Laboratory variability in the diagnosis of type 2 VWD variants

Abstract

Patients with von Willebrand disease were enrolled in our study. Type 2 VWD diagnoses were based on original test results. Repeat evaluation resulted in many patients receiving a different type 2 diagnosis. Some genetic variants were particularly likely to move type 2 subcategories. Abstract IntroductionType 2 von Willebrand disease (VWD) refers to patients with a qualitative defect in von Willebrand factor. Accurate diagnosis of type 2 VWD subtypes can be challenging. Aim of the studyTo compare the historical diagnosis of type 2 VWD with current laboratory testing. MethodsSubjects were enrolled in the Zimmerman Program either because of a preexisting diagnosis of VWD (retrospective cohort) or from evaluation for bleeding symptoms or suspected VWD (prospective cohort). Original diagnosis was assigned by the local center and central diagnosis was based on central laboratory testing. ResultsTwo hundred and seventeen index cases in the retrospective cohort and 35 subjects in the prospective cohort carried a local diagnosis of type 2 VWD (29% and 6% of enrolled index cases, respectively). In the retrospective cohort, the diagnosis was confirmed in 66% of cases with a preexisting diagnosis of 2A, 77% 2B, 54% 2M, and 72% 2N. In the prospective cohort, 31% were confirmed 2A, 60% 2B, 23% 2M, and 100% 2N. Several genetic variants were repeatedly implicated in subjects with changed diagnosis: p.M1304R, p.R1315C, p.R1374C, and p.R1374H. ConclusionsBoth the prospective and retrospective cohorts demonstrated consistent variation in subjects whose diagnosis changed between 2A, 2B, and 2M. The importance of accurately diagnosing type 2 VWD may be most significant in the 2B subtype given potential concerns with the use of desmopressin in type 2B VWD. Some genetic variants appear in multiple types of VWD, making specific diagnoses challenging.

Phenotypic and genetic characterizations of the Milan cohort of von Willebrand disease type 2

“…Several variants are reported in the literature to be associated with different VWD types, and the classification of these variants is still a matter of debate. In a recent report from the Zimmerman cohort, 38 p.Arg1374Cys was associated with type 2A and type 1C and p.Arg1374His with type 1C. p.Arg1315Leu/Cys substitutions are other variants of controversial diagnoses.…”

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

“…Despite the wide range of available laboratory assays, the phenotypic characterization of VWD is complex and currently imperfect, particularly the type 2 subclassification. Consequently, there are discrepancies in VWD diagnoses among clinical laboratories 37 . VWD type 2M is frequently underrecognized and misidentified as VWD type 1 or type 2A 38,39 .…”

“…Consequently, there are discrepancies in VWD diagnoses among clinical laboratories. 37 VWD type 2M is frequently underrecognized and misidentified as VWD type 1 or type 2A. 38 , 39 An accurate distinction between VWD type 1 and type 2 is relevant because of a generally more severe bleeding phenotype in VWD type 2 and a differential response to desmopressin.…”

VWF‐Gly2752Ser, a novel non‐cysteine substitution variant in the CK domain, exhibits severe secretory impairment by hampering C‐terminal dimer formation

“…The phenotypic expression of VWF in heterozygotes in families is highly variable. The reason for this is that the relationship between VWD gene variants and phenotype is notoriously difficult to establish in type 1 and type 2 studies, 38,39 and certain variants may be diagnosed differently in different patients. This may be the reason for the phenotypic variability in the family studied here.…”