von Willebrand disease in women : heavy menstrual bleeding and obstetrical bleeding

Von Willebrand disease is the most common inherited bleeding disorder worldwide with a prevalence, reaching 1% of general population. vWD is equally distributed between genders. However, vWD-affected females experience specific hemostatic challenges during menstruation and childbirth. Despite intensive research within the field, there are still many unsolved issues, related to the fundamental mechanisms of the increased bleeding tendency. This thesis was divided into clinical part (Study I and Study II) and fundamental part (Study III and Study IV). The former has explored current management options for vWD-patients, suffering from excessive menstrual bleeding and postpartum hemorrhage (PPH), respectively. Fundamental part aimed to enhance our understanding of the dynamics of hemostasis contributing to excessive menstrual bleeding in women with VWD.

Study I explored the prevalence of heavy menstrual bleeding (HMB) among vWD affected females, its impact on everyday life activities and overall health-related quality of life. Information was obtained using self-administered forms and medical records. Of the 30 women (18-52 years) included in the study, a half (50%) suffered from HMB. This occurred despite the fact, that the majority of women received treatment for HMB. Almost all women had limitations in their everyday life activities, caused by HMB. The overall health-related quality of life was lower with regards to ‘bodily pain’ in women with HMB, compared to general Swedish population. Close interaction between hematologists and gynecologists is necessary in order to prevent limitations and improve quality of life in women with vWD. Study II investigated the incidence of PPH in women with vWD, its correlation with i) type of vWD ii) levels of vWF and FVIII iii) treatment options. 34 women (59 deliveries) occurred in 14 different clinics (years 1995-2012) were included in the study. The incidence of primary PPH, severe primary PPH and secondary PPH was 44%, 20% and 12%, respectively, which is greater than in general population. Women with type 3 vWD was at greater risk of experiencing severe primary PPH, compared to other types. Another risk factors were instrumental assisted delivery and undiagnosed vWD at the time of delivery. FVIII levels during late pregnancy was inversely correlated to blood loss during delivery. Therefore, in order to decrease morbidity, we should identify women with yet unknown vWD more actively, probably through providing them with the validated self-administered blood questionnaires in the antenatal settings. Once being diagnosed, vWD require comprehended approach, so that PPH could be prevented. Study III assessed the changes in hemostatic variables in women with vWD during a regular menstrual cycle and compared them with healthy controls. 12 vWD affected females (NOT pregnant/breastfeeding/on hormonal treatment) were compared with 102 healthy controls, matched for age and BMI. In women with vWD, thrombin generation profiles were altered, with prolonged lag-time, time to peak and decreased peak thrombin concentration, compared to controls. AT was also higher in the study group, which may potentially contribute to the excessive bleeding in this cohort. Within the vWD group, FVIII and FX were significantly lower during the luteal phase, than in follicular phase. The decrease in procoagulant agents prior to menstruation may predispose women with vWD to the development of HMB. Therefore, altered thrombin generation dynamics, together with increased AT and decline in FVIII and FX prior to menstruation, can potentially play role in the excessive blood loss during menstruation in women with vWD. Study IV explored how do inflammatory and endothelial markers change during the menstrual cycle in women with vWD. 12 vWD affected females (NOT pregnant/breastfeeding) were compared with 102 healthy controls, matched for age and BMI. Within the study group (vWD), endostatin levels were higher during the follicular phase, than in luteal phase. Since endostatin inhibits angiogenesis and coagulation, its rise during early follicular phase (which corresponds to menstrual phase of the uterine cycle) may affect the hemostasis within the uterine cavity and therefore contribute to the development of HMB. Women with vWD were different from healthy controls in terms of balance between pro- and anti-angiogenic markers, with sICAM-1 and IL-6 being higher in women with vWD, compared to controls, while sVCAM-1, cathepsin S and sPselectin were lower. The pattern was constant across the menstrual cycle. Hypothetically, this imbalance could lead to the formation of angiodysplasia - common complication of vWD. The above statement, however, requires verification in larger well-designed studies.

In conclusion; this thesis reports, that the current approaches are still insufficient in terms of preventing common vWD complications - HMB and PPH. It emphasizes the importance of early diagnosis, providing to the patients the reliable information on drugs, proactive management and close collaboration between hematologists and ob&gyn specialists. Furthermore, the thesis provides additional knowledge on how do coagulation and inflammatory systems change in response to the sex steroids fluctuations during the menstrual cycle. It reaffirms intimate interactions between coagulation and inflammatory systems. Our work suggests, that multiple factors with versatile effects, rather than simple decrease in vWF, are responsible for the development of HMB in women with vWD.

List of scientific papers

I. GOVOROV I, Ekelund L, Chaireti R, Elfvinge P, Holmström M, Bremme K, Mints M. Heavy menstrual bleeding and health-associated quality of life in women with von Willebrand's disease. Experimental and therapeutic medicine. 2016;11(5):1923-1929.
https://doi.org/10.3892/etm.2016.3144

II. GOVOROV I, Löfgren S, Chaireti R, Holmström M, Bremme K, Mints M. Postpartum Hemorrhage in Women with Von Willebrand Disease – A Retrospective Observational Study. PloS one. 2016;11(10):e0164683.
https://doi.org/10.1371/journal.pone.0164683

III. GOVOROV I, Bremme K, Lindahl TL, Holmström M, Komlichenko E, Chaireti R, Mints M. Thrombin generation during a regular menstrual cycle in women with von Willebrand disease. [Manuscript]

IV. GOVOROV I, Bremme K, Larsson A, Holmström M, Komlichenko E, Chaireti R, Mints M. Blood inflammatory and endothelial markers in women with von Willebrand disease. [Manuscript]