Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study

BACKGROUND/METHODS: In order to better characterize the genotype-phenotype correlation in type 2M von Willebrand disease (VWD), we sequenced the coding region for the mature subunit of the von Willebrand factor (VWF) gene (exons 18-52, including exon/intron boundaries) in 16 index cases originally submitted to the Canadian Type 1 VWD Study as type 1 VWD, but reclassified as type 2M VWD on the basis of phenotype (excessive mucocutaneous bleeding and von Willebrand factor: antigen (VWF:Ag) and/or von Willebrand factor: ristocetin cofactor (VWF:RCo) between 0.05 and 0.50 IU mL(-1) on at least two occasions and RCo/Ag ratio < 0.6 and no loss of high molecular weight multimers). Available family members (16 affected, 23 unaffected and six unknown) were sequenced for identified mutations. RESULTS: We identified eight different missense mutations (R854Q, T1054M, R1315C, R1374C, R1374H, L1382P, S2179F, and T2647M) within these 16 families. We were significantly more likely to identify a VWF mutation in cases with RCo/Ag ratios < 0.50 (P < 0.05, chi-squared test). Importantly, every index case with an RCo/Ag ratio < 0.40 (4/4 index cases) had a mutation identified within the A1 domain, in contrast to 1/12 cases with an RCo/Ag ratio > 0.40. Difficulties with the standardization of the VWF:RCo may be responsible for the heterogeneity in cases with RCo/Ag ratios between 0.40 and 0.60. CONCLUSIONS: The genotype-phenotype correlation for cases with RCo/Ag ratios < 0.40 is clear. On the basis of our results, the phenotypic definition of type 2M VWD may need to be more stringent, and should be the subject of an international standardization initiative.