Women with Bleeding Disorders

Undiagnosed and untreated bleeding disorders in females have a negative impact on their health and quality of life. Because the most common bleeding disorders, including VWD, manifest primarily by mucosal bleeding, females are likely to be symptomatic due to excessive bleeding with menstruation (menorrhagia), ovulation, and childbirth. Studies have documented increased morbidity due to excessive bleeding in girls and women. Women with bleeding disorders are more likely to be iron deficient and to have received blood transfusions. They are also more likely to undergo gynecologic surgical procedures and to have bleeding complications related to those and other surgical procedures. Furthermore, a number of studies have shown the effect of this excessive bleeding, particularly menorrhagia, on quality of life, including increased symptoms of depression, and increased days lost from work and social activity. Since menorrhagia in women with bleeding disorders frequently begins at menarche, these factors could have an impact on the social and academic development of the adolescent female.

Many areas crucial to the diagnosis and treatment of bleeding disorders in girls and women are poorly understood. For this reason this Working Group reviewed current knowledge in this area and identified areas of research needed to reduce morbidity in this population.

Diagnosis of VWD and Bleeding History 
There was general agreement that a bleeding history may be a valuable component in the diagnosis of bleeding disorders, and may prove cost effective by reducing the number of women who would receive expensive laboratory testing. However, there was concern that setting stringent criteria for determination of a significant mucocutaneous bleeding history may exclude some patients who should have further laboratory screening. The challenge is to develop a tool for history-taking that is reasonably specific, but would not exclude further evaluation in appropriate patients. Evaluation of a bleeding history tool in groups of patients with established disease and with uncertain/undiagnosed disease would be critical.

The correlation between bleeding symptoms and a documented bleeding disorder depends on accurate classification of the symptoms. Quantification of excessive bleeding is difficult and is most often assessed through inexact methods including patient self-report or by surrogate measures such as diagnosis of anemia. The definition of menorrhagia is particularly problematic yet critical to research of these disorders. A universally accepted definition of menorrhagia would be beneficial and should be established with gynecology experts. The diagnosis of the underlying bleeding disorder is also controversial.

The following research needs were identified for diagnosis of VWD:

• Development of novel methods for quantifying blood loss, including blood loss through menstruation (alternatives to alkaline hematin method and pictorial blood assessment chart)
• Determination of criteria for diagnosis of hemostatic defects, such as ideal time in menstrual cycle for testing and development of race- and blood type - specific reference ranges for VWD diagnosis
• Validation of a screening tool based on clinical history, symptoms and laboratory testing with a graded diagnostic scale to determine the likelihood a woman has a bleeding disorder
• Standardization between and within coagulation/hemostasis laboratories of tests for bleeding disorders and interpretation of results
• Development of a global laboratory test for bleeding disorders
• Correlation of diagnosis of VWD and risk of bleeding with surgery or other invasive procedures

Diagnosis of Platelet Function Disorders and its Mechanisms 
Recent studies indicate that, for a substantial number of patients with unexplained menorrhagia, platelet function tests show abnormalities in response to different agonists. The issues that were discussed include: a) The prevalence of abnormal platelet function, either inherited or acquired, remains unknown in patients with menorrhagia and needs to be established. The role of platelet function disorders in post-partum hemorrhage is also unknown. b) Despite major advances in our understanding of platelet biochemistry and physiology, the underlying molecular mechanisms remain unknown in most patients identified with impaired aggregation responses. c) Platelet aggregation and secretion studies have been the foundation of platelet studies to date but are affected by variables such as medications, diet and acquired diseases. Other methods (e.g. Platelet Function Analyzer-100TM) have the potential to provide new information. Expression profiling and proteomics is unstudied in patients with platelet function defects and bleeding symptoms. While additional studies in patients with menorrhagia using the current methods are an initial step, there is a need to incorporate newer methods, including studies on specific signaling mechanisms, and on the platelet proteome and transcriptome. d) Acknowledging that most patients with inherited platelet disorders do not have a severe bleeding disorder, there is a need to assess the relationship between the observed laboratory abnormalities in platelet studies and the clinical bleeding manifestations. The effects of the menstrual cycle and hormones on platelet function remain poorly studied. The usefulness of incorporating screening tests in the diagnosis of platelet function disorders is not determined. e) The generally used hemostatic agents in patients include DDAVP and antifibrinolytic agents. The clinical efficacy of these and other novel agents in patients with menorrhagia warrants additional well-designed and controlled studies.

The following research needs in the area of platelet function disorders were identified:

• Perform biochemical, molecular, and functional studies in patients with abnormal aggregation/secretion responses to understand the mechanisms of the platelet defects
• Develop new approaches to diagnosing platelet function disorders
• Determine racial differences in platelet function abnormalities
• Explore the role of expression profiling and proteomics in defining platelet disorders
• Design studies to assess how the diagnosis of platelet function disorders alters clinical and surgical outcomes
• Determine the prevalence of platelet function disorders in postpartum hemorrhage
• Identify changes in platelet function associated with menstruation, hormonal use, pregnancy, and delivery
• Assess optimal treatment for women identified with platelet function disorders

Menarche, Pregnancy / Puerperium & Menopause 
Many women who have ultimately been diagnosed with a bleeding disorder report that they experienced heavy menstrual bleeding from the time of their first menstrual period (menarche). Unfortunately, there is extremely limited data regarding menorrhagia in adolescents. Irregular and heavy menses are associated with anovulation, which is more likely to occur during adolescence and in perimenopause. The contribution of bleeding disorders to menorrhagia in adolescents is unknown. There are reports of cases of bleeding disorders among women with hemorrhagic ovarian cysts, but no data on prevalence. In a retrospective case-control study, ovarian cysts and endometriosis were reported more often by women with bleeding disorders than controls. Endometriosis may be more common in women with bleeding disorders, or may be more likely to be symptomatic. After adolescence and during the reproductive years, women are less likely to experience heavy menstrual bleeding. They are more likely to have regular menses and they may be taking birth control pills, which reduce menstrual blood loss. During pregnancy, women experience bleeding challenges with miscarriage and childbirth. Case reports, case series and a retrospective case-control study have found that women with bleeding disorders are more likely to bleed during pregnancy and postpartum. However, the prevalence of bleeding disorders among those with such bleeding complications remains unknown. As women with bleeding disorders approach menopause, they may also be more likely to have anovulatory bleeding or bleed if they develop fibroids, polyps and endometrial hyperplasia. These conditions may increase their risk of heavy menstrual bleeding.

There are few longitudinal studies of hemostatic factors among women with or without bleeding disorders. Although a CDC sponsored menorrhagia treatment trial is underway, there is little data to guide DDAVP dosing and duration of treatment. Tranexamic acid is a promising alternative for treatment of menorrhagia and is being studied in the CDC trial, but the associated thrombotic risk is unknown. Other issues that need to be determined include optimal management of menorrhagia, the best therapy for specific defects, the risk of hemorrhagic cysts, the risk of pregnancy loss and the risk of postpartum bleeding.

The following needs were identified during the discussion about menarche, pregnancy/puerperium and menopause:

• Novel methods to measure menstrual and postpartum blood loss
• Diagnostic tools to determine the nature of adolescent menorrhagia - anovulation, hormonal or hemostatic defect
• Studies to better understand the hemostatic changes with various hormonal treatments, changes with the menstrual cycle, and changes with/after delivery
• New therapeutic options for the treatment of menorrhagia

Treatment Options, Limitations and Needs 
Current treatment of VWD is suboptimal, sometimes requiring short-duration intravenous administration of DDAVP or plasma-derived VWF concentrate, options unrealistic for management of menorrhagia. Estrogen, by default, has been the treatment for menorrhagia among women with VWD. Yet, the benefits and risks of long-term estrogen therapy has not been well-studied in women with bleeding disorders. Estrogen formulations, doses, and schedules that are safe and effective for long-term therapy need to be determined. New drug development for bleeding disorders should be encouraged. Novel combination therapies, such as intranasal DDAVP with an anti-fibrinolytic agent, and new modes of drug delivery, such as a vaginal suppository, need to be explored. The ideal therapy for menorrhagia should be easy to use at home or work, applicable for teens as well as adults, noninvasive, long-acting, and with few, if any, side effects. For menorrhagia unresponsive to medical treatment, and when childbearing years are over, hysterectomy has been the usual treatment approach. Excessive bleeding may follow this procedure, and little is known about the risk factors for bleeding. Excessive bleeding may occur at childbirth and postpartum. The risk factors for these bleeding complications, and the relation of VWF or other hemostatic factors to symptoms remain unknown.

Would finding VWF deficiency or platelet defects improve the management of women with menorrhagia? This question is closely tied to the issue of efficacy and safety of hemostatic interventions presently available for such patients. The benefit of tranexamic acid for treatment of menorrhagia is based on limited data, and the use of intranasal DDAVP in menorrhagia remains inconclusive. Consequently, further study is necessary.

The following research needs were identified for treatment of women with bleeding disorders:

• Studies to determine the risks of long-term estrogen therapy
• Studies to determine safe and effective dosing regimens of VWF-containing concentrates for bleeding and non-bleeding states in patients with VWD (e.g. benefit/risk ratios)
• Evaluation of products not currently available in the US, but available outside the US for treatment of VWD and other bleeding disorders
• Safety and efficacy studies of alternative treatment approaches
• Development and evaluation of new therapeutics for VWD and platelet disorders

Working Group Members: 
Chair: Barbara A. Konkle, M.D., University of Pennsylvania 
Sally Crudder, RN, MPH, Center for Disease Control and Prevention 
Nicole Dowling, Ph.D., Center for Disease Control and Prevention 
Andra James, M.D., Duke University Medical Center 
Peter A. Kouides, M.D., Rochester General Hospital 
Robert R. Montgomery, M.D., Medical College of Wisconsin 
Diane J. Nugent, M.D. Children's Hospital of Orange County 
Claire S. Philipp, M.D., Robert Wood Johnson Medical School 
Margaret V. Ragni, M.D., MPH, University of Pittsburgh School of Medicine 
A Koneti Rao, M.D., Temple University School of Medicine 
Margaret E. Rick, M.D., National Institutes of Health

American Society of Hematology Representatives: 
Steven R. Lentz, M.D., Ph.D., University of Iowa 
Jeffrey Coughlin, American Society of Hematology

National Hemophilia Foundation Representatives: 
Steven Humes, MPH, National Hemophilia Foundation 
Ann Marie Nazzaro, Ph.D., National Hemophilia Foundation

NHLBI Staff: 
Rebecca P. Link, Ph.D., Division of Blood Diseases and Resources 
Pankaj Ganguly, Ph.D., Division of Blood Diseases and Resources 
Ahmed Hasan, M.D., Ph.D., Division of Blood Diseases and Resources 
Robert B. Moore, Ph.D., Division of Blood Diseases and Resources