Von Willebrand disease type 2M: Correlation between genotype and phenotype

Abstract

Background: An appropriate clinical diagnosis of von Willebrand disease (VWD) can be challenging because of a variable bleeding pattern and laboratory phenotype. Genotyping is a powerful diagnostic tool and may have an essential role in the diagnostic field of VWD.

Objectives: To unravel the clinical and laboratory heterogeneity of genetically confirmed VWD type 2M patients and to investigate their relationship.

Methods: Patients with a confirmed VWD type 2M genetic variant in the A1 or A3 domain of von Willebrand factor (VWF) and normal or only slightly aberrant VWF multimers were selected from all subjects genotyped at the Radboud university medical center because of a high suspicion of VWD. Bleeding scores and laboratory results were analyzed.

Results: Fifty patients had a clinically relevant genetic variant in the A1 domain. Median bleeding score was 5. Compared with the nationwide Willebrand in the Netherlands study type 2 cohort, bleeding after surgery or delivery was reported more frequently and mucocutaneous bleedings less frequently. Median VWF activity/VWF antigen (VWF:Act/VWF:Ag) ratio was 0.32, whereas VWF collagen binding activity/VWF antigen (VWF:CB/VWF:Ag) ratio was 0.80. Variants in the A3 domain were only found in two patients with low to normal VWF:Act/VWF:Ag ratios (0.45, 1.03) and low VWF:CB/VWF:Ag ratios (0.45, 0.63).

Conclusion: Genetically confirmed VWD type 2M patients have a relatively mild clinical phenotype, except for bleeding after surgery and delivery. Laboratory phenotype is variable and depends on the underlying genetic variant. Addition of genotyping to the current phenotypic characterization may improve diagnosis and classification of VWD.

Keywords: genotype; hemorrhage; hemostasis; phenotype; von Willebrand disease, type 2.

FIGURE 1

Flow chart of patients who met inclusion/exclusion criteria

FIGURE 2

Frequency of bleeding symptoms in our cohort of VWD type 2M patients compared with a cohort of VWD type 1 and 2 patients from the WiN study. A reported bleeding was defined as a subscore ≥1. In the VWD type 2M cohort, 24 patients underwent tooth extraction without hemostatic treatment, 23 patients underwent surgery without hemostatic treatment, 25 women have been menstruating, and 8 women gave birth without hemostatic treatment. VWD, von Willebrand disease; WiN, Willebrand in the Netherlands

FIGURE 3

Multimeric analysis of plasma VWF by using 1.5% SDS‐agarose gel. N demonstrates multimers in a normal subject, I demonstrates multimers representative for the slightly aberrant multimer patterns observed in nine VWD type 2M patients in our cohort, and 2A demonstrates multimers in a patient with a well‐defined VWD type 2A. VWD, von Willebrand disease; VWF, von Willebrand factor

FIGURE 4

Laboratory and clinical phenotype in the three most prevalent VWD type 2M variants in the A1 domain and in the two included variants in the A3 domain. (A) VWF:Ag, (B) VWF:Act, (C) VWF:CB, (D) VWF:Act/VWF:Ag ratio, (E) VWF:CB/VWF:Ag ratio, (F) FVIII, and the (G) bleeding score. Horizontal lines represent median values. Each dot, box, and (reversed) triangle represent a single patient. In panel G, open figures represent females and closed figures represent males. VWD, von Willebrand disease; VWF, von Willebrand factor; VWF:Act, VWF activity; VWF:Ag, VWF antigen; VWF:CB, VWF collagen binding activity; FVIII, factor VIII