A new study published in the journal Blood Advances describes a new initiative focused on traditionally underserved and underdiagnosed subgroup within the bleeding disorders community – hemophilia carriers/females with hemophilia.
The study was spearheaded by a hemophilia treatment center (HTC) at the Cliniques universitaires Saint-Luc, in Brussels, Belgium. While the HTC has been screening female relatives of patients with hemophilia for two decades, accurate information on all carriers/potential carriers within the families of their patients was lacking. The investigators therefore set out to identify potential and obligate hemophilia A (HA) and hemophilia (HB) carriers by updating the family pedigrees of all people with hemophilia (PWH) receiving regular care at the center. Several scenarios denote obligate carrier status, such as being the daughter of a man with hemophilia.
The study was conducted at the HTC from May 2021 to April 2023. A retrospective data analysis of electronic medical records generated from routine carrier screening of female relatives of PWH. The analyses captured data on factor VIII and factor FIX levels, genetic testing results, bleeding history, hemostatic treatment history, and family pedigrees.
Investigators also took the opportunity to identify family members that were previously unaccounted for. “In addition to this retrospective analysis and to further enhance the screening of female relatives of PWHs, we adopted a proactive and systematic approach to reach out to previously unscreened or incompletely screened individuals, explained the authors. “During personal contacts with PWHs regularly followed at the HTC (referred to as “probands” hereafter), either during clinical follow-up visits or telephone interviews, pedigrees of probands were analyzed and unscreened potential and obligate carriers of hemophilia were identified, complementing the pedigree information gathered during the retrospective part of the study.”
The results showed that relatively large groups of carriers within the HTC’s sphere were previously identified, with some omissions. In pedigrees of 287 male PWHs (226 HA and 61 HB) and seven female patients from 236 families (184 HA and 52 HB), a total of 900 female individuals were identified. Of those, 454 were obligate and/or genetically proven carriers, and 118 were noncarriers.
Subsequent genetic testing was conducted in 133 obligate, 237 potential, and four sporadic carriers, with 190 obligate and 328 potential carriers yet-to-be tested. Among carriers with known factor levels (261/454), 42 HA (23.0%) and 23 HB carriers (29.5%) had a factor level below 40 IU/dL, suggesting mild hemophilia. Carriers with a factor deficiency were screened on average six years earlier than other females.
The investigators emphasized the importance of robust efforts in screening for potential hemophilia carriers to ensure that less individuals fall through the gaps.
“The imperative to continually update pedigrees remains essential, given that even groundbreaking treatments such as gene therapy do not alter the hereditary nature of hemophilia. In addition, the transition of PWHs from pediatric to adult care marks a vulnerable phase during which keeping track of the patient's relatives becomes challenging,” assert the authors. “Furthermore, girls who underwent coagulation factor level assessments during childhood still require genetic testing later in life and should not be overlooked. Identified carriers, especially those experiencing abnormal bleeding, should benefit from regular follow-up at the HTC.”
The paper also cited several limitations, including the retrospective quality of the data, certain selection bias, and lack of insight into patients' factor levels. For instance, only the lowest factor levels of each participant were included in the analysis, no adjustments were made for the use estrogen and/or progesterone treatments, and factor levels measured during pregnancy were not considered.
Limitations notwithstanding the authors posit that initiatives such as these could help further the cause of gender equity in bleeding disorders care.
“To conclude, this study, to our knowledge, represents the first reported initiative to systematically identify and screen (potential) hemophilia carriers among families of all PWHs followed at a single HTC. We have gained new insights into practical aspects of carrier diagnostics, while also identifying persistent challenges in providing comprehensive screening to relatives of PWHs,” explained the authors. “Initiatives similar to our study should be replicated by other HTCs internationally, given that they would represent a crucial step toward ensuring equitable access to hemophilia diagnosis and care for all potentially affected individuals, regardless of sex and gender.”
Read the full open access article to learn more about the study’s findings, including the challenges associated with broader carrier screening, plus insights on symptoms and treatment of these populations.
Citation
Krumb E, Lambert C, Van Damme A, Hermans C. Proactive systematic hemophilia carrier screening: a step toward gender equity in hemophilia care. Blood Adv. 2024 Oct 22;8(20):5268-5278. doi: 10.1182/bloodadvances.2024013866. PMID: 39167764; PMCID: PMC11492442.
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