Significant gynecological bleeding in women with low von Willebrand factor levels

Abstract

Gynecological bleeding is frequently reported in women with von Willebrand disease (VWD). Low von Willebrand factor (VWF) may be associated with significant bleeding phenotype despite only mild plasma VWF reductions. The contribution of gynecological bleeding to this phenotype has yet to be described. The optimal clinical bleeding assessment tool (BAT) to evaluate bleeding remains unclear. Using a standardized approach to phenotypic assessment, we evaluated gynecological bleeding and directly compared the Condensed Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD (Condensed MCMDM-1 VWD) and International Society on Thrombosis and Haemostasis (ISTH) BAT scores in 120 women enrolled in the Low von Willebrand in Ireland Cohort study. Heavy menstrual bleeding (HMB) was reported in 89% of female participants; 45.8% developed iron deficiency. Using identical data, Condensed MCMDM-1 VWD menorrhagia domain scores were significantly lower than ISTH BAT scores (2 vs 3; P < .0001), the discrepant results related to 40% of women not seeking medical consultation for HMB, reducing the sensitivity of the Condensed score. For those who reported HMB to physicians, the low VWF diagnosis was not expedited (age at diagnosis 34.2 vs 33.4 years in women failing to present; P = .7). Postpartum hemorrhage (PPH) was self-reported in 63.5% of parous women (n = 74); 21.6% required transfusion, critical care, radiological, or surgical intervention. Our data demonstrate that gynecological bleeding is frequently reported in women with low VWF; despite pregnancy-related increases in plasma VWF levels, these women may experience PPH. Defining the optimal management approach for these patients requires further research. This trial was registered at www.clinicaltrials.gov as #NCT03167320.

Conflict of interest statement

Conflict-of-interest disclosure: M.L. has served on a speaker’s bureau for Shire and received research funding from Baxter. J.S.O. has served on the speaker’s bureaus for Baxter, Bayer, Novo Nordisk, Boehringer Ingelheim, Leo Pharma Shire, and Octapharma; has served on the advisory boards of Baxter, Bayer, Octapharma CSL Behring, Daiichi Sankyo, Boehringer Ingelheim, Shire, and Pfizer; and has also received research grant funding awards from Baxter, Bayer, Pfizer, Shire, and Novo Nordisk. P.D.J. has received research funding from CSL Behring, Bayer, and Shire. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Philipps score and menorrhagia bleeding scores in women with low VWF. (A) Bar chart of the number of women with positive responses to the 4 domains included in the Philipps tool. (B) Comparison of the ISTH BAT and Condensed MCMDM-1 VWD menorrhagia-domain score in women with low VWF using identical clinical information (median 3 vs 2, P < .0001, median and interquartile range [IQR], indicated for Condensed MCMDM-1 VWD; for the ISTH BAT both the median and IQR are equal to 3). (C-D) Bar chart of menorrhagia-domain bleeding scores by lowest recorded plasma VWF levels. When examined by lowest recorded plasma VWF levels, 84% of those female enrollees with lowest levels (30-39 IU/dL) had ISTH BAT menorrhagia-domain scores ≥3 in comparison with 67% of patients with lowest plasma VWF level (40-50 IU/dL) (C). A similar pattern was seen using the Condensed MCMDM-1 VWD score (D).

Figure 2.

Ferritin levels in women with low VWF and pregnancy related changes in plasma VWF levels. (A) Scatter dot plot of lowest recorded ferritin (n = 103) with the median (21.1 μg/L) indicated by the red bar and lower limit of the normal reference range (23.0-393 μg/L) by the dotted line. (B-C) Plasma VWF:Ag levels (B) and VWF:RCo levels (C) at baseline and during pregnancy in a subgroup of 32 women (38 pregnancies). Normal reference range indicated by dotted lines.