Genetic determinants of clinical variability in type 2 von Willebrand disease: bridging genotype and phenotype

The clinical and genetic features of type 2 von Willebrand disease (VWD) have been described, but genotype-phenotype correlations in large cohorts remain incompletely understood. We investigated the relationship between von Willebrand factor gene (VWF) variants and bleeding severity in a large, well-characterized cohort of type 2 VWD patients, aiming to identify genetic determinants underlying clinical variability. Comprehensive laboratory evaluation, VWF molecular testing, in silico analyses, and bleeding assessment using the ISTH bleeding assessment tool (ISTH-BAT) were performed. Among 371 genetically confirmed cases, ISTH-BAT scores were available for 274 individuals: 83 with type 2A, 69 with 2B, 106 with 2M, and 16 with 2N. The highest bleeding scores were observed in type 2A (median 7), followed by 2B (5), 2M (4), and 2N (4). A total of 67 distinct VWF variants were identified. Notably, we observed substantial variability in bleeding severity both across different variants causing the same VWD phenotypes and among individuals carrying the same VWF variant. ISTH-BAT scores were significantly higher in females than in males, and in adults compared to children. Among adults, but not children, bleeding scores differed significantly between some subtypes. No significant differences were observed between patients with blood group O and non-O. While certain mucocutaneous bleeding symptoms such as menorrhagia, cutaneous, and epistaxis were commonly observed across all type 2 subtypes, our data highlight important subtype-specific differences in bleeding phenotype profiles. This study provides one of the largest genotype-phenotype datasets in type 2 VWD, revealing marked variability in bleeding severity both across type 2 VWD subtypes and among patients with the same genetic variants.