Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States

Flood, Veronica H.; Christopherson, Pamela A.; Gill, Joan Cox; Friedman, Kenneth D.; Haberichter, Sandra L.; Bellissimo, Daniel B.; Udani, Rupa; Dasgupta, Mahua; Hoffmann, Raymond G.; Ragni, Margaret V.; Shapiro, Amy D.; Lusher, Jeanne M.; Lentz, Steven R.; Abshire, Thomas C.; Leissinger, Cindy; Hoots, W. Keith; Manco‐Johnson, Marilyn J.; Gruppo, Ralph A.; Boggio, Lisa; Montgomery, Kate; Goodeve, Anne; James, Paula D.; Lillicrap, David; Peake, I. R.; Montgomery, Robert R.

doi:10.1182/blood-2015-10-673681

Cited by 104 publications

(177 citation statements)

References 44 publications

(50 reference statements)

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“…The study by Lavin et al also provides further insight into the poorly understood pathophysiology of low VWF. A probably damaging VWF gene variant was found in only 40% of patients, a percentage similar to that reported by Flood et al 7 Therefore other factors outside the VWF gene likely play a role. The high FVIII:C to VWF:Ag ratio in this study points toward a defect in VWF production and/or secretion, the exact mechanism for which needs to be investigated.…”

supporting

confidence: 54%

Low VWF: an established mild bleeding disorder?

Leebeek

Boender

2017

Blood

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supporting

confidence: 54%

Low VWF: an established mild bleeding disorder?

Leebeek

Boender

2017

Blood

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“…Patients were derived from the Canadian and Milwaukee type 1 VWD cohorts as previously described (20,73,74). Inclusion criteria included a bleeding diathesis, plasma levels of VWF:Ag between 0.05 and 0.50 U/ml, plasma levels of VWF:RCo ≤ 0.6 U/ml, and normal multimers.…”

Section: Genotypingmentioning

confidence: 99%

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

Swystun¹,

Lai²,

Notley³

et al. 2018

Journal of Clinical Investigation

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variants demonstrated that the STAB2 p.E2377K variant associates with a 33.6% and 26.8% increase in VWF and FVIII levels, respectively (25), suggesting that stabilin-2 is a significant regulator of plasma VWF-FVIII levels. Based on its known function and association with plasma VWF levels, stabilin-2 may act as a clearance receptor for VWF and/or FVIII; however, the mechanistic basis for this relationship has not been assessed.In addition to facilitating protein clearance, binding of VWF-FVIII to endocytic receptors can regulate interactions with cells in the immune system. The development of FVIII neutralizing antibodies (termed inhibitors) in response to infused FVIII replace-STAB2 encodes stabilin-2, a class H scavenger receptor expressed on the sinusoidal endothelial cells of the liver, spleen, and lymphatics that functions as a clearance receptor for hyaluronic acid and other glycosaminoglycans (21-23). Stabilin-2 is composed of repetitive extracellular fasciclin and EGF-like domains with a single X-link domain that is C-type lectin-like, located near its transmembrane region. Subsequent to the CHARGE study, additional GWAS-based publications have independently confirmed that common STAB2 variants associate with plasma

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“…UK guidelines have also adopted this cutoff 24. There may be a genetic reason for this, as the incidence of sequence variants in VWF increase with decreasing VWF:Ag, and there does appear to be a significant increase in frequency of such variants with VWF levels below 30 IU/dL 25, 26, 27. However, one confounder of many of the current studies is the predilection for inclusion of subjects with a pre‐existing diagnosis of VWD.…”

Section: Diagnosis Of Vwdmentioning

confidence: 99%

Current issues in diagnosis and treatment of von Willebrand disease

Keesler

Flood

2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Classification of VWD includes quantitative (types 1 and 3) and qualitative (type 2) variants.New assays of VWF‐platelet binding may improve accuracy in diagnosis.Collagen binding represents an additional function of VWF not measured by current tests.Treatment options for VWD include desmopressin, plasma‐derived, and recombinant VWF. Clinically, von Willebrand disease (VWD) presents as mucosal bleeding caused by a decreased quantity or quality of von Willebrand factor (VWF). Diagnosis of VWD requires careful consideration of patient specific factors, bleeding symptoms, and laboratory results. Patients with borderline low VWF levels remain challenging, given that low VWF is not necessarily a guarantee of bleeding, but is present in many patients with symptoms, and treatment of low VWF may improve bleeding. Laboratory diagnosis of VWD is complex and no single test can determine the presence or absence of functional VWF. Historically, VWF binding to platelet GPIbα was measured by the ristocetin cofactor assay (VWF:RCo); a new assay using platelet GPIbα in the absence of ristocetin (VWF:GPIbM) is gradually replacing the VWF:RCo due to improved accuracy in diagnosis. VWF binding to collagen is a separate function, and requires specific testing to determine if a collagen binding defect is present. Regardless of these laboratory complexities, clinicians can empirically treat VWD to alleviate bleeding symptoms by raising VWF levels through desmopressin or VWF concentrate. Recombinant VWF is now available, but clinicians may need to add an initial dose of FVIII when treating emergency bleeds.

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Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States

Abstract: Key Points Type 1 VWD in the United States is highly variable, including patients with very low VWF levels as well as those with mild or minimal VWF deficiency. The frequency of sequence variants in the VWF gene increases with decreasing VWF level, but BS does not vary by VWF level.

Cited by 104 publications

References 44 publications

Low VWF: an established mild bleeding disorder?

Low VWF: an established mild bleeding disorder?

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

Current issues in diagnosis and treatment of von Willebrand disease

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