Von Willebrand disease mutation spectrum and associated mutation mechanisms

Jong, Annika de; Eikenboom, Jeroen

doi:10.1016/j.thromres.2017.09.025

Cited by 55 publications

(102 citation statements)

References 113 publications

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“…Mutation analysis has now been performed in most patients in the WiN Study. Many VWF variants in our study have been linked to multiple VWD (sub)types, and were consequently excluded from subtype analysis . An insufficient number of patients in our study had a mutation consistently linked to type 1 or 2M VWD.…”

Section: Discussionmentioning

confidence: 96%

Clinically relevant differences between assays for von Willebrand factor activity

Boender

Eikenboom

Bom

et al. 2018

Journal of Thrombosis and Haemostasis

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It is unclear whether there are differences between von Willebrand factor (VWF) activity assays. We compared the four most used VWF activity assays in 661 von Willebrand disease (VWD) patients. All assays correlated excellently, but a discrepant classification was seen in 20% of patients. Differences between VWF activity assays have a large impact on the classification of VWD. Summary BackgroundMeasuring the ability of von Willebrand factor (VWF) to bind to platelets is crucial for the diagnosis and classification of von Willebrand disease (VWD). Several assays that measure this VWF activity using different principles are available, but the clinical relevance of different assay principles is unclear. ObjectiveTo compare the four most widely used VWF activity assays in a large VWD patient population. MethodsWe measured VWF:RCo (ristocetin to activate VWF + whole platelets), VWF:GPIbR (ristocetin + platelet glycoprotein Ib receptor [GPIb] fragments), VWF:GPIbM (gain‐of‐function GPIb fragments that bind VWF spontaneously without ristocetin) and VWF:Ab (monoclonal antibody directed against the GPIb binding epitope of VWF to mimic platelets) in 661 VWD patients from the nationwide ‘Willebrand in the Netherlands’ (WiN) Study. ResultsAll assays correlated excellently (Pearson r > 0.9), but discrepant results led to a different classification for up to one‐fifth of VWD patients. VWF:RCo was not sensitive enough to classify 18% of patients and misclassified half of genotypic 2B VWD patients, especially those with p.Arg1306Trp. VWF:GPIbR was more sensitive, accurately classified the vast majority of patients, and was unaffected by the p.Asp1472His variant that causes artificially low VWF:RCo. VWF:GPIbM was the most precise assay but misclassified over a quarter of genotypic 2A, 2B and 3 patients. VWF:Ab, often not considered an actual VWF activity assay, performed at least equally to the other assays with regard to accurate VWD classification. ConclusionAlthough the different VWF activity assays are often considered similar, differences between assays have a large impact on the classification of VWD.

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Section: Discussionmentioning

confidence: 96%

Clinically relevant differences between assays for von Willebrand factor activity

Boender

Eikenboom

Bom

et al. 2018

Journal of Thrombosis and Haemostasis

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“…Deficiency or functional defects may be because of reduced or defective synthesis or accelerated degradation of VWF within the bloodstream. 15 VWF is a large plasmatic glycoprotein (GP), which presents as a series of polymers known as VWF multimers, consisting of a variable number of subunits. Each VWF multimer subunit has binding sites for its platelet receptors (GPIb on nonactivated platelets, GPIIb/IIIa on activated platelets).…”

Section: Characterization Of Von Willebrand Diseasementioning

confidence: 99%

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Žolková

Sokol

Šimurda

et al. 2019

Semin Thromb Hemost

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Sequencing of the gene encoding for von Willebrand factor (VWF) has brought new insight into the physiology of VWF as well as its pathophysiology in the context of von Willebrand disease (VWD). Molecular testing in VWD patients has shown high variability in the overall genetic background of this condition. Almost 600 mutations and many disease-causing mechanisms have been described in the 35 years since the VWF gene was identified. Genetic testing in VWD patients is now available in many centers as a part of the VWD diagnostic algorithm. Molecular mechanisms leading to types 2 and 3 VWD are well characterized; thus, information from genetic analysis in these VWD types may be beneficial for their correct classification. However, the molecular basis of type 1 VWD is still not fully elucidated and most likely represents a multifactorial disorder reflecting a combined impact of environmental and genetic factors within and outside of VWF. Regarding sequencing methods, the previous gold-standard Sanger sequencing is gradually being replaced with next-generation sequencing methods that are more cost- and time-effective. Instead of gene-by-gene approaches, gene panels of genes for coagulation factors and related proteins have recently become a center of attention in patients with inherited bleeding disorders, especially because a high proportion of VWD patients, mainly those with low VWF plasma levels (type 1), appear to be free of mutations in VWF. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are accessible in a very limited number of laboratories. Results from these studies have presented several genes other than VWF or ABO possibly affecting VWF levels, and such findings will need further validation studies.

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“…Below is a side view of the MUC2 polymer. (E) Conserved amino acids near the MUC2 dimer interface are mutated in VWF disease.Side chain atoms of disease mutation positions(de Jong and Eikenboom, 2017) and the C1130 disulfide are shown as spheres. Amino acid numbering of corresponding residues in MUC2 and VWF are indicated, and VWF disease mutations in this region are listed.…”

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confidence: 99%

Assembly Mechanism of Mucin and von Willebrand Factor Polymers

Javitt

Khmelnitsky

Albert

et al. 2020

Preprint

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The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by inflammation and trauma. Mucin glycoproteins and the related von Willebrand factor (VWF) guard the vulnerable cell layers in these diverse systems. Colon mucins additionally house and feed the gut microbiome. Here we present an integrated structural analysis of multimerized intestinal mucin MUC2. Our findings reveal the shared mechanism by which complex macromolecules responsible for blood clotting, mucociliary clearance, and the intestinal mucosal barrier form protective polymers and hydrogels. Specifically, cryoelectron microscopy and crystal structures show how disulfide-rich bridges and pH-tunable interfaces control successive assembly steps in the endoplasmic reticulum and Golgi.Remarkably, a densely O-glycosylated mucin domain performs a specific organizational role in MUC2. The mucin assembly mechanism and its adaptation for hemostasis provide the foundation for rational manipulation of barrier function and coagulation.

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Von Willebrand disease mutation spectrum and associated mutation mechanisms

Cited by 55 publications

References 113 publications

Clinically relevant differences between assays for von Willebrand factor activity

Clinically relevant differences between assays for von Willebrand factor activity

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Assembly Mechanism of Mucin and von Willebrand Factor Polymers

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