title: Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival.
abstract: Type 1 von Willebrand disease (VWD) is characterized by a partial quantitative deficiency of von Willebrand factor (VWF). Few VWF gene mutations have been identified that cause dominant type 1 VWD. The decreased survival of VWF in plasma has recently been identified as a novel mechanism for type 1 VWD. We report 4 families with moderately severe type 1 VWD characterized by low plasma VWF:Ag and FVIII:C levels, proportionately low VWF:RCo, and dominant inheritance. A decreased survival of VWF in affected individuals was identified with VWF half-lives of 1 to 3 hours, whereas the half-life of VWF propeptide (VWFpp) was normal. DNA sequencing revealed a single (heterozygous) VWF mutation in affected individuals, S2179F in 2 families, and W1144G in 2 families, neither of which has been previously reported. We show that the ratio of steady-state plasma VWFpp to VWF:Ag can be used to identify patients with a shortened VWF half-life. An increased ratio distinguished affected from unaffected individuals in all families. A significantly increased VWFpp/VWF:Ag ratio together with reduced VWF:Ag may indicate the presence of a true genetic defect and decreased VWF survival phenotype. This phenotype may require an altered clinical therapeutic approach, and we propose to refer to this phenotype as type-1C VWD.
authors.affiliation: Department of Pediatrics-Hematology/Oncology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. shaberic@mcw.edu
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Haberichter
authors.forename: Michael
authors.initials: M
authors.lastname: Balistreri
authors.forename: Pamela
authors.initials: P
authors.lastname: Christopherson
authors.forename: Patricia
authors.initials: P
authors.lastname: Morateck
authors.forename: Stefana
authors.initials: S
authors.lastname: Gavazova
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Bellissimo
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Manco-Johnson
authors.forename: Joan Cox
authors.initials: JC
authors.lastname: Gill
authors.forename: Robert R
authors.initials: RR
authors.lastname: Montgomery
mesh_terms: D004252:DNA Mutational Analysis; D005169:Factor VIII; D005192:Family Health; D005260:Female; D006207:Half-Life; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011498:Protein Precursors; D015996:Survival Rate; D014842:von Willebrand Diseases / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D014841:von Willebrand Factor / Q000032:analysis*
chemical_list: D011498:Protein Precursors; D014841:von Willebrand Factor; D005169:Factor VIII