An Arg<sup>545</sup>→ Cys<sup>545</sup> substitution mutation of the von Willebrand factor in type IIB von Willebrand's disease

Donnér, Mikael; Andersson, Ann-Mari; Kristoffersson, Ann‐Charlotte; Nilsson, Inga Marie; Dahlbäck, Björn; Holmberg, Lars

doi:10.1111/j.1600-0609.1991.tb01858.x

Cited by 13 publications

(2 citation statements)

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“…Variants Arg1308Cys and Arg1341Gln are associated with 2B VWD . In our study, two patients carried the Arg1308Cys and two patients carried the Arg1341Gln variants.…”

Section: Discussionsupporting

confidence: 46%

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Genetic variants of VWF gene in type 2 von Willebrand disease

et al. 2019

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Introduction von Willebrand disease (VWD) is the most common inherited bleeding disorder. Few studies have explored the molecular basis of type 2 VWD. Aim This study aimed to identify variants associated with type 2 VWD. Methods We collected clinical and laboratory data, as well as response to desmopressin and bleeding assessment tool (BAT) score in patients diagnosed with type 2 VWD. We sequenced exons 17, 18, 20 and 28 of the VWF gene. Results We identified 19 different variants in 40 unrelated patients (47.5%). Most of the variants (84.2%) were found in exon 28. A total of 10/19 variants (52.6%) were identified as “likely causative” in 17/40 patients (42.5%), according to the ISTH‐SSC and EAHAD VWF gene mutations databases. Nine variants were initially identified as potentially benign. However, through analyses in silico, four of these variants were reclassified as “likely pathogenic” (Ile1380Val, Asn1435Ser, Ser1486Leu and Tyr1584Cys). Response to desmopressin was associated with three variants: Met740Ile, Arg1597Gln and Tyr1584Cys. Major bleeding was associated with variants related to VWD subtypes 2B and 2M. Conclusion In conclusion, we identified 19 variants, of which 14 are “likely pathogenic” and therefore associated with VWD. We suggest a possible association of pathogenic variants with major bleeding, response to desmopressin and BAT score ≥10, although this requires further confirmation.

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“…Variants Arg1308Cys and Arg1341Gln are associated with 2B VWD . In our study, two patients carried the Arg1308Cys and two patients carried the Arg1341Gln variants.…”

Section: Discussionsupporting

confidence: 46%

“…Variants Arg1308Cys and Arg1341Gln are associated with 2B VWD. 22,23 In our study, two patients carried the Arg1308Cys and two patients carried the Arg1341Gln variants. Patient number five presented a BAT score of 32 and a broad range of major and minor bleeding events.…”

Section: Discussionmentioning

confidence: 67%

Genetic variants of VWF gene in type 2 von Willebrand disease

et al. 2019

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1-desamino-8-arginine-vasopressin corrects the hemostatic defects in type 2B von Willebrand's disease

et al. 1996

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DDAVP is effective treatment in most types of von Willebrand's disease; however, in type 2B von Willebrand's disease the use of DDAVP has been contraindicated due to DDAVP-induced thrombocytopenia. Several reports have confirmed the thrombocytopenic effects of DDAVP and the presence of circulating platelet aggregates in type 2B von Willebrand's disease. We have infused three type 2B patients with DDAVP. The three patients had different mutations of their vWf. All three patients had a missense mutation which resulted in a single amino acid substitution in the disulfide loop of the A1 domain. Administration of 20 micrograms of DDAVP resulted in significant elevations of factor VIII, vWf antigen, and ristocetin cofactor levels. In contrast to other studies, DDAVP did not induce or enhance thrombocytopenia in these three patients. When blood was obtained by fingerstick and diluted into sodium oxalate (Unopette) or EDTA (Microvette), the platelet counts did not change over 4 hr. In contrast, blood collected directly into evacuated tubes containing sodium citrate, lithium heparin, or EDTA consistently demonstrated varying degrees of thrombocytopenia and platelet clumping. We also observed a shortening of the pre-infusion bleeding time over the 4 hr period. All three patients have been studied twice and each has shown consistent results. DDAVP appears to be a useful form of treatment in type 2B vWd.

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Molecular Genetics of Type 2 von Willebrand Disease

Fressinaud

Mazurier²,

Meyer

2002

Int J Hematol

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Type 2 von Willebrand disease (VWD) is characterized by a wide heterogeneity of functional and structural defects. These abnormalities' cause either defective von Willebrand factor (VWF)-dependent platelet function in subtypes 2A, 2B, and 2M or defective VWF-factor VIII (FVIII) binding in subtype 2N. The diagnoses of types 2A, 2B, and 2M VWD may be guided by the observation of disproportionately low levels of ristocetin cofactor activity or collagen-binding capacity relative to VWF antigen. The abnormal platelet-dependent function is often associated with the absence of high molecular weight (HMW) multimers (type 2A, type 2B), but the HMW multimers may also be present (type 2M, some type 2B), and supranormal multimers may exist ("Vicenza" variant). The observation of a low FVIII-to-VWF:Ag ratio is a hallmark of type 2N VWD. in which the FVIII levels depend on the severity of the FVIII-binding defect. Today, the identification of mutations in particular domains of the pre-pro-VWF is helpful in classifying these variants and providing further insight into the structure-function relationship and the biosynthesis of VWF. Thus, mutations in the D2 domain, involved in the multimerization process, are found in patients with type 2A, formerly named IIC VWD. Mutations located in the D' domain or in the N terminus of the D3 domain define type 2N VWD. Mutations in the D3 domain characterize Vicenza and IIE patients. Mutations in the A1 domain may modify the binding of VWF multimers to platelets, either increasing (type 2B) or decreasing (type 2M, 2A/2M) the affinity of VWF for platelets. In type 2A VWD, molecular abnormalities identified in the A2 domain, which contains a specific proteolytic site, are associated with alterations in folding, impairing VWF secretion or increasing its susceptibility to proteolysis. Finally, a mutation localized in the carboxy-terminus CK domain, which is crucial for the dimerization of the VWF subunit, has been identified in a rare subtype 2A, formerly named IID.

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An Arg⁵⁴⁵→ Cys⁵⁴⁵ substitution mutation of the von Willebrand factor in type IIB von Willebrand's disease

Cited by 13 publications

References 15 publications

Genetic variants of VWF gene in type 2 von Willebrand disease

Genetic variants of VWF gene in type 2 von Willebrand disease

1-desamino-8-arginine-vasopressin corrects the hemostatic defects in type 2B von Willebrand's disease

Molecular Genetics of Type 2 von Willebrand Disease

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An Arg545→ Cys545 substitution mutation of the von Willebrand factor in type IIB von Willebrand's disease

Cited by 13 publications

References 15 publications

Genetic variants of VWF gene in type 2 von Willebrand disease

Genetic variants of VWF gene in type 2 von Willebrand disease

1-desamino-8-arginine-vasopressin corrects the hemostatic defects in type 2B von Willebrand's disease

Molecular Genetics of Type 2 von Willebrand Disease

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An Arg⁵⁴⁵→ Cys⁵⁴⁵ substitution mutation of the von Willebrand factor in type IIB von Willebrand's disease