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.
University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy. sandra.casonato@unipd.it
Alessandra
A
Casonato
Francesca
F
Sartorello
Elena
E
Pontara
Lisa
L
Gallinaro
Antonella
A
Bertomoro
Maria
M
Grazia Cattini
Viviana
V
Daidone
Maryta
M
Szukowska
Antonio
A
Pagnan
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