Genotypic and phenotypic features of Japanese patients with mild to moderate hemophilia A

Abstract

Hemophilia A is the most common inherited bleeding disorder. To better understand the genotypic and phenotypic features of Japanese patients with mild to moderate hemophilia A, we studied 29 unrelated patients with more than 1 % FVIII activity (FVIII:C). Differences were observed in nine of 21 patients in measured FVIII:C levels between the one-stage clotting and chromogenic assays. We identified a mutation in F8 in 28 of the 29 patients. Mutations in two amino acids, Y492 and R550, were detected at a much higher frequency in our patients than in the international hemophilia A mutation database. We demonstrated that all five patients with the Y492C mutation have an identical F8 haplotype that is unique to them, suggesting that the mutation may have originated from a common ancestor. Because non-severe, moderate to mild, hemophilia patients have a longer lifespan, mutations that cause non-severe phenotypes tend to persist in the population. We believe that the Y492C mutation is a distinctive feature of Japanese patients with mild hemophilia A. The identification of a high frequency of R550 mutation that underlies the discrepancies in FVIII:C measurements in the present study suggests that Japanese patients with mild hemophilia may require careful characterization.

Impact of variation in reagent combinations for one‐stage clotting assay on assay discrepancy in nonsevere haemophilia A

“…Twenty‐five of the patients were categorized as the "nondiscrepant group" in the absence of FVIII assay discrepancy in the detected variants. Five of the patients were found to carry variants known to be associated with FVIII assay discrepancy, namely p.Ser308Leu (n = 2), 5,19 p.Gly498Arg, 22 p.Arg550Cys 5,19 and p.Trp707Leu, 14 and were categorized as the "discrepant group." All five individuals in the discrepant group showed "standard" discrepancy (FVIII:C 1st > FVIII:C Chr ), but not "inverse" discrepancy 23 (FVIII:C Chr > FVIII:C 1st ).…”

“…Each of these cut‐offs was suggested using a different single reagent combination for OSA, indicating that the variability in cut‐offs could be due to differences especially in the OSA reagents used for FVIII:C measurements. Indeed, obvious differences between activated partial thromboplastin time (APTT) reagents in OSA tests have been previously reported 14 …”