title: Type 2M von Willebrand disease variant characterized by abnormal von willebrand factor multimerization.
abstract: We describe a von Willebrand disease (VWD) variant characterized by low plasma and platelet von Willebrand factor (VWF), impaired ristocetin-induced VWF binding to platelet glycoprotein Ib (GPIb), and abnormal VWF multimer pattern not associated with the absence of large forms. A C-to-T transition at nucleotide 4120 in exon 28 of the VWF gene was found; this mutation introduces a cysteine at the codon for Arg 611 of mature VWF. In addition to the decreased factor VIII (FVIII) and VWF levels, ristocetin-induced platelet aggregation (RIPA) was almost absent, and VWF ristocetin cofactor activity (VWF:RCo) was significantly more decreased than VWF antigen. The patients (mother and son) also showed a defect in VWF collagen-binding activity. Plasma VWF multimers were decreased, with no limit in the size of large forms, and the normal discontinuous multimer organization was replaced by a diffuse smear, especially detectable in the large forms. This picture was emphasized by 1-deamino-8-D -arginine vasopressin (DDAVP) infusion, so that the abnormal VWF multimers appeared to have a molecular weight higher than those present in, or released by, human umbilical vein endothelial cells. DDAVP also increased FVIII and VWF levels but did not normalize the GPIb-dependent VWF functions expressed as RIPA and VWF:RCo. We include this variant in type 2M VWD, focusing on the abnormality in GPIb-dependent VWF function. We advance that this defect depends on the mutation in the GPIb binding domain of VWF rather than the abnormal VWF multimer pattern.
authors.affiliation: Department of Medical and Surgical Sciences and the Second Chair of Internal Medicine, University of Padua Medical School, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Casonato
authors.forename: E
authors.initials: E
authors.lastname: Pontara
authors.forename: F
authors.initials: F
authors.lastname: Sartorello
authors.forename: A
authors.initials: A
authors.lastname: Bertomoro
authors.forename: C
authors.initials: C
authors.lastname: Durante
authors.forename: A
authors.initials: A
authors.lastname: Girolami
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D005169:Factor VIII / Q000378:metabolism; D005192:Family Health; D005260:Female; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D017354:Point Mutation; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism; D012310:Ristocetin / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D014842:von Willebrand Diseases / Q000235:genetics* / Q000378:metabolism; D014841:von Willebrand Factor / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D006490:Hemostatics; D011108:Polymers; D014841:von Willebrand Factor; D012310:Ristocetin; D005169:Factor VIII; D003094:Collagen; D003894:Deamino Arginine Vasopressin