a complete biological phenotype. This could also improve our knowledge of the FVIII structure-function relationships.
authors.affiliation: Centre Régional de Traitement de l'Hémophilie, CHU Nantes, Nantes, France. marc.trossaert@chu-nantes.fr
authors.forename: M
authors.initials: M
authors.lastname: Trossaërt
authors.forename: P
authors.initials: P
authors.lastname: Boisseau
authors.forename: A
authors.initials: A
authors.lastname: Quemener
authors.forename: M
authors.initials: M
authors.lastname: Sigaud
authors.forename: M
authors.initials: M
authors.lastname: Fouassier
authors.forename: C
authors.initials: C
authors.lastname: Ternisien
authors.forename: A
authors.initials: A
authors.lastname: Lefrançois-Bettembourg
authors.forename: C
authors.initials: C
authors.lastname: Tesson
authors.forename: C
authors.initials: C
authors.lastname: Thomas
authors.forename: S
authors.initials: S
authors.lastname: Bezieau
mesh_terms: D019943:Amino Acid Substitution; D001774:Blood Chemical Analysis / Q000379:methods; D002863:Chromogenic Compounds; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D005169:Factor VIII / Q000032:analysis* / Q000737:chemistry / Q000235:genetics; D005602:France / Q000453:epidemiology; D056726:Genetic Association Studies; D006467:Hemophilia A / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary
chemical_list: D002863:Chromogenic Compounds; D005169:Factor VIII