An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease

Grundy, P. M.; Keeney, S.; Lester, William M.; Enayat, Said; Guilliatt, Andrea M.; Bowen, Derrick John; Pasi, John; Keeling, David; Hill, F. G. H.; Bolton‐Maggs, Paula; Hay, C. R. M.; Collins, Peter; Cumming, A. M.

doi:10.1160/th06-07-0383

Cited by 109 publications

(11 citation statements)

References 23 publications

(41 reference statements)

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“…mutation screening of the VWF gene has limited general utility in genetic diagnostic and family studies in Type 1 VWD." 19 This is also seen in Type 3 VWD, where one study found that in approximately 15% of Type 3 VWD patients, two null mutations in the VWF gene were not observed, suggesting other genes may play a role. 20 Taken together, the current state of the literature on VWD type 1 and low-VWF is indicative of a complex disorder with multiple genetic risk factors.…”

Section: Vwd Due To Genetic Variants Outside the Vwf Genementioning

confidence: 90%

“…This figure is even lower in low‐VWF patients, whose VWF levels are more often explained by synthesis/secretion and not overactive clearance 18 . After discovering only half of their Type 1 patients had any variants in the VWF gene, one group concluded that due to incomplete penetrance and variable expressivity “…mutation screening of the VWF gene has limited general utility in genetic diagnostic and family studies in Type 1 VWD.” 19 This is also seen in Type 3 VWD, where one study found that in approximately 15% of Type 3 VWD patients, two null mutations in the VWF gene were not observed, suggesting other genes may play a role 20 …”

Section: The Vwf Genementioning

confidence: 99%

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von Willebrand disease and von Willebrand factor

2022

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Progress in both basic and translational research into the molecular mechanisms of VWD can be seen in multiple fields. Genetics of VWD:In the past several decades, knowledge of the underlying pathogenesis of von Willebrand disease (VWD) has increased tremendously, thanks in no small part to detailed genetic mapping of the von Willebrand Factor (VWF) gene and advances in genetic and bioinformatic technology. However, these advances do not always easily translate into improved management for patients with VWD and low-VWF levels.VWD and pregnancy: For example, the treatment of pregnant women with VWD both pre-and postpartum can be complicated. While knowledge of the VWF genotype at some amino acid positions can aid in knowledge of who may be at increased risk of thrombocytopenia or insufficient increase in VWF levels during pregnancy, in many cases, VWF levels and bleeding severity is highly heterogeneous, making monitoring recommended during pregnancy to optimize treatment strategies. VWF and COVID-19: New challenges related to the consequences of dysregulation of hemostasis continue to be discovered. The ongoing COVID-19 pandemic has highlighted that VWF has additional biological roles in the regulation of inflammatory disorders and angiogenesis, disruption of which may contribute to COVID-19 induced vasculopathy. Increased endothelial cell activation and Weibel-Palade body exocytosis in severe COVID-19 lead to markedly increased plasma VWF levels. Coupled with impairment of normal ADAMTS13 multimer regulation, these data suggest a role for VWF in the pathogenesis underlying pulmonary microvascular angiopathy in severe COVID-19. Conclusion:With the increased affordability and availability of next-generation sequencing techniques, as well as a push towards a multi-omic approach and personalized medicine in human genetics, there is hope that translational research will improve VWD patient outcomes.

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Section: Vwd Due To Genetic Variants Outside the Vwf Genementioning

confidence: 90%

Section: The Vwf Genementioning

confidence: 99%

von Willebrand disease and von Willebrand factor

2022

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“…We found a slightly lower prevalence of VWF gene variants compared to some previous studies, probably because we have excluded synonymous variants and benign variants. 5,10–17 In line with our study, it was previously described in one study that in VWD patients with normal multimers, patients without a VWF gene variant had higher VWF:RCo compared with patients with a VWF gene variant. 5 However, no significant difference in the BS of both groups were found, probably due to the small number of included patients.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, although several previous studies reported that approximately 30% to 45% of type 1 VWD patients do not have a VWF gene variant, no large studies have been performed yet to investigate whether the laboratory and bleeding phenotype of type 1 VWD patients with and without a VWF gene variant are different. 3,5,10–17…”

Section: Introductionmentioning

confidence: 99%

Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype

et al. 2022

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Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management.

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“… 10 Patients with VWF levels below 0.50 IU/mL should receive a diagnosis of type 1 VWD if they present with abnormal bleeding. These guidelines, along with other published data, 11 , 12 , 13 , 14 demonstrate a lack of correlation between bleeding severity and baseline VWF levels. This discrepancy complicates risk stratification of patients with type 1 VWD and often leads to homogeneous therapeutic management, creating potential for both over and under treatment of bleeding symptoms.…”

Section: Introductionmentioning

confidence: 98%

A transcriptome analysis of basal and stimulated VWF release from endothelial cells derived from patients with type 1 VWD

et al. 2023

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Type 1 von Willebrand disease (VWD) is associated with a reduction in qualitatively normal von Willebrand factor (VWF). Current diagnostic guidelines only take into consideration the contribution of basal VWF levels, despite a lack of correlation with bleeding severity. Defects in stimulated VWF release, which occurs following hemostatic challenge, may contribute to bleeding in Type 1 VWD, but the pathogenic mechanisms are poorly defined. In the present study, a layered multiomic approach including mRNA and miRNA sequencing was used to evaluate transcriptome-wide differences between Type 1 VWD- and control-derived endothelial colony forming cells (ECFCs) during basal and stimulated VWF release. ECFCs from eight Type 1 VWD patients and four controls were included in this study. VWF protein analysis revealed heterogenous responses to stimulation amongst Type 1 VWD and control ECFCs. During basal VWF release, 64 mRNAs and 7 miRNAs were differentially regulated between Type 1 VWD and control ECFCs and 65 putatively pathogenic miRNA-mRNA interactions were identified. During stimulated VWF release, 190 mRNAs and five mRNAs were differentially regulated between Type 1 VWD and control ECFCs and 110 putatively pathogenic miRNA-mRNA interactions were identified. Five gene ontology terms including coagulation, regulation of cell shape, and regulation of cell signalling were also differentially regulated in Type 1 VWD ECFCs during stimulated release. We have shown for the first time that transcriptome-wide differences exist between Type 1 VWD and control ECFCs. These differences may contribute to bleeding in Type 1 VWD, and further investigation may reveal novel biomarkers and therapeutic targets.

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An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease

Cited by 109 publications

References 23 publications

von Willebrand disease and von Willebrand factor

von Willebrand disease and von Willebrand factor

Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype

A transcriptome analysis of basal and stimulated VWF release from endothelial cells derived from patients with type 1 VWD

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