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

Like many others, I was very interested to see the recent 2021 guidelines by the American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia on the diagnosis and management of von Willebrand disease (VWD). These now add to the many prior guidance documents, in particular several key publications; nevertheless, the new guidelines are destined to become those most closely followed. This commentary is in relation to the diagnostic guidelines and focuses on 3 main items related to laboratory testing. First, the “panel suggests newer assays that measure the platelet-binding activity of von Willebrand factor (VWF) (eg, VWF:GPIbM [glycoprotein Ib binding assay for VWF using recombinant mutated GPIb (no ristocetin)], VWF:GPIbR [glycoprotein Ib binding assay for VWF using recombinant GPIb (and ristocetin)]) over the VWF ristocetin cofactor assay (VWF:RCo) (automated or nonautomated assay) for the diagnosis of VWD. ” This is because classical VWF:RCo is diagnostically problematic as a result of high assay variability and poor low VWF level quantification limits, leading to a high diagnostic error rate. Moreover, VWF:GPIbM seems to be favored over VWF:GPIbR, because assays based on ristocetin may falsely identify type 2 VWD as a result of exon 28 polymorphisms that may reduce ristocetin binding. In particular, for 1 polymorphism (D1472H), 35% of the Black controls were homozygous for the H allele, whereas all the White controls with D1472H were heterozygous. Second, for type 2 VWD, the “panel suggests against a platelet-dependent VWF activity/VWF:Ag [VWF antigen] ratio ,0.5 cutoff, and rather using a higher cutoff of ,0.7 to confirm type 2 VWD (2A, 2B, or 2M) for patients with an abnormal initial VWD screen. ” Third, although not a specific recommendation, the panel supports, within its published algorithm, a core test panel comprising VWF:Ag, platelet-dependent VWF activity, and factor VIII coagulant assay (FVIII:C) and relegates collagen binding activity (VWF:CB) to a supplementary assay, as a potential alternative to multimer analysis, to further characterize type 2 VWD, but notably relies on using the prior platelet-dependent VWF activity/Ag ratio of ,0.7. Many of the recommendations build upon one another; for example, poor initial selection of a platelet-dependent VWF activity assay may lead to failure to appropriately characterize type 2 VWD for further testing, including application of VWF:CB or multimer analysis. Also important to note, the term “suggests” indicates a conditional recommendation that is likely to be strengthened (for future updates or adaptation) by further research. Therefore, in this commentary, I provide some additional data to help inform future iterations of such guidance. For this, I largely highlight some recently published work. First, in our most recent external quality assessment (EQA) publication, highlighting VWD diagnostic errors as linked to test types/test panels, we found, as detailed in Table 1, (1) VWF:RCo showed the highest assay variability and poorest quantification limit among all platelet-dependent VWF activity assays; (2) VWF:GPIbR performed by CLIA was the least variable (with the lowest quantification limit) platelet-dependent VWF activity assay, followed in turn by VWF:GPIbR by LIA, VWF:GPIbM (LIA), and VWF:RCo (Figure 1A); (3) CLIA methodology was the least variable method overall (all available assays) (Figure 1A); (4) 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, whereas VWF:GPIbR and VWF:CB were associated with few errors; (5) error rates associated with a standard 3-test panel (ie, as per the guidelines: