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Type 2 von Willebrand disease (VWD2) is an autosomal dominant bleeding disorder caused by qualitative defects in von Willebrand factor (VWF) that impair multimerization and platelet glycoprotein Ib binding. Clinically, VWD2 presents with mucocutaneous bleeding including epistaxis, gingival bleeding, easy bruising, menorrhagia and miscarriage, often with absent high-molecular-weight multimers.
The VWF–VWD2 association is Definitive: over 300 probands across >148 unrelated families have been reported, with robust segregation in multiplex pedigrees and concordant functional data spanning >25 years. Extensive in vitro and cellular studies have confirmed domain‐specific defects in multimer formation and receptor binding.
Inheritance is Autosomal dominant. Segregation analysis includes at least 47 affected relatives in family studies (e.g., candidate haplotype pedigrees)(PMID:16409463). Case series encompass 150 French index cases of type 2 VWD (PMID:9198195) and cohorts of 321 Italian patients (PMID:35452508). The variant spectrum is dominated by missense changes clustering in A1–A2 domains, with >80 distinct alleles, including recurrent founder and de novo events. A representative variant is c.3814T>C (p.Cys1272Arg).
Pathogenic mechanisms include impaired multimerization (type 2A) and gain-of-function platelet binding (type 2B). Recombinant expression in COS cells of A2-domain mutants (e.g., Lys875Glu) demonstrates defective HMW multimer secretion, while A1-loop substitutions (e.g., Arg543Trp) confer spontaneous high-affinity GPIb binding. Animal models and rescue of multimer profiles with wild-type vWF corroborate these mechanisms.
Rare reports describe phenotypic–genotypic discrepancies (IIA clinical pattern with IIB mutations), highlighting complexity in subtype classification but not disputing the core VWF–VWD2 link.
Extensive genetic and functional data unify VWF domain mutations with VWD2 phenotypes, enabling molecular subclassification (2A–2M) and guiding therapeutic choices such as desmopressin responsiveness and concentrate selection. Genetic testing of exon 28 hotspots supports diagnostic confirmation and family screening.
Key Take-home: Molecular analysis of VWF provides definitive diagnosis and informs personalized management of type 2 VWD.
Gene–Disease AssociationDefinitiveOver 300 probands from >148 unrelated families, robust segregation and concordant functional studies over >25 years Genetic EvidenceStrong
Functional EvidenceStrongMultiple recombinant vWF assays demonstrate domain-specific loss or gain of function consistent with human phenotypes |