VWF – Type 2B von Willebrand Disease

Type 2B von Willebrand disease (VWD) is an autosomal dominant bleeding disorder caused by gain-of-function variants in the von Willebrand factor (Gene Symbol) that enhance binding to platelet glycoprotein Ib, leading to selective loss of high molecular weight multimers and thrombocytopenia (PMID:2010538).

Genetic heterogeneity is marked by numerous missense substitutions clustering in the A1 domain, particularly within or adjacent to the disulfide loop bounded by Cys-509 and Cys-695 (PMID:2010538). In total, more than 67 genetically confirmed type 2B VWD patients from 38 unrelated families have been reported, consistent with autosomal dominant transmission and full penetrance (PMID:18805962). The recurrent variant c.3916C>T (p.Arg1306Trp) has been identified across diverse populations and is the most prevalent allele in type 2B VWD (PMID:1672694).

Segregation analysis across multiple pedigrees demonstrates concordant genotype–phenotype correlation; affected relatives in 38 families uniformly carry pathogenic VWF missense variants with complete segregation (PMID:18805962). Clinical hallmarks include intermittent thrombocytopenia, mucocutaneous bleeding, and an absence of high molecular weight multimers at baseline or following physiologic stress.

Functional studies using recombinant vWF confirm that type 2B mutations exhibit spontaneous and low-ristocetin–induced binding to GPIb, resulting in platelet agglutination and multimer clearance (PMID:9108394). The Arg543Trp and Arg545Cys mutant proteins recapitulate the gain-of-function phenotype in flow-based adhesion assays.

A murine knockin model of the p.Val1316Met mutation reproduces severe macrothrombocytopenia and reveals megakaryocyte actin disorganization driven by RhoA/LIMK/cofilin activation. Inhibition of this pathway restores normal proplatelet formation and platelet counts, underscoring a pathogenic mechanism and potential therapeutic target (PMID:27734030).

Occasional discordant presentations, such as an IIA-like multimer pattern with an underlying type 2B genotype, highlight the necessity of molecular testing for accurate subtype classification and management (PMID:8298143).

Integration of extensive segregation data, robust recombinant protein studies, and an in vivo model support a definitive gene–disease association. Genetic testing for VWF variants, especially c.3916C>T (p.Arg1306Trp), is essential for diagnosis, bleeding risk stratification, and personalized therapy in type 2B VWD.

References

• The Journal of clinical investigation • 1991 • The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain. PMID:1672694
• Blood • 2009 • Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. PMID:18805962
• The Journal of clinical investigation • 1991 • Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. PMID:2010538
• Blood • 1997 • Functional studies on platelet adhesion with recombinant von Willebrand factor type 2B mutants R543Q and R543W under conditions of flow. PMID:9108394
• JCI insight • 2016 • LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B. PMID:27734030
• Blood • 1994 • Discrepancy between IIA phenotype and IIB genotype in a patient with a variant of von Willebrand disease. PMID:8298143

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