To identify and characterize a case of coexisting von Willebrand disease (VWD) and hemophilia A, and elucidate the underlying genetic mutations and molecular mechanisms. Coagulation function, VWF activity (VWF:Act), and VWF antigen (VWF:Ag) were measured using a fully automatic coagulometer. FVIII recovery rate and half-life were assessed with PKSolver, and FVIII inhibitors were detected using the Bethesda assay. VWF multimer analysis was performed to clarify the clinical phenotype. Genetic analysis included next-generation sequencing of the VWF gene and multiplex ligation-dependent probe amplification (MLPA) for F8 gene inversions. Bioinformatics tools (ClustalX-2.1, SWISS-MODEL, PyMOL) were used to analyze mutation conservation and impact on protein structure. Laboratory findings revealed severe hemophilia A (FVIII:C 0.5%) and mild type-1 VWD. FVIII recovery was 67.5% with a 4.9 h half-life, and no inhibitors were detected. Genotyping revealed F8 intron 22 inversion, two VWF gene conversion variants (p.V1229G; p.N1231T) inherited maternally, and a paternal missense variant (p.R2118W). In-silico analysis showed loss of the Gly1229-Thr1231 hydrogen bond destabilizing the D'D3 domain, whereas p.R2118W preserved hydrogen bonding in the D4 domain, supporting mild structural impact. We confirmed a case of severe hemophilia A coexisting with type 1 VWD, characterized by VWF gene conversion variants (p.V1229G and p.N1231T) and a heterozygous missense mutation p.R2118W, along with an intron 22 inversion in the F8 gene. These gene conversion variants are rarely reported in China. These findings provide insights into the molecular pathogenesis of combined VWD and hemophilia A.
Wei et al. (Mon,) studied this question.