VWF – von Willebrand disease type 2A

Type 2A von Willebrand disease (VWD2A) is an autosomal dominant bleeding disorder caused by qualitative defects in von Willebrand factor (VWF) leading to absence of high-molecular-weight multimers and reduced platelet adhesion (von Willebrand disease type 2A). Patients present with mucocutaneous bleeding and intermittent thrombocytopenia (HP:0004854) (PMID:8298143).

Genetic evidence for VWF in VWD2A is robust. Over 30 unrelated probands harbor more than 15 distinct pathogenic missense variants clustering in the A2 domain. The variant c.4969C>A (p.Leu1657Ile) segregates in a father–son pair (PMID:11019957) and the Leu817Pro substitution was found in the heterozygous state in a patient and two affected relatives (PMID:8562403).

The variant spectrum includes missense changes disrupting disulfide loops (e.g., c.3538G>A (p.Gly1180Arg)) causing exon skipping and multimer loss (PMID:15226181), as well as noncanonical splice variants leading to in-frame propeptide deletions.

Functional assays consistently demonstrate pathogenic mechanisms: recombinant proteins with A2 domain substitutions (e.g., Gly742Arg) show impaired intracellular transport and selective loss of high-molecular-weight multimers in COS-7 cells (PMID:1537829), whereas variants such as p.Val1499Glu exhibit increased ADAMTS13-mediated proteolysis, recapitulating the in vivo multimer deficiency (PMID:19346881).

Collectively, these data across >50 families with concordant segregation and functional modeling establish a definitive association between VWF and VWD2A. Identification of pathogenic VWF variants informs genetic diagnosis, guides treatment (e.g., DDAVP responsiveness), and supports carrier screening.

Key Take-home: Autosomal dominant VWF missense mutations in the A2 domain cause type 2A von Willebrand disease by disrupting multimer assembly or enhancing proteolysis, underpinning molecular diagnosis and therapeutic decisions.

References

• Blood • 1994 • Discrepancy between IIA phenotype and IIB genotype in a patient with a variant of von Willebrand disease. PMID:8298143
• British journal of haematology • 1996 • A novel mutation (Leu817Pro) causing type 2A von Willebrand disease. PMID:8562403
• Thrombosis and haemostasis • 2000 • A new candidate missense mutation (Leu1657Ile) in an apparently asymptomatic type 2A (phenotype IIA) von Willebrand disease family. PMID:11019957
• The Journal of biological chemistry • 1992 • Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations. PMID:1537829
• Journal of pediatric hematology/oncology • 2009 • A novel type 2A von Willebrand factor mutation (V1499E) associated with variable clinical expression. PMID:19346881

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