Commentary on the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD: reflections based on recent contemporary test data
Emmanuel J. Favaloro
Abstract
on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia on the diagnosis 1 and management 2 of von Willebrand disease (VWD). These now add to the many prior guidance documents, in particular several key publications This commentary is in relation to the diagnostic guidelines 1 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." 1(p283) 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. 6,7 Moreover, VWF:GPIbM seems to be favored over VWF:GPIbR, 1 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. 8 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." 1( p283) 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.