Evaluating errors in the laboratory identification of von Willebrand disease using contemporary von Willebrand factor assays

Commentary on the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD: reflections based on recent contemporary test data

“…For this, I would largely highlight some recent work that has been published. 6,7,[9][10][11][12][13] First, in our most recent external quality assessment (EQA) publication, 9 highlighting "VWD diagnostic errors" as linked to test types/test panels, we found, as detailed in Table 1: (a) VWF:RCo showed highest assay variability and poorest quantification limit among all platelet-dependent VWF activity assays; (b) VWF:GPIbR performed by chemiluminescence immunoassay (CLIA) was the least variable (with lowest quantification limit) platelet-dependent VWF activity assay, followed in turn by VWF:GPIbR by latex immunoassay (LIA), VWF:GPIbM (LIA), and VWF:RCo (Figure 1A); (c) CLIA methodology was the least variable method overall (all available assays) (Figure 1A); (d) for associated diagnostic errors of type 1 ('quantitative' VWF deficiency) vs type 2A/2B (high molecular weight [HMW] VWF deficiency) samples, the most problematic platelet-dependent VWF activity assay was VWF:RCo, followed by VWF:GPIbM; comparatively, VWF:GPIbR and VWF:CB were associated with few errors; (f) error rates associated with a 'standard' 3-test panel (i.e., as per the guidelines 1 -FVIII:C, VWF:Ag, platelet-dependent VWF activity assay) were twice that of a 4-test panel including the VWF:CB; (g) no single 'universal' cut-off value (e.g., 0.5 or 0.7) for activity/Ag was sufficiently robust to effectively identify/exclude type 2A/B VWD; indeed, ideal cut-off values are method 'specific' (Figure 1B), but should a universal cut-off be required, perhaps 0.6, in line with recommendations of the UK Haemophilia Doctors organization 4 could be favored (also see Supplementary Figure 1); (h) best VWD type discrimination was achieved using CLIA methods (i.e., GPIbR/Ag or CB/Ag), followed by GPIbR/Ag (LIA); other methods, including RCo/Ag and GPIbM/Ag showed substantial ratio overlap between type 1 vs 2A/2B VWD (Figure 1B). In summary, the composite of this EQA data would favor CLIA methodology over all other methodologies, and for platelet-binding activity assays would favor VWF:GPIbR over both VWF:GPIbM and VWF:RCo.…”

Comparing the quality of testing for von Willebrand disease in different geographic localities

“…Comparative VWF assay variability, summarizing data from the RCPAQAP 2 . Data shown as coefficient of variation (CV; percent; left y‐axis), as bars of median and upper error bar showing upper third quartile range, for main assay types used by RCPAQAP participants.…”

“…whereas NASCOLA identified relative high variability for VWF:CB, it needs to be clarified that this was exclusively using ELISA based methods 1 . RCPAQAP data 2 largely confirms relative high variability for VWF:CB by ELISA, but conversely identifies relative low variability for VWF:CB by CLIA (Figure 1), which is increasing in usage in our geographic locality, 2 but which is unavailable in North America 5,6 . In addition, a higher number of RCPAQAP participants (40% overall) report VWF:CB data, whereas only 14% of NASCOLA participants do so (Table 1).…”

“…2 This study assessed a similar number of samples (total n = 27; normal = 8, type 1 = 7, type 2 = 10), as distributed to participants, with a partially overlapping period of analysis of 2014-2021. 2 Nevertheless, it is recognised that the Royal College of Pathologists of Australasia Quality Assurance Program (RCPAQAP) data do represent a more recent overall date range. Some other specific similarities and differences are noted in Table 1.…”

2B von Willebrand disease diagnosis: Considerations reflecting on 2021 multisociety guidelines

“…We are pleased to see the panel encouraging critical review of the guidelines, which may facilitate regular revision/update.Compared to types 1 and 3, the diagnosis of type 2 VWD subtypes can be particularly challenging. 5 Type 2B VWD represents ≈5% of all VWD types. 6 The accurate diagnosis of this subtype is critical for many reasons, including concerns or potential harms related to the use of desmopressin (DDAVP).…”