Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD).
BACKGROUND
Type 1 von Willebrand disease (VWD) is a congenital bleeding disorder characterized by a partial quantitative deficiency of plasma von Willebrand factor (VWF) in the absence of structural and/or functional VWF defects. Accurate assessment of the quantity and quality of plasma VWF is difficult but is a prerequisite for correct classification.


OBJECTIVE
To evaluate the proportion of misclassification of patients historically diagnosed with type 1 VWD using detailed analysis of the VWF multimer structure.


METHODS
Previously diagnosed type 1 VWD families and healthy controls were recruited by 12 expert centers in nine European countries. Phenotypic characterization comprised plasma VWF parameters and multimer analysis using low- and intermediate-resolution gels combined with an optimized visualization system. VWF genotyping was performed in all index cases (ICs).


RESULTS
Abnormal multimers were present in 57 out of 150 ICs; however, only 29 out of these 57 (51%) had VWF ristocetin cofactor to antigen ratio below 0.7. In most cases multimer abnormalities were subtle, and only two cases had a significant loss of the largest multimers.


CONCLUSIONS
Of the cases previously diagnosed as type 1 VWD, 38% showed abnormal multimers. Depending on the classification criteria used, 22 out of these 57 cases (15% of the total cohort) may be reclassified as type 2, emphasizing the requirement for multimer analysis compared with a mere ratio of VWF functional parameters and VWF:Ag. This is further supported by the finding that even slightly aberrant multimers are highly predictive for the presence of VWF mutations.
Budde
U
U
Coagulation Laboratory, Hamburg, Germany. ulrich.budde@aesculabor-hamburg.de
Schneppenheim
R
R
Eikenboom
J
J
Goodeve
A
A
Will
K
K
Drewke
E
E
Castaman
G
G
Rodeghiero
F
F
Federici
A B
AB
Batlle
J
J
Pérez
A
A
Meyer
D
D
Mazurier
C
C
Goudemand
J
J
Ingerslev
J
J
Habart
D
D
Vorlova
Z
Z
Holmberg
L
L
Lethagen
S
S
Pasi
J
J
Hill
F
F
Peake
I
I
D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D019281:Dimerization; D005060:Europe; D005192:Family Health; D005838:Genotype; D006801:Humans; D017720:Molecular Epidemiology; D009154:Mutation; D014842:von Willebrand Diseases / Q000145:classification / Q000175:diagnosis* / Q000453:epidemiology; D014841:von Willebrand Factor / Q000032:analysis* / Q000737:chemistry / Q000235:genetics
D015415:Biomarkers; D014841:von Willebrand Factor