Characterizing an Underdiagnosed Condition: Hemophilia in Females

Introduction: Hemophilia is often overlooked in females (XX), delaying diagnosis and appropriate care. Like males, females who carry hemophilia gene mutations can present with low factor levels as well as clinically significant and even life-threatening bleeding. This knowledge has led to new nomenclature that classifies them according to their clotting factor levels: those with low factor levels (<0.4 IU/ml for factor VIII or IX; < 0.6 IU/ml for FXI) are classified as females with hemophilia (FWH), while those with normal factor VIII or IX levels (> 0.4 IU/ml) are classified as hemophilia carriers (HC). Despite our greater understanding of their bleeding phenotype, FWH are still underrepresented in national and international hemophilia registries, leading to limited data to guide their management. It is estimated that one-third of persons with hemophilia are female, yet hemophilia registries continue to report a proportion below 10%. Their underdiagnosis, which leads to inappropriate management, constitutes a healthcare disparity that must be addressed. Increasing our knowledge of their clinical characteristics is paramount for early identification and comprehensive management. Few studies have addressed this. Here, we provide an extensive characterization of HC and FWH.

Methods: We performed a retrospective analysis of 107 HC and FWH (A, B or C) who were seen at Yale New Haven Hospital between 2012 and 2023. All participants were assigned female at birth (XX) and had at least one of the following: obligate carrier status, confirmed genetic mutation or low clotting factor levels. HA and HB severity was classified as mild if factor activity was < 0.4 IU/mL but > 0.05 IU/mL, moderate if < 0.05 UI/mL but > 0.01 IU/mL, and severe if < 0.01 IU/mL. Hemophilia C severity was classified as partial deficiency if factor activity was < 0.6 IU/mL but > 0.2 IU/mL, or severe if it was < 0.2 IU/mL. Demographic, clinical and laboratory data were analyzed using SPSS software. Categorical variables were described using frequencies and percentages, while quantitative variables were described using central tendency and dispersion measures. This study was approved by our Institutional Review Board.

Results: 107 patients were included in the final analysis. We identified 52 hemophilia A carriers (HC-A), 7 hemophilia B carriers (HC-B), 14 females with hemophilia A (FWH-A), 9 females with hemophilia B (FWH-B) and 25 females with hemophilia C (FWH-C). The mean age at hemophilia diagnosis was 24 (± 21) for FWH-A, 16 (± 14) for FWH-B and 17 (± 13) for FWH-C. Among FWH-A and FWH-B, factor deficiency was mild in 86% and 89% of cases, and moderate/severe in 14% and 11%. Among FWH-C, factor deficiency was partial in 88% of cases and severe in 12%. Care at a hemophilia treatment center (HTC) was provided for 67% of HC-A, 86% of HC-B, 93% of FWH-A, 89% of FWH-B, and 100% of FWH-C.

Common manifestations in the entire cohort were easy bruising (53%), heavy menstrual bleeding (HMB) (46%), iron deficiency anemia (IDA) (45%), and epistaxis (25%). Post-partum hemorrhage (PPH) and miscarriages were reported in 10% and 33% of the entire cohort. PPH rate was highest among FWH-A (40%); miscarriage rate was highest among HC-A (39%). Major spontaneous bleeding and major surgical bleeding were most common among FWH-A (14% and 29%, respectively). Major traumatic bleeding was reported in 6% of all patients.

Factor replacement therapy was used in 15% of HC-A, 42% of HC-B, 43% of FWH-A, and 67% of FWH-B. Anti-fibrinolytic agents were utilized in 31% of HC-A, 57% of HC-B, 57% of FWH-A, 67% of FW-HB and 80% of FWH-C. Blood transfusions were given to 17% of HC-A and 14% of FWH-A; with 50% of these transfusions due to PPH.

Conclusions: Our study highlights the significant bleeding manifestations of FWH and HC, showing rates of HMB, PPH, miscarriage and IDA that are several times higher than what has been reported in the general population. The frequency of blood transfusions due to PPH is concerning and suggests suboptimal obstetrical planning around their bleeding risk. Our data portrays substandard management of HC and FWH, especially concerning reproductive care, which may be attributable to the late age of diagnosis. This healthcare disparity must be addressed. Early diagnosis of HC and FWH is essential to provide high-quality healthcare. We advocate for higher inclusion of females in hemophilia registries and clinical trials to provide robust data for comprehensive care.