Focus on Women and Girls with Bleeding Disorders: Recent Research

A Pressing Need

Did you know it has been estimated that approximately 2 million or more women in the U.S. might be living with a bleeding disorder?¹ It’s challenging to be more precise because the actual number of women with factor deficiencies, such as hemophilia A and B, is unknown while women with von Willebrand disorder (VWD) have been estimated to range from 0.6 – 1.3% of American women and girls.^2,3 However, even these estimates may be low. Looking at data from the UK, it is reported that there were 11,288 people treated for VWD in 2021-2022 in a population of 67 million – or 168 people per million.⁴ As a point of comparison, the U.S. has 15,349 patients registered for VWD (treated or not) in a population of 330 million – or 46 people per million.⁵ Because of long-held beliefs about who can have the various types of bleeding disorders, mixed with a dose of sex bias, we conclude that females are likely over-represented in the VWD count, while under-represented in the hemophilia counts. And that the reverse is true for males. Accurate data on prevalence and distribution of bleeding disorders remains elusive; most likely, we have simply failed to capture a large portion of individuals affected by bleeding disorders in the U.S. as well to diagnose their disorder type correctly. It has not escaped our attention that gender bias may also impact accurate diagnosis and treatment of people living with bleeding disorders.

Whatever their prevalence or distribution, bleeding disorders often lead to a reduced quality of life and to life-threatening complications throughout a woman’s life, including general injury or bleeding during the perioperative period (during or after surgery), as well as during every life stage – infancy, childhood, adolescence, young adulthood, adulthood, and older age. However, despite women experiencing bleeding symptoms, most of these disorders remain undiagnosed for years. Many are never diagnosed despite the serious signs and symptoms experienced by the women who have them.¹ Some of this may be attributed to a general lack of awareness of bleeding disorders in women, and some to sex bias – even among professionals. For example, a 2009 CDC study showed that the prevalence of VWD and factor VIII deficiency in women with excessive menstrual bleeding was much higher than U.S. gynecologists perceived it to be.⁶ Systematic review of published studies indicated that an estimated 5-24% of women with heavy menstrual bleeding might have undiagnosed VWD.⁶ A 2017 study confirmed that misrecognition and misdiagnosis of women with VWD can be a repetitive problem.

Likewise, a 2020 study, Patterns of von Willebrand Disease Screening in Girls and Adolescents with Heavy Menstrual Bleeding,⁸ noted that despite recommendations by the American College of Obstetricians and Gynecologists (ACOG) for more than 15 years, fewer than 20% of the 23,888 post-pubertal girls and adolescents with heavy menstrual bleeding included in the analysis underwent screening for VWD. And the problem has been shown to extend beyond adolescence. A 2012 survey⁶ of providers, implemented by ACOG, found that the majority of physicians surveyed reported they would be likely or very likely to consider a bleeding disorder as causing abnormal bleeding in younger patients; however, less than 40% would consider bleeding disorders in reproductive age women.

Clearly, there is a need to increase awareness of the lifelong issues of concern for women with bleeding disorders and to better understand, diagnose, and appropriately treat women with these conditions.

Answering the Call; Advancing Understanding

The goals of recent research respond to the need to better understand the impact of bleeding disorders on women throughout their lifetime. Studies have been undertaken to understand how many women are affected by bleeding disorders, to develop and implement interventions to help prevent complications, to generate awareness fostering early diagnosis and informed treatment, and to refine testing to better identify women at risk for bleeding disorders.

Advances have been facilitated by rigorous data collection. Data collected by the CDC in two major longitudinal research initiatives, Universal Data Collection (UDC) and Community Counts, with collaboration from the American Thrombosis and Hemostasis Network (ATHN), has expanded our knowledge and made meaningful headway in increasing health equity for women and girls, especially those with bleeding disorders.

Universal Data Collection: Setting the Foundation

Using a specially designed data collection instrument for women, the UDC initiative at the CDC collected data from 2009–2010 on more than 4,000 women and girls treated at Hemophilia Treatment Centers (HTCs) in the U.S. The tasks of the study were fourfold¹⁰:

• Characterize the women and girls receiving treatment at an HTC
• Characterize the bleeding episodes associated only with females, including menstruation, pregnancy, and childbirth
• Investigate what services were provided to these patients at HTCs
• Study the care provided to females with bleeding disorders

The research helped to define the symptoms associated with women and bleeding disorders. Of the 4,000+ women and girls participating in the research¹¹:

• 78.3% reported heavy menstrual bleeding as their most common bleeding symptom
• 49.2% reported experiencing more than 4 symptoms of a bleeding disorder
• 76.6% reported pregnancy and childbirth complications, including miscarriage
• 37.6% reported postpartum hemorrhage

Community Counts and ATHNdataset: Building on the Foundation

Following the initial UDC research, the CDC launched a new initiative in January 2012, Community Counts – Registry for Bleeding Disorders Surveillance. Led by the American Thrombosis & Hemostasis Network (ATHN) in partnership with the U.S. Hemophilia Treatment Center Network and the CDC, data collected through October 31, 2022 indicates that Community Counts is happening at 144 HTCs nationwide and includes 62,476 patients.⁵ Demographic data from HTC visits has been collected in a safe and secure national database – the ATHNdataset. The data collected tracks common health issues, medical complications, and causes of death that affect people with bleeding disorders who are cared for in U.S. HTCs.¹²

The impact of bleeding disorders on women and girls is tracked as a subset of the overall data. Data collection is ongoing and research findings are improving our understanding of the prevalence and impact of bleeding disorders on women. Over the decade of data collection, the increase in women and girls participating in the Registry has facilitated more in-depth monitoring of treatment, complications, and outcomes over time. The goal is to support continued research and to improve treatment.

A note about the ATHNdatasubset tracking females: although progress has been made, sex and gender bias still exists among the bleeding disorder community, contributing to misdiagnosis, delay in diagnosis, and underdiagnosis of bleeding disorders in women and girls. While the published numbers from HTC treatment data are reflective of diagnoses made, they may not be reflective of the actual distribution and prevalence of bleeding disorders in women and girls. In our view, females remain under-represented in hemophilia A (15.3% versus males at 84.7%) and over-represented in VWD (66.2% versus males at 33.8%).⁵

Shaping Patient Perceptions

As the saying goes, “perception is reality” – changing thinking can change the world. The CDC has undertaken several research initiatives to better understand what women and girls experience because of delayed diagnosis and treatment as a result of antiquated beliefs that no longer hold true. These studies are designed to pinpoint areas of understanding and misunderstanding that can be improved through better messaging and used to support development of more effective tools and outreach communications.

Harris Interactive Study: Surveying What Women Think

In September 2010, in a collaborative effort between the CDC, the National Hemophilia Foundation (NHF), and Harris Interactive, a web-based survey was conducted to understand what women thought about menstruation and heavy menstrual bleeding, awareness of bleeding disorders and their signs and symptoms, and the types of messages that would best speak to young women and motivate them to seek care if appropriate. The study found that lack of information about bleeding disorders is a serious public health concern.¹ This should come as no surprise given that outdated beliefs and misinformation has been propagated throughout the entire population – even by clinicians.

The study found that messages with a positive slant are most effective at influencing women with symptoms of a bleeding disorder to seek medical care. The most motivating messages were:

• Treatment is available!
• Care for the disorder can prevent pregnancy complications and miscarriages
• Care could result in a work and school life that is not disrupted by heavy bleeding

Better You Know and Journey to Know: Translating Research into Action

The Better You Know campaign was developed by the NHF in partnership with the CDC. It is designed to raise awareness of bleeding disorders among women and girls who may experience symptoms but have not yet been diagnosed. The program includes a free online risk assessment tool, information about normal and abnormal menstrual bleeding, a downloadable menstrual tracking chart, and postcards to increase awareness about bleeding disorders in women. Find all the available materials at Better You Know

An additional initiative developed as part of the program is Journey to Know, an opportunity for participation in a 3-month program for women as well as people with the potential to menstruate who are more than 18 years of age and have bleeding symptom(s). Its purpose is to help people take the step to work with a health care provider and provides support on their journeys to find out the medical reason(s) for their bleeding symptoms. After enrolling in the program, participants will receive:

• Automated check-ins from NHF via email or text to check on progress and encourage participants to continue to seek a diagnosis
• Videos to help with next steps, including information about bleeding disorders, resources available through Better You Know, and how to advocate for themselves when speaking to a health care provider
• Information about virtual opportunities to interact monthly with others on similar journeys and have questions answered by diagnosed women, as well as providers and experts in the field.

To sign up or learn more about the program, visit Journey to Know.

Recent Research Focused on Health Care Providers and Treatment

Much recent research has focused on increasing awareness of bleeding disorders in women, establishing consistent guidelines for definitions and diagnosis, and on improving and expanding options for treatment:

Pregnancy and Delivery in Women with von Willebrand Disease¹³

This 2019 article underscores the challenges for pregnancy and delivery for women with VWD and recommends a careful evaluation of VWD type, subtype, and treatment response in pregnant women to plan the most appropriate treatment at the time of delivery. It additionally addresses problems with amniocentesis, vaginal bleeding associated with detachment of the placenta, and sudden abortion, recommending various interventions in line with the type and severity of VWD diagnosed.

Significant Gynecological Bleeding in Women with Low von Willebrand Factor Levels¹⁴

This study from 2019 found that gynecological bleeding is frequently reported in women with von Willebrand disease (VWD). Low von Willebrand factor (VWF) may be associated with significant bleeding despite only mild plasma VWF reductions. In a study of 120 women, 89% reported heavy menstrual bleeding – bleeding that was not detected using a clinical bleeding assessment tool, resulting in 40% of the women not seeking medical care for the condition. For those who did report their heavy menstrual bleeding to physicians, the low VWF diagnosis was not expedited. Despite pregnancy-related increases in plasma VWF levels, 63.5% of women studied who had given birth self-reported postpartum hemorrhage, requiring transfusion, critical care, radiological, or surgical interventions. Better tools for the detection of heavy menstrual bleeding and better pregnancy management protocols are indicated for women with low VWF.

Patterns of von Willebrand Disease Screening in Girls and Adolescents with Heavy Menstrual Bleeding¹⁵

In this retrospective 2018 study, researchers identified 23,888 post-puberty girls and adolescents with heavy menstrual bleeding (986 with severe heavy menstrual bleeding). Von Willebrand disease screening was performed in 8% of females with heavy menstrual bleeding and 16% with severe heavy menstrual bleeding. Younger age at diagnosis, commercial insurance, and living within a metropolitan statistical area were associated with higher screening rates. Patients who underwent testing for iron deficiency anemia had the highest likelihood of undergoing screening. Among patients living in a metropolitan statistical area, those 60 minutes or more from a hemophilia treatment center were less likely to undergo screening. Researchers concluded that despite recommendations by the American College of Obstetricians and Gynecologists for more than 15 years, fewer than 20% of post-puberty girls and adolescents with heavy menstrual bleeding underwent screening for von Willebrand disease in the cohort studied. Increased clinician awareness and adherence to recommended screening protocols was recommended.

Characterizing Females Patients with Haemophilia A: Administrative Claims Analysis and Medical Chart Review Haemophilia A¹⁶

Women and girls can have factor VIII (FVIII) deficiency with bleeding events requiring treatment. This 2020 study aimed to identify and characterize female patients with HA by a review of medical claims processed between January 1, 2012 – July 31, 2016. Among 353 patients meeting initial inclusion criteria, 86 charts were procured, with 8 patients identified as having HA. The study concluded that identifying females with HA is challenging using healthcare claims, because diagnostic nomenclature is unclear for female patients treated for bleeding events; very few female patients were identified with HA. Nevertheless, even in the small sample, a sizeable burden in comorbidity (presence of other diseases) and healthcare use was observed. It suggested that improved nomenclature and coding for HA diagnoses for women and girls is key to improving research and treatment.

Women and Girls with Haemophilia and Bleeding Tendencies: Outcomes Related to Menstruation, Pregnancy, Surgery and Other Bleeding Episodes from a Retrospective Chart Review¹⁷

A 2021 retrospective, non-interventional review of 2012-2018 medical records from women and girls with hemophilia (WGH) among three hemophilia treatment centers (HTCs) was conducted in the United States. The study found that WGH represent a group of female symptomatic carriers who experience bleeding events more frequently than non-carriers. Bleeding events include spontaneous/traumatic bleeds and prolonged bleeding related to surgery, menstruation, and pregnancy. Challenges for the treatment of WGH include lack of screening, diagnosis, and treatment guidelines. The study concluded that bleeding events in WGH, such as excessive and prolonged bleeding during menstruation, demonstrate a unique burden and require specific medical intervention.

Von Willebrand Disease: Proposing Definitions for Future Research¹⁸

This 2021 article recommends establishing consistent definitions for classifications associated with abnormal bleeding symptoms, with an eye to improving evidence-based guidelines for VWD. The recommendations provide proposed definitions for what constitutes major bleeding, a prophylaxis regimen, desmopression responsiveness, heavy menstrual bleeding, and postpartum hemorrhage.

ASH ISTH NHF WFH 2021 Guidelines on the Diagnosis of von Willebrand Disease¹⁹

These evidence-based clinical guidelines published in 2021 by a multidisciplinary panel from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis. Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic tests and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs. phenotypic testing for types 2B and 2N. Future critical research priorities were also identified.

A New Hemophilia Carrier Nomenclature to Define Hemophilia in Women and Girls: Communication from the SSC of the ISTH²⁰

This 2021 article by Karen P.M. van Galen et al proposes new parameters for the designation of hemophilia carrier status in women and girls. Hemophilia A and B predominantly attract clinical attention in males due to X-linked inheritance, introducing a bias toward female carriers to be designated asymptomatic. Finding that the term “hemophilia carrier” understates bleeding symptoms in women and girls, it recommends a new nomenclature defined by experts and patient advocacy groups and the establishment of five new categories (severe/moderate/mild hemophilia, symptomatic, and asymptomatic), with the belief that clear, precise nomenclature will enhance diagnosis, management, and research on hemophilia carriers.

MASAC VWD Working Group

The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) formed a VWD Working Group in 2016 to improve diagnostic testing and laboratory standards, assess existing standards of care and clinical practice guidelines, develop educational programing for HTCs, providers, and patients, research and develop effective treatments for VWD, and collaborate with partner organizations to identify and achieve common goals. In 2021 they published their latest recommendations addressing²¹:

• Diagnostic evaluation and management of girls and women presenting with symptoms of a bleeding disorder, including appropriate lab testing and additional considerations such as family history, and access to the full complement of multidisciplinary services available at HTCs, including appropriate therapies, clinical management, genetic testing, and counseling.
• Diagnosis and management of women with bleeding disorders during pregnancy, labor, and delivery, including the critical postpartum period with specific recommendations designed to both mitigate the risk of bleeding-related complications in women and early identification of affected infants.
• Current therapies available for treatment of VWD and detailed considerations for the prescription of VWD therapies and for assessing patient responses to treatment, with an eye to ensuring efficacy and avoiding complications

Study on Bleeding During Early Pregnancy¹⁰

Some reports have suggested that women with VWD or other bleeding disorders are more likely to bleed during pregnancy and experience miscarriage and postpartum hemorrhage. Ongoing CDC research studies women who experience bleeding in early pregnancy to see if an underlying bleeding disorder exists, and if so, what treatments can be given to stop bleeding and improve pregnancy outcomes.

Depression and Anxiety in Persons with Von Willebrand Disease²²

This 2022 study assessed sociodemographic and clinical characteristics associated with depression and anxiety in individuals with Von Willebrand disease (VWD) aged ≥12 years. The analyses included 77 participants. The rates of depression and anxiety were 63.6% and 58.3%, respectively. Persons with low VWF displayed higher rates of depression (86.7%) or anxiety (69.2%) compared to those with VWD. The study revealed concerning levels of depression and anxiety in the studied VWD sample. Lack of social support was determined an important factor associated with depression and anxiety in the sample. The study concluded that mental health screening is critical in VWD clinical evaluation and care.

Current Research Initiatives Sponsored by Octapharma

Several research initiatives sponsored by Octapharma are underway to help health care providers better understand how to identify and treat women with bleeding disorders:

Clinical Study to Investigate the Efficacy and Safety of Wilate During Prophylaxis in Previously Treated Patients with VWD²³

An Octapharma-sponsored prospective phase 3 multicenter trial of the efficacy and safety of a plasma-derived von Willebrand Factor/ Factor VIII Complex therapy as a prophylactic treatment for previously treated adult patients with VWD undergoing regular prophylaxis. The study was completed in April 2022, with publication of results pending.

Efficacy, PK, Immunogenicity and Safety of Wilate in Severe Von Willebrand Disease (VWD) Patients <6 Years of Age²⁴

The WIL-33 study aims to determine the efficacy, pharmacokinetics, immunogenicity and safety of wilate as routine prophylaxis in up to 12 pediatric patients under the age of 6 years, with severe von Willebrand Disease, over a period of 12 months. The study is currently recruiting participants.

Von Willebrand Factor in Pregnancy (VIP) Study (VIP)²⁵

In pregnant women with von Willebrand disease (VWD) who by the third trimester do not have von Willebrand factor (VWF) or factor VIII (FVIII) levels greater than 50-100%, specific guidance is lacking for delivery planning in terms of how high of a VWF level should be achieved to reduce bleeding. This is a prospective, open-label, cohort study in women with VWD using Wilate VWF replacement therapy to maintain trough or minimum VWF levels of 100-150% for delivery and the immediate postpartum period, followed by levels of 50-100% for 5-10 days after delivery, depending upon the route of delivery. The primary objective is to document the rate of primary postpartum hemorrhage (PPH). The secondary objective is to document further effectiveness outcomes and safety. The study is currently recruiting participants.

Effectiveness and Tolerability of Eqwilate in Real-life Conditions²⁶

This study is looking at modalities of use, effectiveness, and tolerability of Eqwilate^®, a balanced combination of VWF and FVIII, in von Willebrand patients > 6 years old, in real-life conditions involving on-demand treatment for bleeds and perioperative prophylaxis. The study is currently recruiting participants.

Bleeding Incidence in VWD Patients Undergoing On-Demand Treatment

The purpose of this study is to prospectively obtain reliable data on the bleeding and treatment pattern of patients with VWD undergoing on-demand treatment with a VWF-containing product over a period of 6 months. The data obtained will be used as a basis for historical comparisons with the bleeding and treatment pattern obtained from a clinical study on the efficacy of prophylactic treatment with a VWF/FVIII concentrate. The study was completed in 2021, with publication of results pending.

The Empower Study – Design of a Randomized Clinical Trial to Assess the Efficacy and Safety of a Plasma-Derived Von Willebrand Factor / Factor VIII Concentrate for Heavy Menstrual Bleeding in Women with Von Willebrand Disease²⁷

The EMPOWER pilot trial will determine the feasibility of the trial design, aimed at evaluating the effect of prophylaxis with plasma-derived VWF/FVIII (1:1; pdVWF:FVIII) concentrate compared with placebo on heavy menstrual bleeding in women with VWD. Anticipated to launch by fall 2022, if the pilot trial is deemed feasible and viable, a definitive international randomized controlled trial will be conducted.

NUWIQ Dosing and Outcomes in the Management of Women/Girls with Haemophilia A Needing FVIII Treatment for Surgery – an International, Open-Label, Non-Controlled Study (NuDIMENSION)²⁸

The goal of this study is to evaluate the efficacy and safety of the recombinant FVIII simoctocog alfa (NUWIQ^®) in women/girls with hemophilia A undergoing major surgery. Planned to begin in the fourth quarter of 2022, results will contribute to the evidence needed to generate specific treatment guidelines for these situations.

Other Current Research Initiatives

ISTH New Registry on Hemophilia A/B Carriers²⁹

The real worldwide burden of hemophilia in females, the incidence of symptomatic women, their treatment and their quality of life are still not completely known. As such, the SSC Subcommittee on Women's Health Issues in Thrombosis and Hemostasis has created the International Registry on the Symptomatic Hemophilia A/B Carriers. The aim of this registry is to determine how many women with Hemophilia A and B are actually followed in the different Hemophilia Treatment Centers around the world and how many of these are symptomatic. It also aims to define types of bleeding, most affected sites of bleeding, and clinical and psychological outcomes. The registry is free and open for participants. Learn more about participating here.

Minimize Menorrhagia in Women with von Willebrand Disease (VWDMin)³⁰

A prospective, randomized, crossover trial comparing recombinant von Willebrand Factor (rVWF) vs. Tranexamic Acid (TA) to minimize heavy bleeding in women with von Willebrand disease. Led by Dr. Margaret Ragni, the study will assess rVWF given on day 1 versus Tranexamic acid x 5 days in reducing heavy periods after two menstrual cycles. The expected end date for the trial is December, 2022.

Related Resources

Interested in learning more about women and bleeding disorders? Check out these other Factor My Way resources.

• Women Have Bleeding Disorders Too! (On-Demand Video)
  This on-demand video, presented by Dr. Claudio Sandoval, covers how women can inherit genetic bleeding disorders, how women’s bleeding symptoms are evaluated, what bleeding symptoms mean at various life stages, and what treatments are available.
• Women Have Bleeding Disorders Too! (Educational Article)
  Bleeding disorders in women are often seen as normal, misdiagnosed, or not diagnosed at all, leading to reduced quality of life and development of problematic health conditions. This article discusses genetic inheritance of bleeding disorders, evaluation of women’s bleeding symptoms, their meaning at various life stages, and available treatments.
• The Facts about Women and Bleeding Disorders (Infographic / Fact Sheet)
  Contrary to many common beliefs, bleeding disorders affect many women. Learn about the prevalence of bleeding disorders in women, their signs and symptoms, and the importance of early diagnosis.