NATIONAL HEART, LUNG, AND BLOOD INSTITUTE WORKING GROUP ON
MECHANISTIC PERSPECTIVES ON HORMONE-INDUCED THROMBOSIS IN WOMEN
The National, Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on September 13-14, 2012 in Bethesda, MD to discuss the current knowledge and future research needs of hormone-induced thrombosis in women. The aim of the meeting was to improve our understanding of the mechanisms that affect the thrombotic challenges unique to women throughout their lifespan. The objectives of the Working Group were to:
- Review the current state of knowledge of hormone-induced thrombosis in women and identify critical gaps in research and clinical areas
- Identify risk factors for hormone-induced thrombosis throughout the female reproductive and postmenopausal life cycle
- Prioritize research and clinical goals in this field
- Identify how NHLBI could facilitate research and advance our understanding of hormone-induced thrombosis in women.
The working group consisted of basic and clinical scientists, epidemiologists, and physicians with expertise in coagulation science, hematology, epidemiology, and obstetrics & gynecology including reproductive endocrinology, and maternal-fetal medicine. Representatives from the Women's Health Initiative in the NHLBI's Division of Cardiovascular Sciences (DCVS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Department of Health and Human Services (DHHS), the Centers for Disease Control and Prevention (CDC), and the Food and Drug Administration (FDA) participated in the discussion. Dr. Janine Austin Clayton, Director of the NIH Office of Research on Women's Health addressed the group and summarized the NIH strategic plan for advancing women's health research (http://orwh.od.nih.gov/research/strategicplan/index.asp) .
Exposure to elevated levels of estrogen +/- progestin has been linked with increased risk of both arterial and venous thrombosis in women. While women are naturally exposed to modulating levels of these hormones, exposure to exogenous sources may increase their health risks. Additionally, differences in the baseline state of coagulation factors between mature males and females may independently augment the thrombotic risk in women. Topics of discussion were organized into three sessions:
- Pregnancy and Assisted Reproductive Technologies
- Thrombotic and vascular risks associated with pregnancy
- Assisted reproductive technologies (ART) and associated risk of thrombotic complications
- Information gathered from large, ongoing studies of pregnancy (i.e. National Children's Study)
- Indications for Hormonal Therapy in Non-Pregnant Women
- Contraceptive formulations and relative risk of thrombosis
- Postmenopausal hormone replacement therapy - lessons learned from the Women's Health Initiative
- Epidemiology of venous thromboembolism (VTE) throughout the female life cycle
Mechanisms of Hormone-Induced Thrombosis
- The coagulation system as it may relate to mechanisms of hormone-induced thrombosis
- Estrogen effects on coagulation cascade, plasma proteins, platelets, and endothelial cells
- Genetic studies to elucidate mechanisms of thrombosis in women
To adodress specific gaps in knowledge and research priorities, the Working Group made the following recommendations:
- Analyze prior or existing studies for prognostic indicators and predictors of early risk (i.e. databases from the Women's Health Initiative, National Children's Study, Reproductive Medicine Network, and Contraceptive Network). Data and/or biospecimens from prior or ongoing studies could be utilized to determine thrombotic risks based on hormonal exposure, race, age, obesity, diabetes, or immunologic competence. Potential risks associated with genetic background, drug-drug interactions, ART, and ovarian age could also be evaluated.
- Conduct mechanistic studies of the natural effects of hormones on tissues from healthy women. Evaluate the effects of natural variations in blood levels of estrogen on the normal vascular endothelium, and on the cellular components of thrombus formation. Hormonal effects may differ in tissues depending on levels of hormone receptor expression.
- Identify biomarkers of thrombotic risk associated with hormonal therapy in non-pregnant women. There are currently no available biomarkers to evaluate the effects of estrogen and/or progestins in normal healthy women, healthy pregnant women, and women at moderate and high risk of VTE. Ideally, biomarker studies should be longitudinal, rather than cross-sectional, in order to examine potential cyclical modulation during the menstrual cycle. Studies could also leverage women with specific diseases or those undergoing hormonal therapy to better understand thrombotic risk factors, as well as apply "omic" technologies to help identify women at high, moderate, and low risk for thromboembolism.
- Evaluate how route of estrogen administration and formulation affects risk of hormone-induced thrombosis. In postmenopausal hormone therapy, transdermal estrogen patches are associated with less risk of thrombosis than oral administration. Additional studies are needed to understand the mechanism underlying why the route of estrogen administration affects thrombotic risk.
- Investigate mechanisms involved in pregnancy-associated risk of thrombosis. Pregnancy increases plasma levels of several coagulation factors. These naturally occurring changes in hemostatic factors may alter risk of thromboembolism. Elevated risk of thrombosis is also associated with cesarean deliveries. Studies are needed to identify biomarkers of elevated risk for thrombosis during and immediately following pregnancy. The nature of vascular injuries associated with pregnancy and ART is not fully understood and requires further investigation.
- Develop female animal models for pre-clinical studies. Current animal models are lacking in their ability to evaluate the effects of hormones on thrombosis. There is a need to develop animal models to understand the effects of endogenous and/or exogenous exposure of estrogen +/- progestin on different tissues. Animal testing should specifically focus on female animals, since male animals and male tissues may not accurately reflect responses to estrogen and/or progestin exposure in females. Also, development of animal models is critical because of limitations of performing research on pregnant women. Utilize animal models to evaluate mechanisms of thrombin generation, platelet function and reactivity, and epigenetic changes including glycosylation, sialylation, and methylation.
The Working Group committee will develop a report of the meeting for publication in an appropriate professional journal.
Division of Blood Diseases and Resources
Division of Cardiovascular Sciences
- Andra James, MD, MPH, University of Virginia
- Barbara Konkle, MD, Puget Sound Blood Center and the University of Washington
- John Griffin, PhD, The Scripps Research Institute
- Kurt Barnhart, MD, MSCE, University of Pennsylvania
- Ruth Brenner, MD, MPH, National Children's Study Program Office, NIH
- Kathleen Brummel-Ziedins, PhD, University of Vermont
- Janine Clayton, MD, Office of Research on Women's Health, NIH
- Mary Cushman, MD, MSc, University of Vermont
- John Griffin, PhD, The Scripps Research Institute
- Jill Johnsen, MD, Puget Sound Blood Center and the University of Washington
- Andrew Kaunitz, MD, University of Florida
- Virginia Miller, PhD, Mayo Clinic Rochester
- Michael Paidas, MD, Yale University
- Jacques Rossouw, MD, Women's Health Initiative Branch, NHLBI, NIH
- Nicholas Smith, PhD, University of Washington
- Alisa Wolberg, PhD, FAHA, University of North Carolina
- Erin Wolff, MD, FACOG, NICHD, NIH
- Dale Burwen, MD, MPH, Women's Health Initiative Branch, NHLBI, NIH
- Suzanne Haynes, PhD, Office of Women's Health, DHHS, NIH
- W. Craig Hooper, PhD, Division of Blood Disorders, CDC
- Timothy Lee, PhD, Center for Biologics Evaluation & Research, FDA
- Christos Mastroyannis, MD, Division of Reproductive & Urologic Products, FDA
- Mikael Ovanesov, PhD, Center for Biologics Evaluation & Research, FDA
- Uma Reddy, MD, MPH, Pregnancy and Perinatology Branch, NICHD, NIH
- Lisa Soule, MD, Division of Reproductive & Urologic Products, Center for Drug Evaluation & Research, FDA
- Evi Struble, PhD, Division of Hematology, Center for Biologics Evaluation & Research, FDA
- Naomi Tepper, MD, MPH, FACOD, Division of Reproductive Health, CDC
- Gerald Willett, MD, Division of Reproductive & Urologic Products, FDA
- W. Keith Hoots, MD
- Donna DiMichele, MD
- Jamie Siegel, MD
- Rebecca Link, PhD
- Ronald Warren, PhD
- Andrei Kindzelski, MD, PhD
- Susan Pucie
- Naomi Clarke
- Kathryn Fain
Last Updated: November 2012