Predictors of Diagnostic Delays and Loss to Follow-up in Women with Von Willebrand Disease
Authors: Shelton Jaclyn , Millions Michelle , Khalife Roy , Sun Haowei (Linda) 
Published: December 2023

Background: Diagnostic and treatment delays in von Willebrand disease (vWD) disproportionately affect women. Such delays may lead to poor health outcomes from preventable bleeding complications related to menstruation, childbirth, and surgeries. They may also result in increased health resource utilization, including increased emergency department (ED) visits, transfusions, and surgical interventions. Patient and disease-related factors associated with diagnostic delays and loss to follow-up have been poorly documented, but are important to examine particularly in relation to gynecological outcomes.
Aims: 1) To examine the prevalence and predictors of diagnostic delays and loss to follow-up in women with vWD. 2) To assess the impact of diagnostic delays on rates of ED visits, red cell transfusions, and hysterectomies.
Methods: This retrospective cohort study included women ≥18 years with a diagnosis of vWD followed by the Northern Alberta Bleeding Disorders Program. Diagnostic delay was determined from the time of first documented bleeding event to the time of vWD diagnosis, with delayed diagnosis defined as &gt;5 years. All bleeding events on the ISTH-BAT were included in the above definition, except for easy bruising due to its subjectivity and suboptimal documentation. Loss to follow-up was defined as ≥5 years since last hematology visit at the time of data collection. We collected the following patient and disease-related factors: age, rural status, year of diagnosis (pre-2000, 2000-2010, or 2011-2021), vWD type, baseline vWF activity, ISTH-BAT, family history of vWD, abnormal coagulation screen (INR/aPTT) prior to diagnosis, and status-post endometrial ablation or hysterectomy. Logistic regression was used to assess predictors of diagnostic delays and loss to follow-up. Research ethics approval was obtained.
Results: We included 173 women: 140 (81%) type 1, 23 (13%) type 2, 5 (3%) type 3, and 5 (3%) platelet-type vWD. The median age of diagnosis was 27 years (IQR 18-38). The median time from first bleeding symptom to vWD diagnosis was 12.1 years (IQR 4.6-24.2), with 66 (38%) women presenting with ≥3 bleeding events prior to diagnosis. Further, 71 (41%) presented with ≥1 severe bleeding event (requiring ED visit, hospitalization, red cell transfusion, or surgical hemostasis) prior to diagnosis.
Timing from first bleeding symptom to diagnosis was available in 154 (89%) women, of whom 113 (73%) experienced delayed diagnosis. Compared to women with delayed diagnosis, those diagnosed within 5 years of their first bleeding symptom were more likely to have a known family history of vWD (51% vs 26%, P=0.01) or have been diagnosed between 2000-2010 (56% vs 33%, P=0.002). Urban/rural residence, vWD type, baseline vWF activity, blood type, and abnormal coagulation screen were not significantly associated with diagnostic delays (Table 1).
Of the 155 patients with available follow-up data, 44 (28%) were lost to follow-up for ≥5 years. Only rural residence (OR 1.8, 95% CI 0.9-5.3, P=0.07) trended towards higher odds of loss to follow-up. Age, year of diagnosis, vWD type, baseline vWF activity, ISTH-BAT, and prior hysterectomy/ablation status were not associated with loss to follow-up.
Women with diagnostic delays had a significantly higher ISTH-BAT (median 7 vs 5, P=0.005). They also had significantly higher rates of hysterectomies for heavy menstrual bleeding (HMB; 20% vs 0%, P=0.0006), as well as a non-significant trend towards higher rates of dilatation and curettage (D&C; 12% vs 2%, P=0.11) and endometrial ablations (12% vs 5%, P=0.36) (Table 2). 17 women underwent surgical procedures for HMB (D&C, endometrial ablation, and/or hysterectomy) prior to their vWD diagnosis.
Conclusion: Women with vWD often experience prolonged diagnostic delays. In our study, many women had bleeding symptoms for at least 5 years, and often greater than 10 years, prior to diagnosis. There was also a high rate of loss to follow-up, particularly in rural populations. Delayed diagnosis occurred even in women with a known family history of vWD and in women with severe bleeding events. Alarmingly, the rate of delayed diagnosis increased over time and was associated with higher rates of surgical interventions for HMB. For this reason, a high index of suspicion is paramount to ensure a prompt diagnosis of vWD, as this may prevent severe gynecological bleeding complications and their need for invasive surgical management.