Women and girls face persistent gaps in hemophilia diagnosis and treatment

Women and girls with hemophilia continue to face delayed diagnoses, unequal access to treatment, and underrepresentation in clinical trials, even though many experience significant bleeding, according to a new analysis.

Researchers described these interconnected problems as the “XX gap” in hemophilia care. Closing this gap, they said, requires moving beyond the longstanding view of women and girls as simply carriers who pass hemophilia-causing genetic mutations to their children, and recognizing them as patients with their own healthcare needs.

“Recognizing women and girls as patients, not merely genetic transmitters, is a critical step toward addressing the diagnostic, therapeutic, and research gaps that persist today,” the researchers wrote. “Closing the ‘XX gap’ in hemophilia care is both a clinical necessity and an ethical imperative.”

The analysis, “The XX Factor in Hemophilia: Diagnostic, Therapeutic, and Research Gaps for Women and Girls,” was published in Haemophilia.

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Why hemophilia can affect women and girls

Hemophilia refers to a group of bleeding disorders in which the blood cannot clot properly, leading to unusually easy or prolonged bleeding. The most common forms, hemophilia A and B, are caused by mutations in the F8 and F9 genes, respectively, which provide instructions for making two different clotting factors. These mutations may cause the body to produce too little of the affected factor, none, or a version that does not work properly.

Since both genes are located on the X chromosome, one of the two sex-determining chromosomes, hemophilia A and B have long been considered diseases that mainly affect men and boys, who have only one X chromosome. Women and girls, who typically have two X chromosomes, have traditionally been labeled as carriers and viewed primarily as people who can pass the disease-causing mutations to their children rather than as individuals who might be affected by the disease.

Growing evidence, however, shows this view is outdated. Women and girls can have clotting factor levels ranging from normal to severely reduced, and many experience clinically significant bleeding. The International Society on Thrombosis and Haemostasis now classifies women and girls whose clotting factor levels meet the criteria for hemophilia as having mild, moderate, or severe disease, just as it does for men and boys. The World Federation of Hemophilia also cautions that “outdated carrier-based language” may hinder diagnosis, appropriate care, and participation in research.

Clinical practice, however, has not fully caught up, the researchers noted.

To explore why disparities persist and identify opportunities for improvement, researchers in Canada drew on current literature, emerging evidence, and their clinical experience to develop a framework describing four interconnected contributors to the “XX gap.” Together, these factors contribute to delayed hemophilia diagnosis, undertreatment, and unequal access to evidence-based care.

One contributor is biological complexity. Bleeding severity in women does not always match lab measurements of clotting factor levels. Abnormal bleeding can occur even in some women whose factor levels are considered normal. Other components of the clotting system may also influence bleeding risk, meaning a single clotting factor measurement may not accurately reflect an individual’s bleeding risk.

The second contributor is the diagnostic challenge. Bleeding symptoms in girls, particularly heavy menstrual bleeding, are often normalized or under-recognized, and evaluation for an underlying bleeding disorder may not always occur. Girls, therefore, are rarely diagnosed during childhood. Consistent with this, a retrospective cohort study of women and girls with hemophilia reported a median age at diagnosis of 22.6 years.

Treatment and research gaps persist

The third contributor is unequal access to treatment.  Hemophilia treatment has advanced dramatically, but women and girls have not benefited equally. Across 124 interventional trials, just eight of 7,555 participants — 0.1% — were women or girls. Their limited participation leaves doctors with little evidence to guide treatment across different stages of life, including menstruation, reproductive health, pregnancy, and childbirth. Trial requirements involving contraception, pregnancy testing, and breastfeeding may also make it harder for women to participate in research.

The fourth contributor, research gaps, is closely tied to this lack of representation. Even when women and girls are included in clinical trials, researchers rarely measure outcomes that may matter especially to them, such as menstrual bleeding, reproductive health, or pregnancy outcomes. As a result, studies may miss important parts of the burden of hemophilia in women and girls. Their underrepresentation in both clinical trials and patient registries also leaves post-marketing data — information collected after a treatment is approved — sparse and fragmented.

To close the “XX gap,” the researchers called for earlier testing of girls and women with bleeding symptoms or a family history of hemophilia and referral to specialized hemophilia treatment centers. They said treatment decisions should be based on a person’s bleeding pattern rather than sex or reproductive status. They also called for closer coordination among hematologists, gynecologists, and obstetricians, greater inclusion of women and girls in trials and patient registries, and routine reporting of results by sex.

“Hemophilia in women and girls has long been hidden in plain sight,” the researchers wrote. “The biological basis for disease expression is well established, the clinical burden is increasingly recognized, and therapeutic options continue to expand. What remains is the commitment to ensure that these advances benefit all individuals affected by hemophilia.”