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)
U Budde, R Schneppenheim, J Eikenboom, A Goodeve, K Will, E Drewke, G Castaman, F Rodeghiero, A B Federici, J Batlle, A Pérez, D Meyer, C Mazurier, J Goudemand, J Ingerslev, D Habart, Z Vorlova, L Holmberg, S Lethagen, J Pasi, F Hill, I Peake, U Budde, R Schneppenheim, J Eikenboom, A Goodeve, K Will, E Drewke, G Castaman, F Rodeghiero, A B Federici, J Batlle, A Pérez, D Meyer, C Mazurier, J Goudemand, J Ingerslev, D Habart, Z Vorlova, L Holmberg, S Lethagen, J Pasi, F Hill, I Peake
Abstract
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.
Patients and 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.
Source: PubMed