From the Invisible Hemophilia Carrier to the Lyonization Phenomena: A Long Way to Make Women and Girls With Hemophilia Visible

From the Invisible Hemophilia Carrier to the Lyonization Phenomena: A Long Way to Make Women and Girls With Hemophilia Visible

By Mara Nuñez Toscano, M.D.

Hemophilia has traditionally been a disease linked to men often leaving the female carrier behind the scenes. The disease of women and girls with hemophilia for many years has been underestimated by calling them a "carrier." This sadly resulted in these patients becoming invisible to our medical practice and therefore underestimated the symptomatology of women and girls with hemophilia.

Additionally, the number of female patients with hemophilia is largely underestimated worldwide. This inaccurate number coupled with the fact that many health systems focus their efforts on male patients with hemophilia has overshadowed the experience of females with a bleeding disorder.

The disease of royalty, as hemophilia was formerly known due to its affection to royal family members of British, Spanish, German and Russian regimes, has not been an easy path for female patients to be visible. Leopold, the bleeder prince and probably the first male to make the hemophilia visible to the United Kingdom, unfortunately made his sisters invisible to the medical community because they were thought of as “healthy” girls.

The visibility of patients with hemophilia has been a joint path traveled between patients and the medical community, disseminating information to improve awareness of the disease due to its low incidence in the world population. Another hindrance to the care of women and girls with hemophilia is that the health providers, who are dedicated to the care of females with hemophilia, can be overlooked which adds a challenge to the dissemination of information on aspects of the female disease. 

Considering that for a long-time hemophilia symptoms were thought to only occur in males, the focus of the medical community fell to the patient with severe hemophilia. In turn, the mother and sisters of these patients became invisible, and even when these women had symptoms, they were denied care or ignored. So scientific and medical efforts were predominantly directed to the patient with severe hemophilia, leaving the care of women and girls with hemophilia unrecognized.

Biologically the phenomenon of lyonization can result in a female with a hemophilia mutation to remain with minimal symptoms. On the other hand, lyonization may be skewed to increase the expression of X chromosomes with hemophilia mutations leading to significant bleeding symptoms. This can lead to a large proportion of women and girls whose quality of life is diminished due to hemorrhagic symptoms especially if the symptoms are unrecognized or ignored. Given the X-linked inheritance, in addition to potentially suffering from the disease herself, a woman with hemophilia may carry the emotional burden that her own son may suffer from severe disease or that her daughter may manifest symptoms or suffer from the disease and be overlooked.

As a step in the right direction, the SSC Subcommittees on FVIII/IX and Rare Coagulation Disorders and Women’s Health Issues in Thrombosis and Hemostasis communicated new hemophilia carrier nomenclature in 2021 as a collaborative effort engaging hemophilia experts, patients, and the ISTH community1. Separated the women and girls into those with or without symptoms: including five categories of clinically relevant hemophilia carriers: mild (FVIII/IX > 0.05 and < 0.40 IU/ml), moderate (FVIII/IX 0.01 – 0.05 IU/ml), severe (FVIII/IX < 0.01 IU/ml), symptomatic hemophilia carrier (FVIII/IX ≥ 0.40 IU/ml with a bleeding phenotype), and asymptomatic hemophilia carrier (FVIII/IX ≥ 0.40 IU/ml without a bleeding phenotype). While this communication provides recognition from the international society and community, including not only medical but social recognition, more than a label for a medical condition is required to recognize the disease of women is the same as men.

We must continue with joint efforts such as the SSC nomenclature initiative so that no woman with hemophilia is underestimated, invisible, and untreated. A woman or girl with hemophilia is not only a carrier, but is also a patient that needs our attention and the visibility that for years has remained in the dark.

We live in a new and amazing era in hemophilia which includes life-altering new drugs, but we also live in an exciting time, where we finally recognize that women with hemophilia exist and deserve a better quality of life.

1 Van Galen et al. ‘A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH’. April 2021.

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