VWF – Type 1 von Willebrand Disease

Type 1 von Willebrand disease (VWD1) is a congenital bleeding disorder caused by a quantitative deficiency of von Willebrand factor (VWF), the multimeric glycoprotein essential for platelet adhesion and carrier stabilization of factor VIII (Gene Symbol; Disease Name). Affected individuals typically present with mucocutaneous bleeding, including epistaxis, bruising, and menorrhagia. Laboratory findings include proportionately low VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) with normal multimer distribution. The disorder is most often inherited in an autosomal dominant fashion, although rare recessive forms have been described. Molecular testing of VWF improves diagnostic accuracy beyond phenotypic assays and guides clinical management.

Genetic evidence for a definitive association between VWF and VWD1 includes multiple large cohort and familial studies. Sequencing of 123 Canadian index cases identified causal VWF variants in 63% of patients, contributing to a total of 273 unrelated probands ([PMID:17190853]; [PMID:18315556]). In a cohort of 60 Saudi families, 21 affected relatives segregated rare VWF exon 18 variants with low VWF levels ([PMID:35677804]). Segregation analyses in multiple pedigrees further confirm dominant transmission, with compound heterozygotes demonstrating more severe quantitative defects.

The spectrum of VWF variants in VWD1 is diverse. Over 50 distinct missense mutations have been reported alongside small deletions and promoter alterations. A founder effect for the p.Tyr1584Cys missense variant was observed in 10% of Canadian families, co-segregating with a 5312-19A>C intronic polymorphism ([PMID:12649144]). Promoter mutations such as the 13-bp deletion c.-1522_-1510del13 and splice‐site changes like c.1534-3C>A further contribute to haploinsufficiency. Recurrent in-frame deletions (e.g., p.Lys1408del) and hypomorphic synonymous variants modulate VWF levels, while deep-intronic alterations remain underexplored.

Functional studies corroborate haploinsufficiency as the primary mechanism. The c.-1522_-1510del13 promoter deletion reduces reporter expression by ~50% in endothelial cells (n = 16, P < .001) and by 40% in HepG2 cells, and impairs transgene expression in mouse liver (n = 8, P = .003) ([PMID:20696945]). In vitro expression of D’D3 domain mutants (M771I, Y1146C, T1156M, R782Q) in cell lines demonstrates defective intracellular packaging and markedly reduced VWF secretion ([PMID:27533707]). Recombinant constructs of A1 and D3 domain missense variants recapitulate aberrant FVIII binding and multimer assembly, confirming causality.

Conflicting evidence arises from early screening efforts in 12 unrelated classical VWD1 patients, where SSCP and heteroduplex analyses revealed only known polymorphisms in multimerization domains, and no pathogenic variants were identified ([PMID:10595636]). This highlights the contribution of noncoding modifiers, epigenetic regulation, and ABO blood group effects to the clinical phenotype in mutation-negative cases.

Integration of genetic and experimental data establishes a definitive gene–disease relationship. VWF variants causing reduced transcription, improper folding, or accelerated clearance align with the quantitative defect observed clinically. Molecular testing encompassing known founder alleles, promoter and splice mutations, and next-generation sequencing of VWF coding regions maximizes diagnostic yield. Key Take-home: Comprehensive genotyping of VWF informs precise diagnosis of VWD1, enables risk stratification, and guides personalized therapeutic strategies.

References

• Blood • 2007 • The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. PMID:17190853
• Journal of thrombosis and haemostasis (JTH) • 2008 • Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). PMID:18315556
• Blood • 2003 • Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease. PMID:12649144
• Blood • 2010 • Functional characterization of a 13-bp deletion (c.-1522_-1510del13) in the promoter of the von Willebrand factor gene in type 1 von Willebrand disease. PMID:20696945
• Thrombosis and haemostasis • 1999 • Mutations in von Willebrand factor multimerization domains are not a common cause of classical type 1 von Willebrand disease. PMID:10595636

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