Laboratory variability in the diagnosis of type 2 VWD variants

Abstract

Essentials 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: Introduction Type 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 study To compare the historical diagnosis of type 2 VWD with current laboratory testing. Methods Subjects 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. Results Two 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. Conclusions Both 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.

Keywords: Von Willebrand disease; Von Willebrand factor; genetic; medical laboratory science; polymorphism; ristocetin.

Figure 1.. Confirmed type 2 VWD diagnoses in the retrospective and prospective VWD cohorts.

Type 2 subjects enrolled in the retrospective cohort (RC) and prospective cohort (PC) are represented on the X axis for each type 2 diagnosis. The Y axis denotes number of local diagnoses confirmed by central testing in black and number without a confirmed diagnosis in grey. Both study groups demonstrated consistent variation in subjects with discrepancies between original and central laboratory diagnosis.

Figure 2.. Comparison of local vs central laboratory testing results for type 2 VWD subjects in the retrospective cohort.

Figure 2A. 98 index cases in the retrospective cohort carried a pre-existing diagnosis of type 2A VWD. Following central laboratory testing, the majority of cases (66%) were confirmed as type 2A VWD. Figure 2B. 62 index cases in the retrospective cohort carried a pre-existing diagnosis of type 2B VWD. Following central laboratory testing, the majority of cases (77%) were confirmed as type 2B VWD. Figure 2C. 39 index cases in the retrospective cohort carried a pre-existing diagnosis of type 2M VWD. Following central laboratory testing, around half of the cases (54%) were confirmed as type 2M VWD. Figure 2D. 18 index cases in the retrospective cohort carried a local diagnosis of type 2N VWD. Following central laboratory testing, the majority of cases (72%) were confirmed as type 2N VWD.

Figure 3.. Percent of confirmed type 2 VWD diagnoses in the prospective VWD cohort.

35 index cases in the prospective cohort carried a local diagnosis of type 2 VWD. Following central laboratory testing, 45% retained a diagnosis of type 2 VWD. The pie chart shows diagnoses of this group following central laboratory testing.