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

Abstract

I was very interested to see the recent publication on diagnosis of type 2M von Willebrand disease (VWD) in this jounal. 1 This manuscript investigated 52 patients with 2M VWD, and in particular reported on the correlation between genotype and phenotype; for example, finding different phenotype patterns based on whether mutations were found in the von Willebrand factor (VWF) A1 vs A3 domains. As such, the manuscript certainly advances the field. This Commentary reflects on some recent data that seem to be omitted from the manuscript. First, a recent paper has been published, similarly finding differences in VWF phenotype/genotype correlations for type 2 VWD according to the affected VWF domain but seems to be omitted from the reference citations. 2 It is possible that this paper was not in press at the time of their study. Nevertheless, Woods et al. reported on the differences between and among 2A and 2M VWD according to whether cases reflected variants in the A1 domain (2x 2A, 36x 2M) or the A2 domain (29x 2A, 39x 2M). In brief, in type 2M with disease-causing variants (DCVs) in the VWF-A1 domain, VWF collagen binding (CB), using type 1 collagen, to antigen (Ag) ratio (CB1/Ag) was normal, but with DCVs in the VWF-A2 domain, CB1/Ag was low. There was also a higher frequency of major bleeding in VWD 2M patients with DCVs in the VWF-A2 domain than those with DCVs in the VWF-A1 domain, which the authors proposed could be a summative effect of abnormal C1B/Ag, on top of the reduced VWF platelet glycoprotein Ib (GPIb) binding. In silico modeling also suggested that DCVs impairing the VWF-A2 domain somehow modulate collagen binding to the VWF-A3 domain.Another comment on the data provided in the earlier report 1 is around the different utility of different "platelet GPIb-binding" assays for phenotypic assessment of 2M VWD. In their report, although a single VWF:CB assay was used to interrogate VWF collagen binding in all 2M VWD cases, 1 three different assays were used to interrogate what the authors called VWF "activity" (VWF:Act).

Toward 50 Years of Seminars in Thrombosis and Hemostasis

“…The VWF:CB remains a personal favorite of mine, and I still continue to publish on both the VWF:CB and VWD, with several related papers published in 2022. 2 3 4 5 6 Nevertheless, the VWF:CB does deserve another historical evaluation in STH, but this can await another issue in this series. I mention this in part because VWD was also a favorite of Eberhard's.…”