Glycoprotein 1bM Assay and Von Willebrand Disease: A Change in Diagnosis
Authors: Lazris David , Seaman Craig D. 
Published: December 2024

Introduction: Von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by a deficiency or dysfunction of von Willebrand factor (VWF) that manifests as mucocutaneous bleeding, such as easy bruising and heavy menstrual bleeding, and can lead to bleeding complications following surgery or trauma. Type 1 VWD accounts for approximately 75% of cases and often presents with mild symptoms, making it challenging to distinguish pathological bleeding from trivial or minor bleeding commonly reported in the healthy population. Diagnosis is further complicated by the limitations of current laboratory tests. The VWF ristocetin cofactor (VWF:RCo) assay, long considered the gold standard assay to measure VWF activity, may be affected by external factors (i.e. stress, inflammation, and estrogen), and internal factors, such as the D1472H polymorphism. Present in an estimated 17 and 63% of Caucasians and African Americans, respectively, the D1472H polymoprhism affects VWF binding to ristocetin without altering in vivo VWF activity. Newer assays, such as the VWF glycoprotein 1bM (VWF:GP1bM) assay, are more reliable, offering lower variability and higher reproducibility, and are not affected by the D1472H polymorphism. Current hematology societal guidelines recommend these newer assays over traditional VWF assays for diagnosing VWD. This study aims to perform a descriptive analysis of the impact of the VWF:GP1bM activity assay on the diagnosis of VWD among previously diagnosed patients at the Hemophilia Center of Western Pennsylvania (HCWP).

Methods: In this retrospective chart review, relevant data was abstracted from the HCWP electronic health record (EHR). Inclusion criteria consisted of 1) historical diagnosis of VWD, in part based on VWF:RCo activity, 2) VWF:GP1bM activity performed separate from and subsequent to the historical diagnosis of VWD, and 3) 18 years of age at the time of data abstraction. Patients with a concomitant hereditary bleeding disorder were excluded. Demographics; VWF:RCo (oldest value) and GP1bM (most recent value) activity; D1472H polymorphism status; estrogen use and pregnancy status at the time of laboratory testing; and bleeding symptoms as documented in the initial HCWP office note were recorded. The primary outcome was change in diagnosis and defined as a change in historical VWF:RCo assay-based diagnosis to an alternative current VWF:GP1bM assay-based diagnosis. Means and standard deviations for continuous variables and frequencies for categorical variables were used to summarize the data. A Student's t-test was performed to compare VWF:RCo and GP1bM activity according to estrogen use and pregnancy status. Logistic regression was performed to predict the association of the D1472H polymorphism with a change in diagnosis.

Results: This study analyzed 138 patients with a mean age of 36.7 years (SD 16.9). Most patients were female, 81.9%; White, 88.4%; and non-Hispanic, 98.6%. The mean VWF:RCo and VWF:GP1bM activity were 0.56 and 0.73 IU/dL, respectively. VWF:RCo, 0.84 vs 0.53 IU/dL, p&lt;0.01, and GP1bM, 1.27 vs 0.68 IU/dL, p&lt;0.01, activity was higher in pregnant patients. The most common bleeding symptoms were heavy menstrual bleeding, 73.9%; ecchymosis, 63.8%; epistaxis, 44.9%, dental-related bleeding, 34.5%; and prolonged bleeding with wounds, 23.9%. The most common initial diagnosis was type 1 VWD, 94.2%. The most common diagnoses after GP1bM testing were type 1 VWD, 52.9%; no bleeding disorder, 26.1%; bleeding of unknown cause, 9.4%; and platelet dysfunction, 9.4%. The GP1bM assay led to a change in diagnosis in 42.7% of patients. Of the 73.1% of patients with VWF gene sequencing, 18.8% had the D1472H polymorphism, The presence of the D1472H polymorphism was associated with a 10.6 greater odds, p&lt;0.01, change in diagnosis.

Discussion: This study emphasizes the importance of using the GP1bM assay to ensure the proper diagnosis of VWD as evidenced by the large percentage of patients who had a change in diagnosis with the use of this test, many of whom were found to have no bleeding disorder. This is particularly important in those with the D1472H genetic polymorphism, where there was a 10.6- fold increase in the odds of a change in diagnosis when using the GP1bM assay. Overall, this study adds to a growing body of literature highlighting the importance of GP1bM testing in VWD in order to ensure an accurate diagnosis and proper treatment.