Focus on Women and Girls with Bleeding Disorders: Recent Research

A Pressing Need

Did you know that approximately 1%, or as many as 2 million women in the U.S., might have an undiagnosed bleeding disorder, including hemophilia A and von Willebrand disease (VWD)¹? These disorders often lead to a reduced quality of life and to life-threatening complications during every stage of life, including menstruation, childbirth, and menopause, in addition to challenges faced in surgery. Despite their prevalence, most of these disorders remain undetected for years. Many are never diagnosed despite the serious medical challenges 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 – even among professionals. For example, a 2009 CDC study showed that the prevalence of VWD or other blood factor deficiencies such as hemophilia A in women with excessive menstrual bleeding was much higher than U.S. gynecologists perceived it to be.² Systematic review of published studies indicated that an estimated 5-24% of women with heavy menstrual bleeding might have undiagnosed VWD.² 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,⁴ 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 survey² 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 treat women with these conditions.

Answering the Call; Advancing Understanding

The goals of much 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 – especially those associated with pregnancy, to generate awareness fostering early diagnosis and informed treatment, and to refine testing to better identify people at risk for bleeding disorders. In fact, anecdotal evidence suggests that such research has begun to expand awareness of women and bleeding disorders. For example, in just 20 years, from 1990 to 2010, the population of females with a bleeding disorder cared for at HTCs grew 346%, while the overall HTC population grew by only 90%.⁵ And over the past decade, from 2012 to 2021, the percentage of females treated at HTCs doubled, from 33.5% in 2012 to 67% in 2021.⁶ More women are now being diagnosed and treated –that’s a win.

Significant 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 fourfold⁸:

• 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 research⁹:

• 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 2012, Community Counts – Registry for Bleeding Disorders Surveillance. Led by ATHN in partnership with the U.S. Hemophilia Treatment Center Network and the CDC, Community Counts is happening at 140 HTCs nationwide and includes over 100,200 patients. Demographic data from HTC visits through September 2021 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.¹⁰ 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. The goal is to support continued research and to improve treatment.

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 think, know, and believe about bleeding disorders. These studies are designed to pinpoint areas of understanding that can be improved through better messaging and to support development of 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

A total of 1,243 young women aged 18 to 25 participated in the survey. The results indicate that¹:

Better You 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

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:

DREAM Award¹¹

The DREAM (Dataset Research Engagement and ATHN Mentorship) Award is the first mentored research award offered through the collaboration of the Hemostasis and Thrombosis Research Society (HTRS) and ATHN. Designed to enhance the care of patients with bleeding and clotting disorders, the award provides grants to young investigators at ATHN-affiliated US HTCs, working under the guidance of experienced mentors. The 2017 award sponsored a cross-sectional study of females with bleeding disorders enrolled in the ATHNdataset. Led by award recipient Kristina Haley, the research goals were to:

• Characterize the population of women with bleeding disorders (published 2020)
• Create an enrichment dataset focused on reproductive tract bleeding in order to characterize bleeding symptoms specific to the population of women with bleeding disorders (analysis underway)
• Characterize the impact of heavy menstrual bleeding and treatment strategies for women with bleeding disorders (analysis underway)

Pregnancy and Delivery in Women with von Willebrand Disease¹²

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.

Von Willebrand Disease: Proposing Definitions for Future Research¹³

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.

ASDH ISTH NHF WFH 2021 Guidelines on the Diagnosis of von Willebrand Disease¹⁴

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 ISTH¹⁵

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 addressing¹⁶:

• 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 Pregnancy⁷

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. This 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.

Current Research Initiatives

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

ISTH New Registry on Hemophilia A/B Carriers¹⁷

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.

VWF/F8 Prophylaxis Study¹⁸

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 anticipated completion date is April 2022.

Minimize Menorrhagia in Women with von Willebrand Disease (VWDMin)¹⁹

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 August 15, 2022.

Related Resources

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

• Heavy Menstrual Bleeding—What’s a Woman to Do? (On-Demand Video)
  This on-demand video presented by Octapharma’s resident hematologist, Dr. Claudio Sandoval, covers the stages of puberty, what constitutes heavy menstrual bleeding, its causes, how it is medically evaluated, and what therapies are available.
• Heavy Menstrual Bleeding—What’s a Woman to Do? (Educational Article)
  Many women, particularly those with an underlying bleeding disorder such as von Willebrand disease or hemophilia, experience troublesome, heavy menstrual bleeding. This informative article covers the fundamentals of puberty and menstruation, definition and symptoms of heavy menstrual bleeding, diagnosis, and treatment options.
• 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.