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

Abstract

von Willebrand disease (VWD) arises from deficiency and/or defects of von Willebrand factor (VWF). Assessment requires test panels, including VWF activity and antigen. Appropriate diagnosis including differential identification of qualitative versus quantitative defects remains problematic but has important management implications. Data using a large set (n=27) of varied plasma samples comprising both quantitative VWF deficiency ('Type 1 and 3') vs qualitative defects ('Type 2') tested in a cross-laboratory setting have been evaluated to assess contemporary VWF assays for utility to differentially identify sample types. Different VWF assays and activity/antigen ratios showed different utility in VWD and type identification. Identification errors were linked to assay limitations, including variability, and laboratory issues (e.g., test result misinterpretation). Quantitative deficient (type 1) samples were misinterpreted as qualitative defects (type 2) on 35/467 occasions (7.5% error rate); 11.4% of these errors were due to laboratories misinterpreting their own data, which was instead consistent with quantitative deficiencies. Conversely, qualitative defects were misinterpreted as quantitative deficiencies at a higher error rate (14.3%), but this was more often due to laboratories misinterpreting their data (40% of errors). For test-associated errors, VWF:RCo and VWF:GPIbM were associated with the highest variability and error rate, which was many-fold higher than that using VWF:CB. Chemiluminescence ('CLIA') procedures were associated with lowest inter-laboratory variability and errors overall. These findings in part explain the high rate of errors associated with VWD diagnosis. VWF:GPIbM showed a surprisingly high rate of test associated errors, whilst CLIA procedures performed best overall.

Keywords: VWD; VWF; assay variability; diagnosis; errors; interpretation; laboratory testing; von Willebrand disease; von Willebrand factor.