The XX Factor in Hemophilia: Diagnostic, Therapeutic, and Research Gaps for Women and Girls

INTRODUCTION: Hemophilia has traditionally been viewed as an X-linked disorder affecting men and boys, with women and girls labeled as "carriers", presumed to be clinically unaffected. This paradigm has contributed to under-recognition, delayed diagnosis, and undertreatment of females with hemophilia-associated genotypes despite an increasingly recognized burden of bleeding. AIM: To propose a conceptual framework for understanding and addressing persistent gaps in the diagnosis, management, and research of women and girls with hemophilia-associated genotypes. METHOD: Drawing on contemporary literature, emerging evidence, and clinical experience, the authors developed a framework to identify factors contributing to inequities in hemophilia care and opportunities for improvement. RESULTS: The framework identifies four key domains contributing to the "XX gap" in hemophilia care: biological complexity, diagnostic challenges, therapeutic inequities, and research gaps. Biological factors, including variable X-chromosome inactivation, contribute to heterogeneous factor levels and bleeding phenotypes. Diagnostic challenges include under-recognition of bleeding symptoms, reliance on factor levels alone, and gender bias in clinical assessment. Therapeutic inequities persist despite advances in hemophilia care, with limited evidence to guide management across the lifespan. Research gaps are reinforced by underrepresentation in clinical trials, restrictive eligibility criteria, and limited real-world data. Collectively, these domains contribute to delayed diagnosis, unmet clinical needs, and inequitable access to evidence-based care. CONCLUSIONS: Women and girls with hemophilia-associated genotypes remain underserved within traditional care models. This framework highlights priorities for improving recognition, diagnosis, treatment, and research inclusion. Addressing these interconnected gaps is essential to advancing equitable, patient-centered, and evidence-based care for all individuals affected by hemophilia.