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

Abstract

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“Von Willebrand disease type 2M: Correlation between genotype and phenotype”: Comment from Favaloro

“…Accordingly, VWF:Ab/Ag tended to be higher than VWF:RCo/Ag, VWF:GPIbR/Ag, and VWF:GPIbM/Ag in each case, but especially for the 3974C>T = Ser1325Phe variant (D). As expected, and consistent with data from prior studies from our laboratory 3 and from Maas et al, 1 given these are variants within the A1 VWF domain, VWF:CB would be fairly concordant with VWF:Ag, and thus arising VWF:CB/Ag ratios would be fairly normal. Ab, antibody; Ag, antigen; CB, collagen binding; GPIb, glycoprotein Ib; GPIbM, gain-of-function "mutated" GPIb; GPIbR, recombinant GPIb; RCo, ristocetin cofactor; VWD, von Willebrand disease; VWF, von Willebrand factor In conclusion, in 2021, it is no longer appropriate to lump all assays purporting to reflect VWF activity associated to platelet GPIbbinding function into a single bucket.…”

“…4 Nevertheless, these data clearly show different patterns between different "VWF:Act" assays in two different cases of type 2M VWD (Figure 1). Both cases (3965A>c = His1322Pro and 3974C>T = Ser1325Phe [homozygous]) represent VWF A1 variants, and the findings from Maas et at., 1 for A1 variants in their case series, reflected low relative "VWF:Act/Ag" (median 0.32 [interquartile range 0.24-0.48]) but normal VWF:CB/Ag (0.80 [0.65-1.01]). In the two cases shown in Figure 1, VWF:CB/Ag ratios were (as "expected") normal, and VWF:Act/Ag ratios were generally low; however, VWF:Ab/Ag ratios were the least low, especially for the 3974C>T = Ser1325Phe variant, where ratios were generally normal.…”

“…Thus, ristocetin cofactor (VWF:RCo) was used in 35 patients, a monoclonal-based assay (VWF:Ab) was used in nine patients, a gainof-function "mutated" GPIb (VWF:GPIbM) assay in three patients, and a recombinant GPIb (VWF:GPIbR) in five patients. 1 However, the patients were more or less treated as a homogeneous group for such VWF:Act, and only composite data were reported in the main manuscript. The authors "justified" this on the basis that all these assays essentially reflected assays able to identify "VWF-dependent platelet adhesion."…”

Von Willebrand disease type 2M: Correlation between genotype and phenotype: Comment from Woods et al.

“…

We read with interest the recent manuscript by Maas et al 1 In this study, the authors investigated a group of von Willebrand disease type 2M (VWD2M) with disease-causing variants (DCVs) in von Willebrand factor (VWF) A1 and VWF A3 domains. In addition to VWF:Act, VWF:CB using collagen type III and multimeric analysis were included in their VWF testing.

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“…Therefore, VWF multimeric analysis must always be performed routinely, and VWF:CB should not replace it. In this way, many cases of false VWD type 2A and therefore misdiagnosing of VWD type 2M could be avoided.Von Willebrand disease type 2M: Correlation between genotype and phenotype: Reply to comment from Dr. Favaloro and to comment from Dr. Woods et alWe would like to thank Dr. Favaloro for his interest in and comments on our recent publication about the correlation between genotype and phenotype in patients with von Willebrand disease (VWD) type 2M,1,2 and we also thank Dr. Woods et al for their interest in our publication and the clear description of their recently published results on the differences in the clinical and laboratory profiles of patients with VWD type 2A and type 2M…”