Low VWF: an established mild bleeding disorder?

Leebeek, Frank W.G.; Boender, Johan

doi:10.1182/blood-2017-09-807180

Cited by 5 publications

(3 citation statements)

References 9 publications

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“…A recent study in unequivocal bleeders with 'low VWF' (30-50 IU dL À1 ) found no correlation between BS and VWF levels, and most patients had normal VWF propeptide/VWF:Ag ratios and sustained response of VWF:Ag and VWF:RCo to desmopressin (DDAVP), consistent with decreased VWF synthesis or secretion [39]. This suggests that most bleeders with 'low VWF' have type 1 VWD, and are not just individuals with VWF situated within the 2.5th percentile distribution [39,52].…”

Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 99%

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

Mezzano

Quiroga

2019

Journal of Thrombosis and Haemostasis

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Summary The best‐known inherited mild bleeding disorders (MBDs), i.e. type 1 von Willebrand disease (VWD), platelet function disorders (PFDs), and mild to moderate clotting factor deficiencies, are characterized clinically by mucocutaneous bleeding, and, although they are highly prevalent, still pose difficult diagnostic problems. These include establishing the pathological nature of bleeding, and the uncertainties surrounding the clinical relevance of laboratory results. Furthermore, the high frequency of bleeding symptoms in the normal population and the subjective appraisal of symptoms by patients or parents makes elucidating the pathological nature of bleeding difficult. Standardized bleeding assessment tools and semiquantitative bleeding scores (BSs) help to discriminate normal from abnormal bleeding. However, as most MBDs have similar bleeding patterns, for example, bleeding sites, frequency, and severity, BSs are of little help for diagnosing specific diseases. Global tests of primary hemostasis (bleeding time; PFA‐100/200) lack sensitivity and, like BSs, are not disease‐specific. Problems with the diagnosis of type 1 VWD and PFD include assay standardization, uncertain definition of von Willebrand factor cut‐off levels, and the lack of universal diagnostic criteria for PFD. Regarding clotting factor deficiencies, the bleeding thresholds of some coagulation factors, such as factor VII and FXI, are highly variable, and may lead to misinterpretation of the clinical relevance of mild to moderate deficiencies. Remarkably, a large proportion of MBDs remain undiagnosed even after comprehensive and repeated laboratory testing. These are tentatively considered to represent bleeding of undefined cause, with clinical features indistinguishable from those of classical MBD; the pathogenesis of this is probably multifactorial, and unveiling these mechanisms should constitute a fertile source of translational research.

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Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 99%

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

Mezzano

Quiroga

2019

Journal of Thrombosis and Haemostasis

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“…Recent recommendations from the UK Haemophilia Centre Doctors Organization and the US National Heart, Lung, and Blood Institute have further subclassified partial VWF quantitative deficiency into type 1 VWD (0.03–0.3 U mL −1 ) and a ‘low‐VWF’ phenotype (0.3–0.5 U mL −1 ) . Overall, approximately 35% of patients with partial quantitative VWF deficiency do not have an identified pathogenic variant in their VWF coding region or consensus splice site, and a lower proportion of coding region variants have been identified in ‘low‐VWF’ individuals . Although some of the pathogenic variants have been hypothesized to be found in distal regulatory regions or deep intronic sequences of VWF , linkage analysis performed on two separate cohorts demonstrated that the proportion of families showing linkage to the VWF locus is ~ 0.44 ; thus, non‐ VWF QTL may contribute to the ‘low‐VWF’ phenotype in the absence of a pathogenic VWF variant.…”

Section: Influence Of Variability At the Vwf Locus On Plasma Levels Omentioning

confidence: 99%

Genetic regulation of plasma von Willebrand factor levels in health and disease

Swystun

Lillicrap

2018

Journal of Thrombosis and Haemostasis

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To cite this article: Swystun LL, Lillicrap D. Genetic regulation of plasma von Willebrand factor levels in health and disease. J Thromb Haemost 2018; 16: 2375-90. of genetic modifiers of plasma VWF levels may allow for better molecular diagnosis of type 1 VWD, and enable the identification of individuals at increased risk for thrombosis. Validation of trait-mapping studies with in vitro and in vivo methodologies has led to novel insights into the life cycle of VWF and the pathogenesis of quantitative VWF abnormalities.

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“…27,42 • Low VWF was also reported in elderly people with a bleeding history. 43 • No correlation was observed between platelet VWF and intensity of bleeding disorder. 27…”

Section: Von Willebrand Disease Type 1 Vs Threshold Vonmentioning

confidence: 96%

Clinical significance of slightly reduced von Willebrand factor activity (30–50 IU/dL)

Bykowska¹,

Ceglarek²

2020

Polish Archives of Internal Medicine

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Clinical significance of low von Willebrand factor 225 gene at chromosome 22q11.2. The presence of the pseudogene VWF makes the molecular analysis of VWF more difficult. 2 Biosynthesis of von Willebrand factor VWF is synthesized by endothelial cells and megakaryocytes as a pre-pro VWF consisting of a 22-amino acid signal peptide, 741-amino acid propeptide, and 20 150-amino acid mature molecule. 2 After posttranslational modification (signal peptide cleavage, dimerization, glycosylation, sulfation, and multimerization) in the Golgi apparatus, VWF propeptide (VWFpp) is cleaved by the enzyme furin from a mature VWF molecule in the acidic compartment of trans-Golgi. Introduction Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is characterized mainly by mucosal bleeding and bleeding after surgery or trauma. It was described for the first time in 1926 by Eric von Willebrand. 1 The disorder is indicated by defective platelet adhesion and aggregation caused by either deficiency or dysfunction of the plasma glycoprotein von Willebrand factor (VWF). Inheritance of von Willebrand disease The inheritance of VWD can be autosomal dominant or recessive. The VWF gene is located on the short arm of chromosome 12 (12p13.2), and its pseudogene corresponds to exons 23-34 of the VWF

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Low VWF: an established mild bleeding disorder?

Cited by 5 publications

References 9 publications

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

Genetic regulation of plasma von Willebrand factor levels in health and disease

Clinical significance of slightly reduced von Willebrand factor activity (30–50 IU/dL)

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