Clinical phenotype in genetically confirmed von Willebrand disease type 2N patients reflects a haemophilia A phenotype

Meegeren, M.E.R. van; Mancini, Tiziano; Schoormans, S.C.M.; Haren, B. J. T. van; Duren, C. van; Diekstra, Adinda; Gorkom, Britta A P Laros-van; Brons, Paul; Simons, Annet; Hoefsloot, Lies H.

doi:10.1111/hae.12733

Cited by 16 publications

(22 citation statements)

References 26 publications

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“…6 The similarity between the 2 phenotypes can lead to type 2N VWD being confused with HA. 7 The finding of reduced FVIII levels without further investigations on VWF levels and functions was indeed what caused a misdiagnosis in the reported VWD family. The proband was a 20-year-old male from abroad, diagnosed with HA in his home land at an earlier age, based on his reduced FVIII levels alone.…”

Section: Type 3 Von Willebrand Disease Mistaken For Moderate Haemophimentioning

confidence: 92%

“…The proband was found to carry 2 heterozygous mutations in the VWF gene: the c.5557C>T null mutation, which generates a premature stop codon at position 1853 of the VWF protein (p.R1853*), 8 We also measure VWF:FVIIIB to rule out type 2N VWD, which has a phenotype partially overlapping that of HA. 7 The value of measuring VWF:Ag in bleeding patients is reinforced by the chances of identifying combined FVIII and VWF quantitative defects, 13 or FVIII gene defects combined with a type 2N VWF mutation. 14 This report highlights the importance of investigating VWF as part of the diagnostic work-up for a suspected case of HA to rule out type 3 VWD or reveal any combined quantitative or functional VWF defects, not only for the sake of a precise characterization, but also and more importantly to ensure proper treatment.…”

Section: Type 3 Von Willebrand Disease Mistaken For Moderate Haemophimentioning

confidence: 99%

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Type 3 von Willebrand disease mistaken for moderate haemophilia A: a lesson still to be learned

et al. 2018

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Section: Type 3 Von Willebrand Disease Mistaken For Moderate Haemophimentioning

confidence: 92%

Section: Type 3 Von Willebrand Disease Mistaken For Moderate Haemophimentioning

confidence: 99%

Type 3 von Willebrand disease mistaken for moderate haemophilia A: a lesson still to be learned

et al. 2018

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Section: Type 2n Vwdmentioning

confidence: 99%

“…36 Typically, FVIII:C levels mimic those seen in mild haemophilia A (range 5–40 IU/dL), whilst VWF:Ag levels are normal or mildly reduced. 36 Inheritance is recessive; at least one of the two mutations affects VWF:FVIIIB. The second mutation can be a further copy of the same missense mutation, a different VWF:FVIIIB missense mutation or commonly a null allele (nonsense, splice-site, deletion/insertion).…”

Section: Type 2n Vwdmentioning

confidence: 99%

Diagnosing von Willebrand disease: genetic analysis

Goodeve

2016

Hematology

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Investigation of a patient with possible von Willebrand disease includes a range of phenotypic analyses. Often, this is sufficient to discern disease type, and this will suggest relevant treatment. However, for some patients, phenotypic analysis does not sufficiently explain the patient’s disorder and for this group, genetic analysis can aid diagnosis of disease type. PCR and Sanger sequencing have been mainstays of genetic analysis for several years. More recently, next generation sequencing has become available, with the advantage that several genes can be simultaneously analysed where necessary, e.g. for discrimination of possible type 2N von Willebrand disease or mild haemophilia A. Additionally, several techniques can now identify deletions/duplications of an exon or more that result in von Willebrand disease including multiplex ligation-dependent probe amplification and micro-array analysis. Algorithms based on next generation sequencing data can also identify missing or duplicated regions. These newer techniques enable causative VWF defects to be identified in more patients than previously, aiding a specific VWD diagnosis. Genetic analysis can also be helpful in the discrimination between type 2B and platelet-type von Willebrand disease and in prenatal diagnosis for families with type 3.

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“…Type 2N VWD is characterized by VWF:Ag levels in the normal to low range, with plasma FVIII levels between 5% and 30% as a consequence of missense VWF variants resulting in impaired binding of VWF to FVIII . Type 2N VWD patients have a bleeding phenotype that presents in a manner similar to mild to moderate hemophilia A in association with trauma, the postpartum period, occasional hemarthrosis and muscle hematomas . Type 2N VWD is an autosomal recessive condition with missense variants that are predominantly localized to the D'D3 (FVIII‐binding) region of VWF.…”

Section: Introductionmentioning

confidence: 99%

Abnormal von Willebrand factor secretion, factor VIII stabilization and thrombus dynamics in type 2N von Willebrand disease mice

Swystun

Georgescu

Mewburn

et al. 2017

Journal of Thrombosis and Haemostasis

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Background von Willebrand factor (VWF) and factor VIII (FVIII) circulate as a non-covalent complex, with VWF serving as the carrier for FVIII. VWF indirectly influences secondary hemostasis by stabilizing FVIII and transporting it to the site of primary hemostasis. Type 2N von Willebrand disease involves impaired binding of VWF to FVIII, resulting in decreased plasma levels of FVIII. Objectives In these studies, we characterize the impact of three type 2N VWD variants (R763A, R854Q, R816W) on VWF secretion, FVIII stabilization and thrombus formation in a murine model. Methods Type 2N VWD mice were generated by hydrodynamic injections of mutant murine VWF cDNAs and the influence of these variants on VWF secretion and FVIII binding was evaluated. In vivo hemostasis and the dynamics of thrombus formation and embolization were assessed using a murine tail vein transection hemostasis model and an intravital thrombosis model in the cremaster arterioles. Results Type 2N VWD variants were associated with decreased VWF secretion using cell and animal-based models. FVIII-binding to type 2N variants was impaired in vitro and was variably stabilized in vivo by expressed or infused 2N variant VWF protein. Both transgenic type 2N VWD and FVIII knockout (KO) mice demonstrated impaired thrombus formation associated with decreased thrombus stability. Conclusions The type 2N VWD phenotype can be recapitulated in a murine model and is associated with both quantitative and qualitative VWF deficiencies and impaired thrombus formation. Patients with type 2N VWD may have normal primary hemostasis formation but decreased thrombus stability related to ineffective secondary hemostasis.

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Clinical phenotype in genetically confirmed von Willebrand disease type 2N patients reflects a haemophilia A phenotype

Cited by 16 publications

References 26 publications

Type 3 von Willebrand disease mistaken for moderate haemophilia A: a lesson still to be learned

Type 3 von Willebrand disease mistaken for moderate haemophilia A: a lesson still to be learned

Diagnosing von Willebrand disease: genetic analysis

Abnormal von Willebrand factor secretion, factor VIII stabilization and thrombus dynamics in type 2N von Willebrand disease mice

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