The Y/C1584 mutation of von Willebrand factor in type 2M von Willebrand disease: frequency and clearance of von Willebrand factor

Millar, Carolyn M.; Riddel, A. F.; Griffioe, A.; Jenkin, P. V.; Brown, Simon

doi:10.1111/j.1365-2141.2005.05637.x

Cited by 6 publications

(5 citation statements)

References 8 publications

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“…The substitution Tyr1584Cys has been identified in 3–25% of patients with VWD type 1, compared with < 2% of healthy controls [14,35–38]. This mutation does not reduce the intravascular survival of VWF [39] but slightly increases the susceptibility of VWF to cleavage by ADAMTS‐13 [36], which may impair platelet plug formation. The Tyr1584Cys mutation is associated weakly with low VWF:Ag or VWF:RCo [14], which is consistent with increased intracellular retention of the recombinant 1584Cys variant [35].…”

Section: Phenotypic Classification Of Vwdmentioning

confidence: 99%

Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor

Sadler

Budde²,

Eikenboom

et al. 2006

Journal of Thrombosis and Haemostasis

1,045

1,441

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Summary. von Willebrand disease (VWD) is a bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). VWD is classified into three primary categories. Type 1 includes partial quantitative deficiency, type 2 includes qualitative defects, and type 3 includes virtually complete deficiency of VWF. VWD type 2 is divided into four secondary categories. Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high‐molecular‐weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite a relatively normal size distribution of VWF multimers. Type 2N includes variants with markedly decreased affinity for factor VIII. These six categories of VWD correlate with important clinical features and therapeutic requirements. Some VWF gene mutations, alone or in combination, have complex effects and give rise to mixed VWD phenotypes. Certain VWD types, especially type 1 and type 2A, encompass several pathophysiologic mechanisms that sometimes can be distinguished by appropriate laboratory studies. The clinical significance of this heterogeneity is under investigation, which may support further subdivision of VWD type 1 or type 2A in the future.

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Section: Phenotypic Classification Of Vwdmentioning

confidence: 99%

Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor

Sadler

Budde²,

Eikenboom

et al. 2006

Journal of Thrombosis and Haemostasis

1,045

1,441

View full text Add to dashboard Cite

show abstract

“…Apart from the p.Thr789Ala replacement, the p.Tyr1584Cys phenotype is also associated with altered VWF plasma levels. Whether the reduced VWF levels associated with the p.Cys1584 variant are related to increased clearance is also unclear as conflicting data have been reported with respect to this substitution . Most other SNPs in the VWF gene that affect VWF levels are located in non‐coding regions of the gene or do not alter the amino acid sequence, making it unlikely that they influence clearance of the protein .…”

Section: A Genetic View On the Regulation Of Vwf Levelsmentioning

confidence: 99%

Clearance of von Willebrand factor

Casari

Lenting

Wohner

et al. 2013

Journal of Thrombosis and Haemostasis

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Summary Quantitative deficiencies in von Willebrand factor (VWF) are associated with abnormal hemostasis that can manifest in bleeding or thrombotic complications. Consequently, many studies have endeavored to elucidate the mechanisms underlying the regulation of VWF plasma levels. This review focuses on the role of VWF clearance pathways. A summary of recent developments are provided, including results from genetic studies, the relationship between glycosylation and VWF clearance, the contribution of increased VWF clearance to the pathogenesis of von Willebrand disease and the identification of VWF clearance receptors. These different studies converge in their conclusion that VWF clearance is a complex phenomenon that involves multiple mechanisms. Deciphering how such different mechanisms coordinate their role in this process is but one of the remaining challenges. Nevertheless, a better insight into the complex clearance pathways of VWF may help us to better understand the clinical implications of aberrant clearance in the pathogenesis of von Willebrand disease and perhaps other disorders as well as aid in developing alternative therapeutic approaches.

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“…We have analyzed the results of three studies on the VWFpp/ VWF:Ag ratio related to clearance of VWF:Ag after DDAVP as a component in the etiology of type 1 and type 2 VWD (table 4) [14, 28, 33]. In addition, we analyzed the findings in mild VWD related to the C1584 mutation in the A2 domain and subsequently compared it with controls of blood group O versus non-O [35, 36]. …”

Section: Role Of the Vwfpp/ag Ratio In The Differential Diagnosis Of mentioning

confidence: 99%

“…Table 5 summarizes the results of VWFpp/ VWF:Ag ratios related to the level of VWF:Ag and VWF:Ag survival times after DDAVP in VWD type 1/2E and type 1 Vicenza due to mutations in the D3 domain, VWD type 1SC due to a mutation in the D4 domain and mild VWD type 1 due to mutations in the D1-D2-D′ domains, the D4-B1-B3-C1-C2 domains and the C1584 mutation with blood group O [28,34,35,36]. …”

Section: Role Of the Vwfpp/ag Ratio In The Differential Diagnosis Of mentioning

confidence: 99%

Laboratory Diagnosis of von Willebrand Disease Type 1/2E (2A Subtype IIE), Type 1 Vicenza and Mild Type 1 Caused by Mutations in the D3, D4, B1–B3 and C1–C2 Domains of the von Willebrand Factor Gene

et al. 2009

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Autosomal dominant von Willebrand disease (VWD) type 1/2E is a quantitative/qualitative defect in the von Willebrand factor (VWF) caused by heterozygous cysteine and non-cysteine mutations in the D3 domain of the VWF gene and results in a secretion-multimerization-clearance defect in mutant VWF with the loss of large VWF multimers not due to proteolysis. The multimers of patients with dominant VWD type 1/2E due to mutations in the D3 domain show an aberrant triplet structure with lack of outer bands but with pronounced inner bands of the triplet structure combined with a relative decrease in large multimers reflecting heterozygosity for multimerization defects. There is a good response to desmopressin (DDAVP) followed by rapid clearance of VWF:antigen (Ag), factor VIII coagulant activity (FVIII:C) and VWF:ristocetin cofactor activity (RCo) as the main cause of VWD type 1 or 2 with typical 2E multimeric pattern (VWD type 1/2E). Cysteine mutations in the D3 domains (C1130, C1149 and C1190) show pronounced features of VWD 1/2E with the relative loss of large and relative increase in small VWF multimers with abnormal triplet structure in heterozygotes. Such abnormalities are less pronounced in patients with a milder form of VWD type 1 due to non-cysteine mutations W1144G, T1156M and W1120S in the D3 domain. VWD type 1 Vicenza is caused by the R1205H mutation in the D3 domain and characterized by equally low levels of FVIII:C, VWF:Ag and VWF:RCo. The response to DDAVP in VWD Vicenza is good for FVIII:C, VWF:Ag and VWF:RCo, which is followed by a rapid clearance in less than a few hours of FVIII:C and VWF parameters. The ratios for FVIII:C/VWF:Ag, VWF:RCo/Ag and VWF:CB/Ag remain normal before and after DDAVP indicating that VWD Vicenza clearly differs from VWD type 1, 1/2E and 2M. A new set of missense mutations in D4, B1–B3 and C1–C2 domains has been discovered as the cause of a mild VWD type 1 secretion defect with normal VWF multimers or smeary VWF multimeric pattern. Cysteine mutations in exons 38, 40, 42 and 43 (D4, B1–B3 and C1 domain), show smeary patterns (either smf or sm), with the presence of large VWF multimers and a laboratory phenotype of mild VWD type 1 with variable penetrance of bleeding manifestations. Recent studies showed that the ratio of VWF propeptide (pp) to VWF:Ag can be used to predict a shorter than normal half-life for VWF:Ag. There is a strong inverse correlation between rapid clearance of VWF:Ag after DDAVP and increased VWFpp/Ag ratios >10 in VWD type 1 Vicenza, and >2 in VWD type 1/2E but normal or slightly increased (1–<2) VWFpp/Ag ratios in mild-type VWD due to nonsense or missense mutations in the D1, D2, D4, B and C domains.

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The Y/C1584 mutation of von Willebrand factor in type 2M von Willebrand disease: frequency and clearance of von Willebrand factor

Cited by 6 publications

References 8 publications

Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor

Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor

Clearance of von Willebrand factor

Laboratory Diagnosis of von Willebrand Disease Type 1/2E (2A Subtype IIE), Type 1 Vicenza and Mild Type 1 Caused by Mutations in the D3, D4, B1–B3 and C1–C2 Domains of the von Willebrand Factor Gene

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