Laboratory Diagnosis and Molecular Basis of Mild von Willebrand Disease Type 1

Michiels, Jan; Berneman, Zwi N.; Gadisseur, Alain; Planken, Marc van der; Schroyens, Wilfried; Vliet, H. H. D. M. Van

doi:10.1159/000214847

Cited by 10 publications

(17 citation statements)

References 63 publications

(94 reference statements)

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“…40 The D3 domain is important in VWF multimerization, which could impact VWF tertiary structure and ultimately circulating levels of VWF and its clearance. 39 It is also interesting to note that the rate of VWF clearance is found to be accelerated in patients with VWD Vicenza, which often have mutations, including intronic, in the D domains [41][42][43] (we did not find positive SNPs in the exon encoding D4 and flanking intronic sequence). However, extensive biologic experiments are required to establish a mechanistic link between positive SNPs and VWF expression in general and the putative role of this 50-kb region in regulating VWF expression in particular.…”

Section: Discussionmentioning

confidence: 69%

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Campos

Sun

et al. 2011

Blood

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IntroductionThe von Willebrand factor (VWF) is an essential component of hemostasis at sites of vascular injury. This hemostatically active adhesion ligand also plays a critical role in thrombus formation at the site of a ruptured atherosclerotic plaque and in platelet aggregation induced by high fluid shear stress in areas of severe vascular stenosis. The former results in myocardial infarction when it occurs in coronary arteries, whereas the latter is a major cause of thromboembolism associated with ischemic stroke. 1 VWF is the largest multimeric glycoprotein in the plasma. It is exclusively synthesized in endothelial cells and megakaryocytes initially as a monomeric glycoprotein. In the endoplasmic reticulum and Golgi apparatus of these cells, the monomers form C-terminal disulfide-linked dimers. A various number of dimers subsequently form multimers through N-terminal disulfide linkages, a process assisted by the proteolytic release of a 714-amino acid propeptide. 2,3 The newly synthesized VWF multimers are either constitutively released into the circulation or stored in the Weibel-Palade bodies of endothelial cells and ␣-granules of megakaryocytes/platelets. 4,5 On stimulation, these granules secrete the stored VWF multimers that are rich in ultra-large and hemostatically hyperactive forms. 4,6 Ultra-large VWF multimers are also secreted under endothelial stress caused by inflammation but are rapidly and partially cleaved by the zinc metalloprotease AD-AMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats) into smaller, variable-sized multimers. 7-9 The hemostatic activity of VWF multimers is determined not only by multimer size, 4,10 but also by the quantity of VWF antigen in the circulation. The plasma level of VWF multimers is determined by a dynamic balance between the rate of production and that of clearance. Although acquired conditions are known to affect synthesis and secretion, 11 genetic factors play a major role in regulating VWF synthesis and clearance. It has been reported that genetic factors are responsible for up to 66% of variation in plasma VWF antigen level, of which 30% is related to ABO blood type. 12,13 The human VWF gene is located on chromosome 12. 14,15 It spans approximately 180 kb of nucleotides and contains 52 exons that encode a multidomain prepolypeptide of 2791 amino acids. [14][15][16] The VWF gene is highly polymorphic. 17 Single nucleotide polymorphisms (SNPs) of the coding and promoter sequences in the VWF gene have been extensively studied and found to influence the levels of VWF in the circulation. Furthermore, as a heavily glycosylated polypeptide, 16,18 the level of circulating VWF is also affected by the structure of its carbohydrate side chains, which are associated with ABO blood group, primarily because of the presence or absence of a functional glycosyltransferase that adds either a N-acetylgalactosamine or a D-galactose to a D-galactose side chain on the H antigen. 19 This structural variation in glycosylation has been reported to directly...

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Section: Discussionmentioning

confidence: 69%

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Campos

Sun

et al. 2011

Blood

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“…Use of a DDAVP challenge with a core four-test panel (i.e., VWF:Ag, VWF:RCo, FVIII:C, and PFA-100) in our center for VWD diagnosis and typing has been found to improve the diagnosis and classification of VWD (Table 1). 20,21 The Geographic Approach to the Diagnosis of Von Willebrand Disease and Its Difficulties The test combination of FVIII:C, VWF:Ag, and VWF:RCo is the most common test panel used worldwide for the identification, diagnosis, and classification of an individual's VWD, but experience tells us that an individual will be misdiagnosed in $25% of the time using this test panel. 22 Although addition of a PFA-100 test to this panel may enable distinguishing mild/possible type 1 VWD from moderate to severe type 1, type 2, and type 3 VWD, it is not adequate in differentiating other types of VWD from each other.…”

Section: The Laboratory Diagnosis Of Von Willebrand Diseasementioning

confidence: 99%

Laboratory Diagnosis and Management ofvon Willebrand Disease in Turkey: Izmir Experience

Akın

Kavaklı²

2011

Semin Thromb Hemost

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Von Willebrand disease (VWD) is caused by a deficiency or dysfunction of Von Willebrand factor (VWF). The pathophysiology, classification, diagnosis, and management of VWD are relatively complex, but their understanding is important for proper diagnosis and management of patients with VWD. There are inherent difficulties in both the identification and classification of VWD because of clinical uncertainty and the limitations in the test processes and test panels typically used by laboratories. The most common test panel employed by laboratories, particularly in the geographic regions covered by the mutational studies, would comprise factor VIII coagulant (FVIII:C), VWF protein (antigen; VWF:Ag), and ristocetin cofactor (VWF:RCo). In our center, use of a desmopressin challenge with our core four-test panel (i.e., VWF:Ag, VWF:RCo, FVIII:C, and PFA-100) is expected to further assist laboratory diagnosis of VWD in Turkey. Molecular genetics is a rather new approach for Turkey, with gene analyses related to VWD being initiated in one center and the results used for confirmation of diagnosis in limited cases.

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“…In patients with unexpected bleeding, additional laboratory tests should be performed to identify platelet dysfunction [20] or an additional haemostatic abnormality e.g. underlying von Willebrand disease [21,22].…”

Section: Introductionmentioning

confidence: 99%

Diagnosis and management of chronic ITP: comments from an ICIS expert group

Grainger¹,

Godeau²,

Bussel

et al. 2010

Ann Hematol

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Immune thrombocytopenia (ITP) is a common disorder in children and adults. In a patient with newly diagnosed ITP, the treatment strategy is relatively well defined. Second-line treatments are more controversial, and the management of chronic ITP is even more so. During the 3rd ICIS Expert Meeting on Consensus and Development of Strategies in ITP, held in Basel on September 3-5, 2009, a group of experts were tasked with reaching a consensus on some frequently asked questions relating to diagnosis and management of children and adults with chronic ITP. The content of this article is designed to provide a practical support to trained haematologists in their care of patients with chronic ITP.

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Laboratory Diagnosis and Molecular Basis of Mild von Willebrand Disease Type 1

Cited by 10 publications

References 63 publications

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Laboratory Diagnosis and Management ofvon Willebrand Disease in Turkey: Izmir Experience

Diagnosis and management of chronic ITP: comments from an ICIS expert group

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