Genetic variants of VWF gene in type 2 von Willebrand disease

Abstract

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.

ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease

“…94 Patients with type 2A or 2M are less likely to respond to desmopressin, but this would be identified at the time of a desmopressin trial. 95 Other treatment decisions are not likely to vary significantly between subtypes.…”

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

“…No response to DDAVP has been observed in patients carrying p.Val1360Ala (2M), p.Arg1597Trp (2A), p.Arg1341Gln (2B), and p.Arg1308Cys (2B) variants. 42 Recently, König et al developed a new GPIIb/IIIa binding assay and were able to identify four VWF mutations associated with type 2 VWD, which exhibited significantly reduced GPIIb/IIIa binding: p.Cys2257Arg, p.Gly2441Cys, p.Cys2477-Tyr, and p.Pro2722Ala. Previously only two variants (p.Val2517Phe and p.Arg2535Pro) exhibiting altered GPIIb/ IIIa binding had been identified.…”

Von Willebrand Disease Type 2B Mimicking Autoimmune Thrombocytopenia in Neonatal Period

“…Factor VIII/VWF replacement therapy is often preferred. Nevertheless, replacement therapy may not always provide bleeding control and platelet transfusion is needed in these cases (1)(2)(3). This case emphasized that VWD type 2B rarely may be presented in addition to NAIT and neonatal autoimmune thrombocytopenia which are common in resistant neonatal thrombocytopenia.…”

“…Von Willebrand disease (VWD) is an inherited bleeding disease related with deficiency, dysfunction or both of VWF (1)(2)(3). There are three basic types of VWD.…”

“…Whereas type 2 is due This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to to the qualitative, Type 1 and 3 are the quantitative defect of VWF (1)(2)(3). In VWD type 2B, patients tend to have a bleeding tendency related to loss of high molecular weight VWF multimers and labile thrombocytopenia (1)(2)(3). Neonatal alloimmune thrombocytopenia (NAIT) and maternal immune thrombocytopenia should be considered when an infant with severe thrombocytopenia without infection (2,4).…”