Women with hemophilia A may face disparities in diagnosis, treatment
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As a disease that traditionally has been thought to only affect men, hemophilia has acquired the false reputation of being a “male-only” disease.
However, women also live with hemophilia and may experience additional symptoms or bleeding complications during menstruation or pregnancy that may make the disease harder to diagnose. Historically, this has led to a lack of testing, accurate diagnosis and care of these women.
“I’m a female treater, and a lot of hemophilia treatment centers have a strong backbone support system of women running them and managing many of these patients,” Katharine Batt, MD, MSc, a hematologist, investigator with a research focus in health outcomes and former medical director of Wake Forest School of Medicine’s Hemostasis and Thrombosis Center, said in an interview with Healio. “From a provider standpoint, we have a really strong female presence providing care for what’s predominantly a male population. Yet, we are seeing mothers who are sometimes also affected. The question is, where do they go?”
In a study of more than 1,500 patients, Batt and colleagues found that women with hemophilia A and hemophilia A carriers may be undermanaged and undertreated for their disease.
Batt spoke with Healio about the misunderstandings around hemophilia in women, the gaps in clinical trial representation and the future implications of her study, sponsored by Takeda and presented in August during the National Hemophilia Foundation’s Bleeding Disorders Conference.
Healio: How are women with hemophilia defined differently than men?
Batt: Genotypically, they may have only one mutated X, if we’re talking about a woman who is not a true hemophilia A patient. By genetic standards, that would indicate carrier status.
The way the X chromosome is manifested, there is a variable silencing of the X presentation, which means that a woman with one mutated X can have more presentation of that mutated X than the normal chromosome, or more of a traditional hemophilia phenotype. When you measure her factor VIII levels, for example, you see her case is not that different from a mild case of hemophilia A in a man.
So, we’ve got a definition issue. These women are bringing their sons to a very well-established center, but where do they go for care?
Healio: Are women with hemophilia underrepresented in clinical trials? How does this definition issue affect that?
Batt: If you were to compare the amount of research on the male hemophilia population with that on women with hemophilia, there is a dramatic difference. Absolutely, they are underrepresented in the current scientific literature.
Part of the reason comprehensive data on women with hemophilia is limited is that clinical trials generally enroll only patients with severe hemophilia, a population that consists largely of men. Patients with moderate and mild hemophilia are often excluded.
Healio: How does the definition problem impact the ability of these women to receive diagnosis and care?
Batt: The fundamental care paradigm for women has not been the same as for men. For a male hemophilia patient — irrespective of factor VIII activity levels, even bleeding — care at a hemophilia treatment center is seen as fundamental. For women, who have traditionally not been seen as suffering from hemophilia, the need for care at a hemophilia treatment center has not been obvious. So, who’s looking out for the general well-being of these women and monitoring them? More than likely, her only connection to a hematologist is indirectly through her male children.
Healio: How did you conduct your study?
Batt: This study was designed to identify and define the clinical and demographic characteristics around female hemophilia A and, most specifically, around the “carrier.” We also looked at a subset of patients with what we called a dual diagnosis: they were diagnosed with both hemophilia A and hemophilia A carrier status. We then looked at the characteristics of the female hemophilia A carrier population against a non-hemophilia A general population, just to get a bit more understanding of the health care resource utilization and bleeding rates. We used a claims database and had stringent inclusion-exclusion criteria to ensure we got to the patients who had hemophilia A. We looked at the characteristics of four cohorts: male hemophilia A, female hemophilia A, female hemophilia A carrier and dual diagnosis.
Healio: What did you find?
Batt: There were a number of significant findings, but perhaps most dramatic were the differences in age between the male and female cohorts. Men were dramatically younger, aged between 20 and 27 years, while in the female hemophilia A population, the age was in the mid-40s — irrespective of insurance type (commercial or Medicaid). In contrast, the hemophilia A carrier group and the dual-diagnosis cohorts were in their 30s — a little younger than the female hemophilia population.
Although one of the study’s primary aims was to better identify the carrier clinical characteristics, as we dug into the analysis, we started to see a lot of bleeding across the board in the female hemophilia A group, the carrier group and the dual-diagnosis group.
In the dual-diagnosis group, there was a surprising amount of bleeding, more even than among the male hemophilia A cohort. We also found a lot of joint health or musculoskeletal complaints among all the female cohorts. This was somewhat less surprising, since there was significantly less treatment prescribed and factor VIII usage among these women. For the most part, only medications for mild hemophilia A, such as desmopressin or tranexamic acid, were used and with low prescription rates.
We found that, overall, health care resource utilization — especially outpatient visits and hospitalizations — was high among the women, higher even than among the male cohort. Because pharmacy costs were relatively low compared with the male hemophilia cohort, most of the costs were based on clinic visits and inpatient stays.
Healio: How should women with hemophilia be treated?
Batt: There are some insurance implications around that. Typically, prescription coverage and reimbursement are tied to a diagnosis of hemophilia, so if you are diagnosed as a woman with hemophilia A, you can probably get access to factor VIII a lot easier. If you’re a woman with a diagnosis of hemophilia A carrier, that isn’t necessarily seen as a disease, so there may be reimbursement implications. This may be why our dual-diagnosis population seemed to be a sicker population, because the need to treat more aggressively required a diagnosis of hemophilia and not just carrier state.
Healio: What is the best approach to preventing joint bleeds in women with hemophilia?
Batt: The ongoing question is: what’s the right trough level? Obviously, you want to get a high enough trough level to prevent spontaneous bleeding, but how do you minimize ongoing joint damage?
The question of trough level has spilled over nicely into questions concerning patients with female hemophilia A, or hemophilia A carriers. These patients typically have higher trough levels, so what does their general status look like? Some research is starting to show that when you compare these women with the healthy female population, they have a worse quality of life. They are having more joint interference and other symptoms you would expect to see in male patients with hemophilia A. Historically, we have assumed that because these women have what is described as an adequate trough level, their lives are no different than anyone without hemophilia. Yet, the data around quality of life suggest that we probably have this wrong.
Healio: What should clinicians do when they see a female patient whose hemophilia A carrier status seems more indicative of actual hemophilia A?
Batt: We need to start evaluating these women at an earlier age and collecting more data. We need to understand their trajectory from an earlier age, rather than seeing much later with significant GI bleeds or a long history of heavy menstrual bleeding. Once we identify them and understand their baseline, we can start following these patients and better understand their patient journey. A lot of it is just earlier awareness.
More specifically, we know these women are coming in with their sons who have a hemophilia diagnosis. In our bleeding centers, we can start to really peel apart the fact that the mother is part of the son. When the sons visit, let’s have a separate evaluation for the mothers. Let’s make sure we have their family history, and let’s follow them. The bleeding centers are the next place where we can try to improve things.
For more information:
Katharine Batt, MD, can be reached at Wake Forest Baptist Health Hematology and Oncology Cancer Center, 301 Medical Center Blvd., Winston Salem, NC 26157-0001; email: katharine.batt@gmail.com.
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Batt K, et al. Poster 35. Presented at: National Hemophilia Foundation Annual Virtual Bleeding Disorders Conference, Aug. 26-28, 2021.
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