Towards tailoring care in the gynaecology for women with bleeding disorders Heleen Petri Eising
Towards tailoring care in the gynaecology for women with bleeding disorders Heleen Petri Eising
ISBN: 978-94-6506-746-9 Provided by thesis specialist Ridderprint, ridderprint.nl Printing: Ridderprint Layout and design: Hans Schaapherder, persoonlijkproefschrift.nl Cover and chapterpages: Heleen Petri Eising Copyright 2025 © Heleen Petri Eising, Amsterdam, The Netherlands All right reserved. No parts of this publication may be reproduced, stored, or transmitted in any form or by any means, without the prior written permission of the author, or when applicable, of the publishers of the scientific papers. Financial support for research end printing of this thesis has been kindly provided by Stichting wetenschapsfonds Gelre Ziekenhuizen and van de Tol Stichting. The research presented in this thesis was conducted at GROW – Research Institute for Oncology and Reproduction, Department Obstetrics and Gynaecology of Maastricht University. A digital version of this thesis can be found on: https://www.Junction.Care
Towards tailoring care in the gynaecology for women with bleeding disorders PROEFSCHRIFT Ter verkrijging van de graad van doctor aan de Universiteit van Maastricht, op gezag van de Rector Magnificus, Prof. dr. Pamela Habibović volgens het besluit van het College van Decanen, in het openbaar te verdedigen op woensdag 19 februari 2025 om 13.00 uur door Heleen Petri Eising
Promotor: Prof. dr. M.Y. Bongers (Universiteit van Maastricht) Copromotor: Dr. J.C. Leemans (Máxima MC) Beoordelingscommissie: Prof. Dr. M.E.A. Spaanderman (voorzitter, Universiteit van Maastricht) Prof. Dr. H-P. Brunner - La Rocca (Universiteit van Maastricht) Prof. Dr. F.W. Jansen (Leids UMC) Dr. L. Nieuwenhuizen (Máxima MC)
Paranimfen Marieke Punt Megan Milota
Voor mijn ouders en grootouders
CONTENTS Chapter 1 General introduction 11 Chapter 2 Prophylactic and therapeutic strategies for intraoperative bleeding in women with von Willebrand disease and heavy menstrual bleeding: a systematic review (Blood Rev 2023 Pages 101131) 19 Chapter 3 High prevalence of reduced thrombin generation and/or decreased platelet response in women with unexplained heavy menstrual bleeding (Int J Lab Hem. 2018;40:268–275.) 37 Chapter 4 The ISTH-BAT score and outcomes after endometrium ablation in women with heavy menstrual bleeding (Haemophilia 2023 Vol. 29 Issue 6 Pages 1573-1579) 53 Chapter 5 Total Self-BAT scores associated with choice of heavy menstrual bleeding treatment (Submitted) 67 Chapter 6 Women prefer proactive support from providers for treatment of heavy menstrual bleeding: A qualitative study in adult women with moderate or severe Von Willebrand disease (Haemophilia 2018;950–956.) 95 Chapter 7 A narrative medicine intervention on the obstetric-gynecological work floor using co-created site-specific poetry (Submitted) 109 Chapter 8 General discussion and future perspectives 131 Chapter 9 English summary 143 Chapter 10 Nederlandse samenvatting 149 Chapter 11 Impact paragraph 161 Appendices List of publications Dankwoord Curriculum Vitae 169 173 177
CHAPTER 1 GENERAL INTRODUCTION
12 Chapter 1 GENERAL INTRODUCTION Menstrual health At the 50th session of Human Rights Council panel on menstrual hygiene management, human rights and gender equality discussion (June 2022), the World Health Organisation (WHO) adopted Menstrual Health in the Human Rights Council agenda. WHO calls for three actions. Firstly, to recognize and frame menstruation as a health issue with physical, psychological, and social dimensions, and one that needs to be addressed from before menarche to after menopause. Secondly, to recognize that menstrual health means that people who menstruate, have access to information and education about it; to the menstrual products they need, especially for those who are displaced because of war or natural calamities; water, sanitation, and disposal facilities; to competent and empathic care when needed; to live, study and work in an environment in which menstruation is seen as positive and healthy not something to be ashamed of; and to fully participate in work and social activities. Thirdly, to ensure that these activities are included in the relevant sectoral work plans and budgets, and their performance is measured. More and more governments are calling for attention and change in menstrual health in recent years. Currently, there is also a discussion in the Netherlands about menstrual leave for those women whose periods are severe. Women with underlying bleeding disorders are one such group. These women are more likely to experience heavy bleeding throughout their lives, anemia, physical or emotional pain, and increased absenteeism from school and work. Despite the increased attention to menstruation as a global health issue, attention to the optimal route to timely detect bleeding disorders in women is lagging. As a result, there will continue to be delays in diagnosis and care for these people in 2024. Strategies to reduce bleeding in women Heavy menstrual bleeding (HMB) is mostly the first symptom of a bleeding tendency and various bleeding disorders (1-4). Von Willebrand disease (VWD) type 1 is one of the most common inherited bleeding disorders with a prevalence ranging from 5%-24% in patients with HMB (2). However, women with a bleeding disorder may also experience various other bleeding symptoms in addition to HMB, with which women may present at the outpatient clinic (5). An overall bleeding history besides an obstetrical-gynecological history is an important factor in reducing the diagnostic delay in bleeding disorders and could be crucial in optimizing gynaecological management (6-10). Awareness is key in screening for bleeding disorders in women with HMB or other gynaecological conditions (1, 11) Interventions such as narrowing knowledge gaps, increasing awareness of female care pathways, and promoting empathetic care are essential to improve the quality of care (2). Lack of progress for women with bleeding disorders Despite the increasing focus on the need to ensure menstrual health worldwide (3-5), women continue to have lengthy delays in referral and diagnosis of underlying bleeding disorders,
13 General introduction and clinical pathways remain underdeveloped (2, 6). Also, the lived experiences of women with bleeding disorders are often normalized (7). Therefore, it is crucial to provide an overview of the existing globally available literature on the prophylactic and therapeutic strategies for intraoperative bleeding in women with von Willebrand disease and heavy menstrual bleeding. To investigate the patients’ preferences regarding the type of support from providers for treatment of HMB, it is necessary to explore the perspective of women with VWD and suffering from HMB. To optimize the route to diagnosis for women with bleeding disorders, specialist laboratory testing should be improved. Table 1: Challenges faced by women and girls with bleeding disorders worldwide. Challenges facing women and girls with bleeding disorders worldwide Diagnostic inequality Normalisation of HMB within families Stigmatization Poor awareness of bleeding among health-care providers Delay in referral and diagnosis Global inequities in specialist testing Suboptimal treatment Lack a culture of prophylaxis for women and girls with bleeding disorders Knowledge gaps on optimal treatments Poor representation in clinical trials Lack female care ways Adopted from: Doherty D, Lavin M. Challenges facing women and girls with bleeding disorders. Lancet Haematol. 2023; 10: e875-e6. 10.1016/S2352-3026(23)00302-2.) Besides a gynaecological evaluation to rule out other causes of HMB, such as uterine fibroids, polyps, or hormonal imbalances, gynaecologists should take a comprehensive medical history to assess the severity and impact of menstrual bleeding (9). They should recognize symptoms indicative of bleeding disorders, such as easy bruising, hematuria, sexual bleeding, or excessive bleeding after procedures or giving birth (8). If initial screening suggests a potential bleeding disorder, a hematologist or a specialized bleeding disorders clinic should be consulted for further specific diagnostic laboratory testing, evaluation and management to determine the most appropriate pathway for each individual case (10). The high prevalence of reduced thrombin generation and/or decreased platelet response in women with unexplained heavy menstrual bleeding should be evaluated. Tools to predict bleeding in women Treatment options for heavy menstrual bleeding due to underlying bleeding disorders vary depending on the cause and severity of the symptoms and the accessibility to medications or surgical treatments. The choice of treatment also depends on factors such as the woman’s age, desire for future fertility, and overall health. Medications, hormonal therapies (pills, devices), tranexamic acid (TXA) and surgical interventions like endometrial ablation or hysterectomy may be recommended by healthcare professionals. A bleeding disorder can contribute to excessive 1
14 Chapter 1 or prolonged bleeding during surgery, and significantly increasing the likelihood of requiring blood transfusions compared to women without a bleeding disorder (1, 11). Bipolar endometrial ablation using radiofrequency energy (Novasure) is a minimally invasive procedure to remove the uterine lining, used to treat HMB and is an effective alternative to hysterectomy (12, 13). It is a minimally invasive procedure that can be performed in an outpatient setting. Studies show that around 80% of women with HMB and bleeding disorders experience a significant reduction in menstrual flow after the procedure and significant improvement in quality of life (14). To reduce the time between making the decision to seek care and the initiation of an appropriate treatment, a standardized questionnaire for screening bleeding disorders is a valuable step worldwide to reduce diagnostic delay (15). Bleeding assessment tools (BAT) are free and can be easily used by health care providers or patients and are reliable and feasible to detect a bleeding tendency (9, 15-17). Because the BAT questionnaire is a reliable and easy to use tool, we wanted to investigate whether this BAT score also influences the choice of HMB treatment and the outcome of surgical treatment for HMB. Therefore, the results of ISTH-BAT scores and outcomes after endometrial ablation in women with heavy menstrual bleeding should be evaluated, along with comparing the total Self-BAT scores with the chosen treatment options for heavy menstrual bleeding. Communication between health care providers and women with heavy menstrual bleeding Besides failure to recognize bleeding symptoms in women with HMB among health care providers, family and social relationships may contribute to minimize the significance of bleeding symptoms or normalize symptoms which can prolong the delay in help-seeking (6, 8). To bridge this gap, this thesis introduces a narrative medicine (NM) approach to the obstetric-gynecological work floor using a co-created site-specific poem in a gynecological clinical setting. Narrative medicine (NM) approaches using the arts, is heralded by the WHO as a valuable means to improve clinical practice (18). A NM arts-based intervention in healthcare settings has proven to be a potent strategy for overcoming health care providers and patients’ discomfort when breaching sensitive topics like stigmatization (19). When considering how to optimize support for women with bleeding disorders and gynaecological conditions, it may be fruitful to focus on concepts and concerns that are independent of diagnoses, such as ‘distress’ or ‘shame’ (20). Guided reflection on workplace experiences and personal perspectives can help clinicians become more attuned to patients’ perspectives and support needs (21). AIM OF THIS THESIS This thesis describes a study to investigate and optimize the route to diagnosis in adult (above 18 years of age) women with bleeding disorders in gynaecology. We focus on women, but acknowledge that this term might not include the gender identity of all people with the potential to menstruate (22). Bleeding disorders are defined by a bleeding tendency, either caused by acquired or inherited primary (platelets disorders) or secondary (coagulation factor)
15 General introduction haemostasis defects or hyperfibrinolysis (2). This thesis employs a trans- and interdisciplinary approach which will strengthen our insight into the pathways to diagnosis as related to social and environmental factors contributing to under- or misdiagnosis bleeding disorders among women with HMB. To better understand how to raise awareness for bleeding disorders and develop strategies to reduce delays in diagnosing bleeding disorders in women within a gynecological setting, we conducted several studies on this issue, focusing on women with HMB, both with and without underlying bleeding disorders. The following questions were considered essential: 1. Concerning strategies: What are intraoperative strategies to reduce intraoperative bleeding and what are patient preferences regarding surgical interventions for HMB in women with bleeding disorders? 2. Concerning prediction: How do diagnostic BAT scores associate with treatment choices and outcomes after endometrial ablation in women with HMB? 3. Concerning communication: What impact does a narrative medicine approach using site-specific arts have on healthcare providers’ awareness of stigmatization, and how do women benefit from these initiatives? To address these questions, we conducted the following studies: • Chapter 2 gives an overview of prophylactic and therapeutic strategies for managing intraoperative bleeding in women with von Willebrand disease and heavy menstrual bleeding. • Chapter 3 discusses the high prevalence of reduced thrombin generation and/or decreased platelet response in women with unexplained heavy menstrual bleeding. • Chapter 4 evaluates the results of ISTH-BAT scores and outcomes after endometrium ablation in women with heavy menstrual bleeding. • Chapter 5 evaluates the total Self-BAT scores compared to choice of heavy menstrual bleeding treatment. • Chapter 6 investigates women’s’ preferences toward the type of support from providers for the treatment of heavy menstrual bleeding. • Chapter 7 discusses a narrative medicine intervention on the obstetric-gynecological workfloor using co-created site-specific poetry. • Chapter 8 provides a general discussion on the clinical implications of this thesis and suggestions for further research. • Chapter 9 and 10 summarize the results of the thesis in English and Dutch. • Chapter 11 contains the impact paragraph. 1
16 Chapter 1 REFERENCE LIST 1. James PD. Women and bleeding disorders: diagnostic challenges. Hematology Am Soc Hematol Educ Program. 2020;2020(1):547-52. 2. Doherty D, Lavin M. Challenges facing women and girls with bleeding disorders. Lancet Haematol. 2023;10(11):e875-e6. 3. Mol BW, Bongers MY, Brolmann HA. Treatment of menorrhagia. Lancet. 2001;357(9271):1886-7. 4. van den Brink MJ, Beelen P, Herman MC, Geomini PM, Dekker JH, Vermeulen KM, et al. The levonorgestrel intrauterine system versus endometrial ablation for heavy menstrual bleeding: a cost-effectiveness analysis. BJOG. 2021;128(12):200311. 5. Herman MC, Mol BW, Bongers MY. Diagnosis of heavy menstrual bleeding. Womens Health (Lond). 2016;12(1):15-20. 6. Weyand AC, James PD. Sexism in the management of bleeding disorders. Res Pract Thromb Haemost. 2021;5(1):51-4. 7. Sanigorska A, Chaplin S, Holland M, Khair K, Pollard D. The lived experience of women with a bleeding disorder: A systematic review. Res Pract Thromb Haemost. 2022;6(1):e12652. 8. Punt MC, Ruigrok ND, Bloemenkamp KWM, Uitslager N, Urbanus RT, Groot E, et al. Prevalence, burden and treatment effects of vaginal bleeding in women with (suspected) congenital platelet disorders throughout life: a cross-sectional study. Br J Haematol. 2022;196(1):215-23. 9. Punt MC, Blaauwgeers MW, Timmer MA, Welsing PMJ, Schutgens REG, van Galen KPM. Reliability and Feasibility of the Self-Administered ISTH-Bleeding Assessment Tool. TH Open. 2019;3(4):e350-e5. 10. Curry N, Lowe G, Clark TJ. Inherited bleeding disorders in heavy menstrual bleeding: The case for joint haematological and gynaecological care. BJOG. 2023;130(5):439-41. 11. Kontogiannis A, Matsas A, Valsami S, Livanou ME, Panoskaltsis T, Christopoulos P. Primary Hemostasis Disorders as a Cause of Heavy Menstrual Bleeding in Women of Reproductive Age. J Clin Med. 2023;12(17). 12. Bongers MY. Second-generation endometrial ablation treatment: Novasure. Best Pract Res Clin Obstet Gynaecol. 2007;21(6):989-94. 13. Bhattacharya S, Middleton LJ, Tsourapas A, Lee AJ, Champaneria R, Daniels JP, et al. Hysterectomy, endometrial ablation and Mirena(R) for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis. Health Technol Assess. 2011;15(19):iii-xvi, 1-252. 14. Rubin G, Wortman M, Kouides PA. Endometrial ablation for von Willebrand disease-related menorrhagia--experience with seven cases. Haemophilia. 2004;10(5):477-82. 15. Rodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost. 2010;8(9):2063-5. 16. Jain S, Zhang S, Acosta M, Malone K, Kouides P, Zia A. Prospective evaluation of ISTH-BAT as a predictor of bleeding disorder in adolescents presenting with heavy menstrual bleeding in a multidisciplinary hematology clinic. J Thromb Haemost. 2020;18(10):2542-50. 17. Elbatarny M, Mollah S, Grabell J, Bae S, Deforest M, Tuttle A, et al. Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project. Haemophilia. 2014;20(6):831-5. 18. Greenhalgh T. Narrative based medicine: narrative based medicine in an evidence based world. BMJ. 1999;318(7179):323-5. 19. Charon R. The patient-physician relationship. Narrative medicine: a model for empathy, reflection, profession, and trust. JAMA. 2001;286(15):1897902. 20. Parker M, Hannah M, Zia A. “If I wasn’t a girl”: Experiences of adolescent girls with heavy menstrual bleeding and inherited bleeding disorders. Res Pract Thromb Haemost. 2022;6(4):e12727. 21. Kerins J, Smith SE, Tallentire VR. ‘Just pretending’: Narratives of professional identity transitions in internal medicine. Med Educ. 2023;57(7):627-36. 22. Babbar K, Martin J, Varanasi P, Avendano I. Inclusion means everyone: standing up for transgender and non-binary individuals who menstruate worldwide. Lancet Reg Health Southeast Asia. 2023;13:100177.
17 General introduction 1
CHAPTER 2 Prophylactic and therapeutic strategies for intraoperative bleeding in women with von Willebrand disease and heavy menstrual bleeding: A SYSTEMATIC REVIEW H.P. Eising, M.C. Punt, J.C. Leemans, M.Y. Bongers Blood Rev 2023 Pages 101131 Accession Number: 37716881 DOI: 10.1016/j.blre.2023.101131 https://www.ncbi.nlm.nih.gov/pubmed/37716881
20 Chapter 2 ABSTRACT Background Optimal peri-operative management for women with Von Willebrand disease (VWD) and heavy menstrual bleeding (HMB) remains undetermined. Aim and methods To evaluate (pre)operative management in relation to (post)operative bleeding after endometrial ablation (EA) and hysterectomy in VWD women with HMB by performing a database search between 1994 and 2023. Results Eleven cohort studies and 1 case-report were included, of overall ‘low’ quality, describing 691 operative procedures. Prophylaxis (Desmopressin, clotting factor concentrates or tranexamic acid) to prevent bleeding was described in 100% (30/30) of EA procedures and in 4% (24/661) of hysterectomies. Bleeding complications despite prophylaxis were described in 13% (3/24) of hysterectomies vs 0% (0/30) in EA. Conclusion VWD women often seem to experience bleeding complications during hysterectomy and all women with VWD received preprocedural hemostatic agents during EA, indicating potential under- and overdosing of current prophylactic strategies. Prospective studies are needed to determine the optimal (pre)operative strategy for gynecological surgical procedures in women with VWD. Keywords Bleeding disorders, Endometrial Ablation Techniques, Heavy Menstrual Bleeding, International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, von Willebrand Diseases Highlights - Both EA and hysterectomy are helpful procedures for VWD women with HMB. - Insufficient data is available from published studies for VWD women with HMB making the optimal prophylactic strategy for hysterectomy and EA uncertain in terms of agent and dosing.
21 Systematic review INTRODUCTION Von Willebrand Disease (VWD) is the most common autosomal inherited bleeding disorder in women and is classified as: VWD type 1 (too low von Willebrand factor (VWF)-antigen level), VWD type 2 (dysfunctional VWF-antigen) or VWD type 3 (absent of VWF-antigen). Heavy menstrual bleeding (HMB) occurs in 64-74% of women with VWD, for which a significant percentage of women (20%) undergo a surgical procedure (1), (2), (3) Endometrial ablation (EA) was introduced to achieve long-term reduction of HMB without disruption of the anatomy. (4-6) Patients experience a high satisfaction on symptom relief, with a low incidence of bleeding complications (2%) and EA is therefore nowadays predominantly used as primary surgical option in women with HMB. (5-8) However, women with HMB and VWD opt more often for a hysterectomy due to the advantage of permanent relief of HMB. (3, 9, 10) As surgical techniques for both hysterectomy and EA continue to evolve, corresponding changes in bleeding complications rate should be noted, entail this review for VWD women. Apart from this, limited information is available regarding the variety of potential prophylactic treatment strategies in VWD women who underwent EA or hysterectomy. Therefore, we aimed to summarize the up-to-date evidence on bleeding events and to address optimal prophylactic and therapeutic perioperative strategies in VWD women for the surgical procedures of HMB to benefit clinical decision-making. METHODS Protocol and registration This review protocol was registered at PROSPERO (CRD42018104535) (https://www.crd.york. ac.uk/prospero/) and conducted according to the PRISMA 2020 guidelines. (11) All articles reporting on women with any type of VWD and HMB who either underwent second generation EA or hysterectomy were eligible for inclusion. Only articles written in English, German or Dutch, containing original patient data and reporting of outcome bleeding complications and/or satisfaction rate were included. Excluded were studies with unclear reporting of type bleeding disorder or unclear reporting bleeding complications and studies conducted with other type than second-generation EA. The review questions were: 1. Which prophylactic and therapeutic strategies for intraoperative bleeding in VWD women undergoing EA or hysterectomy for HMB have been published? 2. What is the relation of these prophylactic and therapeutic strategies towards intraoperative bleeding in VWD women undergoing EA or hysterectomy? 3. How often did HMB reoccur after EA and if so, where further surgical procedures undertaken? Search and study selection The complete search syntax was developed in collaboration with a librarian. We performed an electronic search in January 2023 in PubMed, EMBASE, Cochrane databases and the Register of Current Controlled Trials (Supplement S1. Full search string all databases). We limited the results to literature published from January 1, 1994, to January 1, 2023, to increase the likelihood that the second-generation EA, currently (the most common used method), was used. 2
22 Chapter 2 After identifying relevant titles and abstracts of the selected studies, two independent authors (HPE, MCP) made a final selection of eligible articles after full-text assessment of the remaining relevant studies. Reference lists of relevant articles were cross-checked for additional relevant studies. Duplicates were removed manually. Any disagreements were resolved by discussion and, if necessary, by consulting a third reviewer (JCL). Data collection and risk of bias assessment Data was independently extracted from the selected articles by two reviewers (HPE, MCP) using a standardized format including items about the general study characteristics (design, setting, VWD population), type of VWD, type of surgical treatment and the outcomes. We accepted any definition or description of bleeding complication that was used by the primary study related to blood loss which required re-intervention, re-treatment or blood transfusion. Second generation EA included bipolar endometrium ablation, balloon endometrium ablation, microwave ablation, thermal ablation or endomyometrial ablation. Hysterectomy included any laparoscopic, vaginal or laparotomic type of hysterectomy. VWD classification was based on terminology provided in the selected studies. Studies with unclear reporting of VWD as a type of bleeding disorder were excluded. Study design was defined as cohort study when the patients were included into the study during a certain period of time, and a case study was defined if patient selection was not described. (12) Outcomes were classified as counts and percentages in cohort studies if available or possible to extract. Study quality was assessed by two independent authors (HPE, MCP) with the Methodological Index for Non-Randomized Studies (MINORS) (13) instrument. The items are scored 0 (not reported), 1 (reported but inadequate), 2 (reported but adequate), NA (Not Applicable). The global ideal score is 16 for noncomparative studies. Any disagreements were resolved by consulting a third author (JCL). RESULTS Our search resulted in 1102 records, of which 1090 records were excluded with the following reasons, no bleeding disorder (N=532), no EA or hysterectomy (N=221), oncology (N=81). Eligible for inclusion were 256 records (Figure 1: Prisma flow chart for identifying eligible studies on prophylactic and therapeutic strategies for intraoperative bleeding in von Willebrand disease women undergoing EA or hysterectomy for heavy menstrual bleeding). After assessment of the abstracts, 244 studies were excluded with following reasons, review (N=24), study protocol (N=1), non VWD patients (N=161), no EA or hysterectomy (N=42), no pre-described outcome (complication/pre-treatment) (N=16). The final selection consisted of one case report (14) and eleven retrospective studies (3, 14-24) describing a total of 691 VWD women. The exact number per type VWD was unclear due to incomplete reporting in four studies. (14, 15, 17, 21) Data on study characteristics, adverse events and bleeding complications in EA or hysterectomy are summarized in Table 1. (3, 14-24)
23 Systematic review Figure 1: Prisma flow chart for identifying eligible studies on prophylactic and therapeutic strategies for intraoperative bleeding in von Willebrand disease women undergoing endometrial ablation or hysterectomy for heavy menstrual bleeding. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. Two of the included 12 studies described both EA and hysterectomy treatment in VWD women with HMB. (20, 22) Each of the included 12 studies reported different outcome criteria concerning HMB; the amount of blood loss during menstruation in milliliter, through hemoglobin levels or HMB being objectified by the standard pictorial blood assessment chart (PBAC). Duration of patient follow-up varied from 6 up to 73 months after treatment or was not specified. No study compared (post)operative bleeding events during hysterectomy or EA between women with VWD and the healthy population. The methodological heterogeneity of the surgical procedures hampered data pooling and meta-analysis. Records identified from Databases (n = 1102) Records removed before screening: Duplicate records removed (n = 12) Records excluded (n = 834) - No bleeding disorder (n = 532) - No endometrial ablation or hysterectomy (n = 221) - Oncology (n = 81) Reports excluded (n = 244): - Review (n = 24) - Protocol (n = 1) - No von Willebrand Disease patients (n = 161) - No endometrial ablation or hysterectomy (n = 42) - No predescribed outcome (complication/pretreatment) (n = 16) Identification Identification of studies via databases and registers Records screened (n = 1090) Screening Reports assessed for eligibility (n = 256 ) Studies included in review (n = 12) Included 2
24 Chapter 2 Table 1: Study characteristics, adverse events and bleeding complications in endometrial ablation or hysterectomy (N=12). Study Author, year, country Design N operated VWD; (type VWD) Follow-up (months) Primary Outcome(s) Perioperative prophylaxis Bleeding complications - VWD% (N bleeding /N total) - Control%) Hysterectomy de Wee et al, 2011, Netherlands3 Retrospective cohort 84 (type 1, type 2, type 3) NR Self-reported complications NR Self-reported intra/ postoperative bleeding - VWD: 58% (29/50 data available surgeryrelated bleeding) - Control: NR Ragni et al, 1999, USA22 Retrospective cohort 7 (type 1) NR Physician reported bleeding complications NR Postoperative bleeding - VWD: 28.6% (2/7) - Control: NR James et al, 2009, USA19 Retrospective cohort 545 (NR) NR Physician reported bleeding complications NR Intra/ postoperative bleeding - VWD 2.8% (15/545) - Control 0.9% (12218/1357588); Death - VWD 0.2% (1/545) - Control 0.1% (1764/1357588) Transfusion - VWD 7.3% (40/545) - Control 2.1% (28509/1357588) Kadir et al, 1999, United Kingdom21 Retrospective cohort 5 (type 1, type 2, type 3) NR Physician reported bleeding complications DDAVP VWF/FVIII concentrate Vault hematoma - VWD 20% (1/5) - Control NR) Wound hematoma - VWD 20% (1/5) - Control NR) Hematuria/ postoperative bleeding - VWD 20% (1/5) - Control NR [continued on next page]
25 Systematic review Table 1: [continued] Study Author, year, country Design N operated VWD; (type VWD) Follow-up (months) Primary Outcome(s) Perioperative prophylaxis Bleeding complications - VWD% (N bleeding /N total) - Control%) Polet et al, 1996, South-Africa12 Case report 1 (NR) NR Physician reported bleeding complications None Vaginal vault bleeding - VWD 100% (1/1) - Control 0%) Alesci S et al, 2012, Germany20 Retrospective cohort 12 (type 1, type 2A, type 2N, acquired) NR Physician reported bleeding complications VWF/FVIII concentrate None occurred Halimeh S et al, 2012, Germany18 Retrospective cohort 7 (type 1, type 3) NR Physician reported bleeding complications TA None occurred Endometrial ablation Kanaoka et al, 2001, Japan17 Retrospective cohort 1 (type 1) 15 (12-18) months Physician reported bleeding complications, satisfaction (questionnaire not specified) Buserelin nasal spray None occurred Rubin et al, 2004, USA14 Retrospective cohort 7 (type 1, type 2) 45 (31-73) months Physician reported bleeding complications, satisfaction (questionnaire not specified) DDAVP (type 1); VWF/FVIII (type 2A) None occurred El-Nashar et al, 2007, USA16 Retrospective cohort 2 (type 1) 24 (11-39) months Physician reported bleeding complications Received but type not specified None occurred [continued on next page] 2
26 Chapter 2 Table 1: [continued] Study Author, year, country Design N operated VWD; (type VWD) Follow-up (months) Primary Outcome(s) Perioperative prophylaxis Bleeding complications - VWD% (N bleeding /N total) - Control%) Huq et al, 2011, United Kingdom15 Retrospective cohort 5 (NR) 32 (6-76) months Physician reported bleeding complications, satisfaction (questionnaire not specified) TA, DDAVP None occurred Baggish et al, 1997, USA13 Retrospective cohort 1 (NR) 54 (12-120) months Physician reported bleeding complications Plasma None occurred Alesci S et al, 2012, Germany20 Retrospective cohort 7 ( type 1, type 2A, type 2N, acquired) NR Physician reported bleeding complications VWF/FVIII concentrate None occurred Halimeh S et al, 2012, Germany18 Retrospective cohort 7 (type 1, type 3) NR Physician reported bleeding complications TA None occurred (N number, NR Not Reported, HMB Heavy menstrual bleeding, VWF Von Willebrand factor, DDAVP desmopressin, VWD von Willebrand Disease ; TA tranexamic acid).
27 Systematic review Risk of bias A summary of the quality assessment for all included studies is provided in Table 2. The quality of the included studies was rated as ‘low’ (median MINORS score 11 out of 16). The certainty in the evidence was ‘low’ for all outcomes due to the observational designs of all studies (11 retrospective studies and one case report). Prophylactic and therapeutic strategies In the individual patient data, information on adequate prophylactic and therapeutic strategies in both EA and hysterectomies could be extracted for 54 procedures. Prophylaxis consisted mostly of tranexamic acid (type 1 or type 3), (17, 20) desmopressin (type 1), (16, 17) VWF/FVIII concentrate (type 1, type 2A, type 2N, or acquired). (22, 16) Levels of hemoglobine of VWF before surgery were not mentioned in any of the included articles. Information about specific sugical management procedures like the use of bipolar electrosurgical intruments, intended for effectively seals of vessels to reduce intraoperative bleeding during hysterectomies, were not mentioned. The described surgical procedures in included VWD women (type 1, type 2A, type 2N, type 3 and acquired) were (sub)total abdominal hysterectomy, vaginal hysterectomy, laparoscopic hysterectomy (LH) or (robotic) laparoscopic assisted vaginal hysterectomy (LAVH) in 7 studies (N=661; one case report (14) and 6 retrospective studies). (3, 20-24) and bipolar EA techniques in 7 studies (N=30; all retrospective studies). (15-20, 22) Bleeding complications in relation to surgical procedures (hysterectomy, EA) The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) was used for screening underlying bleeding disorders in one EA study. (17) No other included studies reported on validated screening tools to determine the patients’ bleeding tendency before surgery. Individual information on the VWD diagnosis was described before surgery in 16% (108/691) (3, 15-20, 22, 23) of the included procedures, while in 5% (38/691) (3), (14), (24) of the procedures a VWD diagnosis was made after surgery, and in 79% (545/691) (21) of cases, the timing of the VWD diagnosis was not described. Eleven out of twelve studies evaluated bleeding complications by using medical records. (14-24) One study evaluated bleeding complications by self-reporting feedback. (3) In the individual patient data, information on intra- or postoperative bleeding complications during hysterectomy in VWD women was available in 7% (49/661) procedures. Namely, this was reported in 4 retrospective studies as being 3% (15/545) (21), 29% (2/7) (24), 58% (29/50) (3), 60% (3/5) (23) and a case-report described one vaginal vault bleeding. (14) One cohort study reported 7% (40/545) transfusion rate in VWD women compared to 2% (28509/1357588) in the control group. (21) Two cohort studies did not report any intra- or postoperative bleeding during hysterectomy. (20, 22) In none of the 7 EA cohort studies, intra- or postoperative bleeding events occurred in VWD women (0%, 0/30). (15-20, 22) 2
28 Chapter 2 Table 2: Assesment of MINORS criteria for all included studies (N=12). De Wee et al3 Ragni et al22 James et al19 Kadir et al21 A clearly stated aim 2 2 2 2 Inclusion of consecutive patients 2 2 2 2 Prospective collection of data 2 2 0 2 Endpoints appropriate to the aim of the study 2 2 2 2 Unbiased assessment of the study endpoint 1 1 1 1 Follow-up period appropriate to the aim of the study 1 1 0 2 Loss to follow-up less than 5% 1 1 0 1 Prospective calculation of the study size 0 0 0 0 An adequate control group NA NA NA NA Contemporary groups NA NA NA NA Baseline equivalence of groups NA NA NA NA Adequate statistical analyses NA NA NA NA Total MINORS score 11 11 7 12 The items are scored 0 (not reported), 1 (reported but inadequate), 2 (reported but adequate), NA (Not Applicable) The global ideal score is 16 for noncomparative studies. Bleeding complications in relation to prophylactic management in hysterectomy or EA Overall, in 4% (24/661) of all the hysterectomy cases prophylaxis was described. (20, 22, 23) During hysterectomies, 13% (3/24) of bleeding complications occurred in women who received prophylaxis versus 14% (87/637) bleeding complications occurred without mentioning prophylaxis. A retrospective study included 5 VWD patients (type 1, 2 and 3) who underwent abdominal hysterectomies because of HMB. (23) Three patients had bleeding complications; one vault hematoma was described after receiving no prophylaxis (VWD type 1) which was managed through conservative treatment; one wound hematoma after desmopressin infusion as prophylaxis (VWD type 1) which required surgical drainage; and lastly one postoperative bleed and hematuria occurred despite VWF concentrate as prophylaxis (VWD type 3), for which the woman required 4 units of blood transfusion. (23) All (100%, 30/30) EA cases (15-20, 22) received prophylaxis: tranexamic acid (N=10; type not specified, type 1 or type 3), (17, 20) desmopressin (N=8; type not specified or type 1), (16, 17) VWF/ FVIII concentrate (N= 8; type 1, type 2A, type 2N, or acquired), (16, 22) unspecified (N=2; type 1), (18) buserelin nasal spray (N=1; type 1) (19) and plasma transfusion (N=1; type not specified). (15) None of these 30 patients (0%) with VWD experienced bleeding complications.
29 Systematic review Polet et al12 Kanaoka et al17 Rubin et al14 El-Nashar et al16 Huq et al15 Baggish et al13 Halimeh S et al18 Alesci S et al20 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 0 0 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 2 2 2 2 2 2 0 0 2 2 2 2 2 2 0 0 0 0 0 0 0 0 0 0 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 13 13 13 13 13 13 7 7 Recurrence of HMB after initial EA Recurrence of HMB after initial EA described in 5 out of the 30 of the VWD women of which 3 (two type 1, one type 2A) underwent a hysterectomy 10, 11 and 26 months after the initial EA procedure. (16) The fourth patient developed recurrence of menorrhagia after initial hypomenorrhea following EA, but no surgical procedure was performed. (16) Another VWD patient (type unknown) underwent an electrosurgery EA but underwent a second ablation 6 months later for residual endometrium. (15) DISCUSSION The hysterectomy and EA techniques have evolved during the last 30 years, as women who underwent abdominal surgery experience higher rates of bleeding complications compared to vaginal or laparoscopic surgery. (25) In addition, bipolar radio frequency and microwave ablative devices appeared more effective than thermal balloon and free fluid ablation in the treatment of HMB. (6) However, the type of surgical procedure (hysterectomy vs EA) is still frequently reported as a risk factor for intraoperative bleeding. (26) In this systematic review, we included 12 studies to evaluate the association between prophylaxis and any (post)operative bleeding events in VWD women who either underwent EA or a hysterectomy. 2
30 Chapter 2 Regardless adequate prophylaxis, we found an increased incidence of intraoperative bleeding events in VWD women who underwent hysterectomy as compared to EA (13% vs 0%) or compared to the incidence of adverse bleeding events in women undergoing a hysterectomy without VWD (4%) as reported by a Cochrane review comparing EA to any type of hysterectomy performed in healthy women with HMB. (26) Also, VWD women received more often blood transfusions during or after hysterectomy compared to the general population. This is likely due to the fact that in a significant part of the women who underwent a hysterectomy, the diagnosis VWD was made after surgery. (3, 21) Blood transfusions have the power to save lives, but this limited resource can also harm patients by transfusion-associated reactions and generate excessive costs. EA offers an alternative to hysterectomy as a surgical treatment for HMB. (26) However, the higher rate of adverse bleeding events in hysterectomy versus EA emphasizes impact of diagnosing possible underlying bleeding disorders in women with HMB before surgery. (26-29) Therefore, this review contributes to importance of attention for underlying bleeding disorders in daily gynecological practice. (30) At least an assessment of the patient’s bleeding history, evaluation for mild bleeding disorder using a validated bleeding assessment tool or screening on bleeding disorders for risk assessment should be part of consultation for women with HMB in optimal gynecologic care process. (31) EA is a reliable technique and safe procedure in VWD women who experience HMB. (15-20, 22) In contrast to healthy women, all women with VWD received preprocedural hemostatic agents during EA. Our findings support current national and international guidelines recommending primary prophylaxis before gynecological surgery in patients with VWD for the prevention of bleeding complications during and after surgery. (32) Taking into consideration the evolved EA techniques and the absence of bleeding complications during EA presented here, the question arises whether it is necessary to give prophylaxis to all, some or maybe none of the women with VWD during the EA procedure. So, optimizing prophylactic strategy is needed to avoid the risk of over-dosing, leading to unnecessary treatment and costs versus risking under-dosing, which may lead to adverse bleeding events. The included studies did not and could not be due to the lack of power, examine the relationship between bleeding complications and the severity of the type of VWD, possible prophylactic and therapeutic perioperative strategies. Prophylaxis was described in 4% of the hysterectomy (20, 22, 23) vs 100% of the EA procedures. (15-20, 22) The diversity of the included study population (VWD type 1, type 2A, type 2N, type 3, acquired), the variousness per type of prophylactic treatment strategy and unknown gynecological confounders, make subpopulation analysis and future recommendations unreliable. Also, the definition of surgery-related bleeding complications differed between the included studies. Although most studies used intra- and postoperative bleeding as a lower limit, (3, 20-22, 24) haematoma, (23) transfusion, (21, 23) or death (21) were also used. Limitations that need to be addressed concern the restriction to English, German and Dutch literature and the heterogeneity and observational retrospective nature of studies. Because of small numbers of included VWD women and the study design, the overall quality of evidence
31 Systematic review for the comparison bleeding complications during or after EA to hysterectomy in women with VWD was judged to be low. Large studies or randomized clinical trials addressing outcome of EA and/or hysterectomy in women with VWD versus healthy controls are lacking. CONCLUSIONS In conclusion, this systematic review highlights the awareness of possible underlying bleeding disorders in women with HMB is of great importance before either EA or hysterectomy. Despite the limitations of the studies analyzed, our review suggests that both EA and hysterectomy are usable procedures for VWD women with HMB due to evolving surgical techniques. However, our review also revealed that none of the VWD patients who underwent EA experienced bleeding complications, in contrast to those who underwent hysterectomy despite of adequate medical prophylaxis. Therefore, this review contributes to the need to optimize prophylactic or therapeutic strategies for VWD women undergoing either EA or hysterectomy. Future considerations This review serves as a call to action to improve the quality of research and care for VWD women with HMB. Research agenda High-quality prospective studies are needed to optimize: 1) the diagnostic work up considering identifying underlying bleeding disorders before surgery and 2) the peri-operative prophylactic and therapeutic strategies for EA or hysterectomy in women with VWD to avoid the risk of over-dosing, leading to the administration and costs of unnecessary treatment versus risking under-dosing and consequently risking adverse bleeding events. Practice points - Both EA and hysterectomy are helpful procedures for VWD women with HMB. - Insufficient data is available from published studies for VWD women with HMB making the optimal prophylactic strategy for hysterectomy and EA uncertain in terms of agent and dosing. 2
32 Chapter 2 SUPPORTING INFORMATION Supplement 1: Full search string all databases PubMed (“Endometrial Ablation Techniques”[Mesh] OR second generation endometrial ablation*[tiab] OR rollerball* OR balloon* OR novasure* OR “Hysterectomy”[Mesh] OR Hysterectom*[tiab] OR uterus extirpation*[tiab]) AND (“Menorrhagia”[Mesh] OR “Menorrhagia”[tiab] OR “Heavy Menstrual Bleeding”[tiab] OR “Hypermenorrhea”[tiab] OR “Heavy Period*”[tiab] OR “von Willebrand Diseases”[Mesh] OR “Vascular Hemophilia*”[tiab] OR “von Willebrand’s Factor Deficiency” [tiab] OR “Von Willebrand Disorder”[tiab] OR “von Willebrand Disease*”[tiab] OR “bleeding disorders*”[tiab] OR “inherited coagulation disorders*”[tiab] OR “hemorrhagic disorders*”[tiab]) Embase (‘uterus extirpation*’:ab,ti OR hysterectomy*:ab,ti OR ‘hysterectomy’/exp OR ‘second generation endometrial ablation*’:ab,ti OR ‘endometrial ablation*’:ab,ti OR ‘endometrium ablation*’:ab,ti OR ‘endometrium ablation’/exp) AND (‘menorrhagy’:ab,ti OR ‘hypermenorrhoea’:ab,ti OR ‘hypermenorrhea’:ab,ti OR ‘heavy menstruation’:ab,ti OR ‘heavy menstrual bleeding’:ab,ti OR menorrhagia:ab,ti) AND (‘von willebrand disease’/exp OR ‘von willebrand disorder’:ab,ti OR ‘willebrand disease*’:ab,ti) Central Second generation endometrial ablation* OR ablation* OR novasure* OR rollerball* OR balloon AND Hysterectomy
33 Systematic review REFERENCE LIST 1. Lee CA. Women and von Willebrand disease. Haemophilia. 1999;5 Suppl 2:38-45. 2. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet. 1998;351(9101):485-9. 3. De Wee EM, Knol HM, Mauser-Bunschoten EP, van der Bom JG, Eikenboom JC, Fijnvandraat K, et al. Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease. Thromb Haemost. 2011;106(5):885-92. 4. DeCherney AH, Diamond MP, Lavy G, Polan ML. Endometrial ablation for intractable uterine bleeding: hysteroscopic resection. Obstet Gynecol. 1987;70(4):668-70. 5. Bongers MY, Bourdrez P, Mol BW, Heintz AP, Brolmann HA. Randomised controlled trial of bipolar radio-frequency endometrial ablation and balloon endometrial ablation. BJOG. 2004;111(10):1095102. 6. Daniels JP, Middleton LJ, Champaneria R, Khan KS, Cooper K, Mol BW, et al. Second generation endometrial ablation techniques for heavy menstrual bleeding: network meta-analysis. BMJ. 2012;344:e2564. 7. Glazerman LR. Endometrial ablation as a treatment for heavy menstrual bleeding. Surg Technol Int. 2013;23:137-41. 8. Middleton LJ, Champaneria R, Daniels JP, Bhattacharya S, Cooper KG, Hilken NH, et al. Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding: systematic review and meta-analysis of data from individual patients. BMJ. 2010;341:c3929. 9. Kouides PA, Phatak PD, Burkart P, Braggins C, Cox C, Bernstein Z, et al. Gynaecological and obstetrical morbidity in women with type I von Willebrand disease: results of a patient survey. Haemophilia. 2000;6(6):643-8. 10. Warner PE, Critchley HO, Lumsden MA, Campbell-Brown M, Douglas A, Murray GD. Menorrhagia I: measured blood loss, clinical features, and outcome in women with heavy periods: a survey with follow-up data. Am J Obstet Gynecol. 2004;190(5):1216-23. 11. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. 12. Dekkers OM, Egger M, Altman DG, Vandenbroucke JP. Distinguishing case series from cohort studies. Ann Intern Med. 2012;156(1 Pt 1):37-40. 13. Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg. 2003;73(9):7126. 14. Polet R, de Jong P, van der Spuy ZM, Shelton M. Laparoscopically assisted vaginal hysterectomy (LAVH)--an alternative to total abdominal hysterectomy. S Afr Med J. 1996;86(9 Suppl):1190-4. 15. Baggish MS, Sze EH. Endometrial ablation: a series of 568 patients treated over an 11-year period. Am J Obstet Gynecol. 1996;174(3):908-13. 16. Rubin G, Wortman M, Kouides PA. Endometrial ablation for von Willebrand disease-related menorrhagia--experience with seven cases. Haemophilia. 2004;10(5):477-82. 17. Huq FY, Al-Haderi M, Kadir RA. The outcome of endometrial ablation in women with inherited bleeding disorders. Haemophilia. 2012;18(3):413-20. 18. El-Nashar SA, Hopkins MR, Feitoza SS, Pruthi RK, Barnes SA, Gebhart JB, et al. Global endometrial ablation for menorrhagia in women with bleeding disorders. Obstet Gynecol. 2007;109(6):1381-7. 19. Kanaoka Y, Hirai K, Ishiko O, Ogita S. Microwave endometrial ablation at a frequency of 2.45 GHz. A pilot study. J Reprod Med. 2001;46(6):559-63. 20. Halimeh S., Davies J., Pollard D. Menorrhagia in women with severe bleeding disorders. Blood Adv. 2012;2012(21). 21. James AH, Myers ER, Cook C, Pietrobon R. Complications of hysterectomy in women with von Willebrand disease. Haemophilia. 2009;15(4):926-31. 22. Alesci SR, Schrumpf, L.; Krekeler, S.; Miesbach, W. Gynecological surgery and obstetrical procedures in patients with bleeding disorders (von Willebrand Disease and carriers for haemophilia) Hamostaseologie. 2012;2012(1):A43. 23. Kadir RA, Economides DL, Sabin CA, Pollard D, Lee CA. Assessment of menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders. Haemophilia. 1999;5(1):408. 24. Ragni MV, Bontempo FA, Hassett AC. von Willebrand disease and bleeding in women. Haemophilia. 1999;5(5):313-7. 25. Schmidt PC, Kamdar NS, Erekson E, Swenson CW, Uppal S, Morgan DM. Development of a Preoperative Clinical Risk Assessment Tool for Postoperative Complications After Hysterectomy. J Minim Invasive Gynecol. 2022;29(3):401-8 e1. 2
34 Chapter 2 26. Bofill Rodriguez M, Lethaby A, Fergusson RJ. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2021;2:CD000329. 27. Clarke-Pearson DL, Geller EJ. Complications of hysterectomy. Obstet Gynecol. 2013;121(3):654-73. 28. James AH, Kouides PA, Abdul-Kadir R, Edlund M, Federici AB, Halimeh S, et al. Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel. Am J Obstet Gynecol. 2009;201(1):12 e1-8. 29. Knol HM, Bogchelman DH, Kluin-Nelemans HC, van der Zee AG, van der Meer J, Meijer K. Routine evaluation and treatment of unexplained menorrhagia: do we consider haemostatic disorders? Eur J Obstet Gynecol Reprod Biol. 2010;152(2):191-4. 30. Eising HP, Sanders YV, de Meris J, Leebeek FWG, Meijer K. Women prefer proactive support from providers for treatment of heavy menstrual bleeding: A qualitative study in adult women with moderate or severe Von Willebrand disease. Haemophilia. 2018;24(6):950-6. 31. Punt MC, Blaauwgeers MW, Timmer MA, Welsing PMJ, Schutgens REG, van Galen KPM. Reliability and Feasibility of the Self-Administered ISTH-Bleeding Assessment Tool. TH Open. 2019;3(4):e350-e5. 32. Care CoAH. Committee Opinion No.580: von Willebrand disease in women. Obstetrics Gynecology. 2013;2013 dec(6):1368-73.
www.ridderprint.nlRkJQdWJsaXNoZXIy MTk4NDMw