von Willebrand disease: Diagnosis and treatment, treatment of women, and genomic approach to diagnosis

Laffan, Michael; Sathar, Jameela; Johnsen, Jill M.

doi:10.1111/hae.14050

Cited by 26 publications

(21 citation statements)

References 54 publications

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“…VWF represents a high-molecular weight adhesive glycoprotein that plays an essential role in primary haemostasis by promoting platelet adhesion to the subendothelium and platelet plug formation at the sites of vascular injury. VWF has a second role in haemostasis which is to bind FVIII and protect it from premature clearance and degradation [ 20 , 21 , 22 ]. It is known that non-O blood type individuals have higher (approximately 25%) FVIII:C and VWF:Ag than O blood type individuals [ 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Application of Factor VIII:C to VWF:Ag Ratio for the Screening of Haemophilia A Carriers

Yoo

Jung

Choi

et al. 2022

JCM

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Analyses of factor VIII procoagulant activity (FVIII:C) and the FVIII:C to VWF:Ag ratio (FVIII:C/VWF:Ag ratio) have been investigated as screening bioassays to detect haemophilia carriers. This study aimed to determine the validity of the FVIII:C/VWF:Ag ratio and FVIII:C analyses as screening tests. We reviewed the medical records of 137 genetically confirmed, proband haemophilia A patients and 179 of their familial females who had undergone carrier testing. The collected data included the severity and mutation type of F8 gene from probands and age, ABO blood type, FVIII:C, VWF:Ag, and the result of targeted gene analysis in females. We diagnosed 110 females as carriers, and their FVIII:C and FVIII:C/VWF:Ag ratio were lower than those in 69 non-carriers (FVIII:C: 59.3 IU/dL vs. 106.1 IU/dL, p = 0.000; FVIII:C/VWF:Ag ratio: 0.62 vs. 1.08, p = 0.000). In receiver operating characteristic analysis, the areas under the curve (AUC) of the FVIII:C/VWF:Ag ratio and FVIII:C were 0.936 and 0.876, respectively. The cut-off value of FVIII:C/VWF:Ag ratio (0.81) at the maximum Youden J index provided a sensitivity of 82.8% and specificity of 96.6%. The cut-off value of FVIII:C (83.8 IU/dL) showed a sensitivity of 81.8% and specificity of 79.7%. Considering the AUC, the FVIII:C/VWF:Ag ratio is a good screening test to detect haemophilia A carriers, as evidenced by its specificity of 96.6%; however, it may also induce false-negative results.

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Section: Discussionmentioning

confidence: 99%

Clinical Application of Factor VIII:C to VWF:Ag Ratio for the Screening of Haemophilia A Carriers

Yoo

Jung

Choi

et al. 2022

JCM

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“…Finally, with next-generation sequencing it becomes ever easier to obtain genetic testing [38][39][40] ; however, current caveats remain (Table S1). Whilst in experienced hands, genetic testing is greatly valued, in inexperienced hands there is a potential danger to overcall genetic variants as damaging or disease causing when they are not.…”

Section: Discussionmentioning

confidence: 99%

How we diagnose 2M von Willebrand disease (VWD): Use of a strategic algorithmic approach to distinguish 2M VWD from other VWD types

et al. 2020

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Introduction von Willebrand disease (VWD) is the most common inherited bleeding disorder and caused by an absence, deficiency or defect in von Willebrand factor (VWF). VWD is currently classified into six different types: 1, 2A, 2B, 2N, 2M, 3. Notably, 2M VWD is more often misdiagnosed as 2A or type 1 VWD than properly identified as 2M VWD. Aim To describe an algorithmic approach to better ensure appropriate identification of 2M VWD, and reduce its misdiagnosis, as supported by sequential laboratory testing. Methods Comparative assessment of types 1, 2A, 2B and 2M VWD using various laboratory tests, including VWF antigen and several VWF activity assays, plus DDAVP challenge data, ristocetin‐induced platelet agglutination (RIPA) data, multimer analysis and genetic testing. Results Types 1, 2A, 2B and 2M VWD give characteristic test patterns that can provisionally classify patients into particular VWD types. Notably, type 1 VWD shows low levels of VWF, but VWF functional concordance (VWF activity/Ag ratios >0.6), with both baseline assessment and post‐DDAVP. Types 2A, 2B and 2M VWD show VWF functional discordance (low VWF activity/Ag ratio(s)) dependent on the defect, but type 2M separates from 2A/2B VWD based on specific test patterns, especially with collagen binding vs glycoprotein Ib binding assays. RIPA identifies 2B VWD. Multimers separate 2M from 2A/2B. Conclusion We provide strategies to improve correct diagnosis of VWD, especially focussed on 2M VWD, and which can be used by most diagnostic haemostasis laboratories, reserving genetic analysis (if required) for confirmation.

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“…Yet, there seems to be a parallel between the increasing number of female hematologists and the greater recognition of significant VWDassociated morbidities, especially when related to women reproductive health. [13][14][15] The second tool to evaluate disease severity are health-related quality of life (HR-QoL) studies, widely accepted as crucial instruments of patient-centered care. 16 For VWD, a few studies have addressed this issue using either 1) validated HR-QoL questionnaires, 2) questionnaires not officially validated or 3) through interviews.…”

Section: Vwd and Quality Of Lifementioning

confidence: 99%

von Willebrand disease: what does the future hold?

Denis

Sophie

Lenting

2021

Blood

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Von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von Willebrand factor (VWF) concentrates, desmopressin and anti-fibrinolytic agents as main tools to control bleeding. This is in contrast to hemophilia A, for which a continuous innovative path has led to novel treatment modalities. Despite current VWD management being considered effective, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women. Apparently, despite our perceived notion of current therapeutic efficiency, there is space for innovation with the goal to reach superior efficacy. Developing innovative treatments for VWD is complex, especially given the heterogeneity of the disease and the multifunctional nature of VWF. In this perspective article, we describe several potential strategies that could provide the basis for future VWD treatments. These include genetic approaches such as gene therapy using dual-vector adeno-associated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase FVIII levels in VWD-type 3 or 2N patients will be discussed. Finally, antibody-based options to interfere with VWF degradation (for congenital VWD-type 2A or acquired Von Willebrand syndrome-type 2A) or increase endogenous VWF levels (for VWD-type 1) will be presented. By highlighting these potential strategies, we hope to initiate an innovative path, which ultimately would allow us to better serve VWD patients and their specific needs.

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von Willebrand disease: Diagnosis and treatment, treatment of women, and genomic approach to diagnosis

Cited by 26 publications

References 54 publications

Clinical Application of Factor VIII:C to VWF:Ag Ratio for the Screening of Haemophilia A Carriers

Clinical Application of Factor VIII:C to VWF:Ag Ratio for the Screening of Haemophilia A Carriers

How we diagnose 2M von Willebrand disease (VWD): Use of a strategic algorithmic approach to distinguish 2M VWD from other VWD types

von Willebrand disease: what does the future hold?

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