A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: an elusive phenotype and a difficult diagnosis.
Mutations in the A1 domain of von Willebrand factor (VWF) may be associated with gain of function in the VWF-platelet GPIb interaction and consumption of large VWF multimers, as seen in type 2B von Willebrand disease (VWD). We report a new VWF abnormality associated with greater VWF-GPIb interaction in the presence of all VWF multimers. The index case is a woman with a lifelong history of bleeding, found hyperresponsive to ristocetin with spontaneous platelet aggregation (SPA). She had normal factor VIII, VWF:Ag, VWF:RCo and VWF:CB levels, normal VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios, and a full panel of plasma and platelet VWF multimers. A missense mutation (4115T>G) was found in exon 28 of the VWF gene, which replaced a isoleucine with a serine at position 1372 of pre-pro-VWF (I1372S) at heterozygous level. Recombinant VWF carrying the I1372S mutation and showing a normal VWF multimer organisation was capable of inducing SPA on normal platelet-rich plasma (unlike wild-type VWF), as well as a hyper-response to ristocetin in the same platelets (0.6 mg/ml ristocetin vs. 1.2 of wild-type VWF). The new I1372S VWF mutation, characterized by SPA and hyper-responsiveness to ristocetin thus has some of the features of type 2B VWD, but not the lack of large VWF multimers, so we defined this variant as type 2B-like VWD. Why I1372S VWF is associated with bleeding symptoms, despite normal VWF levels and multimer organisation, remains to be seen.
Casonato
Alessandra
A
University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy. sandra.casonato@unipd.it
Sartorello
Francesca
F
Pontara
Elena
E
Gallinaro
Lisa
L
Bertomoro
Antonella
A
Grazia Cattini
Maria
M
Daidone
Viviana
V
Szukowska
Maryta
M
Pagnan
Antonio
A
D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000097:blood / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics*; D010979:Platelet Function Tests; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012310:Ristocetin; D014162:Transfection; D014842:von Willebrand Diseases / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor; D012310:Ristocetin