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. 2016 Mar 18;95(11):e3038. doi: 10.1097/MD.0000000000003038

FIGURE 3.

FIGURE 3

Distribution of von Willebrand disease (VWD) types and subtypes in 670 index cases patients. The central ring represents the proportion of VWD types in the 670 IC patients: 25% of type 1, 18% of type 2A, 17% of type 2B, 19% of type 2M, 12% of type 2N, 8% of type 3, and 1% of undetermined (U) VWD. The peripheral disks indicate the proportion of the miscellaneous mechanisms responsible for some VWD type. For type 1 VWD, the main mechanism was classical dominant negative mutations of VWF gene leading to synthesis/secretion defects (53%), whereas mutations responsible for an accelerated VWF clearance represented 20% of cases; heterozygous mutations usually described in type 3 VWD accounted for 20% of patients (type 3 carriers); mutations within VWF propeptide cleavage site were rare (3.5%) and the mechanism remained unknown in 3.5% of cases (no mutation found). In patients with type 2A VWD, the most common subtype was 2A(IIA) (62%) including a large majority of mutations within the A2 VWF domain inducing an increased VWF proteolysis by ADAMTS13 (59%), whereas mutations within the A1 VWF domain were rare (4%); subtype 2A(IIE) was frequent, accounting for 34.5% of type 2A, whereas subtypes 2A(IIC) and 2A(IID) were rare, representing 3% and 1%, respectively. Type 2B VWD included either a majority of classical 2B mutations located within the A1 VWF domain (85%) or some New York mutations within the D3 VWF domain (15%). In patients with type 2M VWD, the most common mechanism was mutations within the A1 VWF domain inducing a 2M/2A-like phenotype (63%) related to a defective binding of VWF to GPIb; the 2M phenotype consisted in a decreased binding of VWF to collagen (37%) related either to mutations within the A1 VWF domain or the A3 VWF domain. Type 2N VWD included patients with either bi-allelic 2N mutations (2N/2N, 54%) or a combination of a mono-allelic 2N mutation (expressed allele) with a mutation inducing a silent allele (2N/3, 46%).IC = index cases, VWD = von Willebrand disease, VWF = von Willebrand factor.