Hemophilia A and B are caused by pathogenic variants affecting the genes encoding clotting factor VIII and factor IX, respectively; these genes are located on the X chromosome. The structured known_genes field in this packet is not populated; gene-specific designations are not included here, but molecular genetic testing is used to confirm the causative variant and facilitate family studies. Because the relevant genes are X-linked, hemophilia A and B predominantly affect males, who carry one X chromosome; females who inherit one pathogenic variant are typically unaffected or have milder symptoms, though approximately 30% of carrier females have factor activity below 40% and are at risk for clinically significant bleeding, per GeneReviews. Approximately 30% of affected males have no family history, representing de novo pathogenic variants. Germline mosaicism in carrier mothers has also been documented. The high spontaneous mutation rate in the relevant genes accounts for the similar birth prevalence of hemophilia A across diverse populations. Acquired hemophilia arises from autoimmune production of inhibitory antibodies against endogenous coagulation factors, representing a distinct etiology from the inherited forms.

The diagnosis of hemophilia is established by demonstrating decreased clotting factor activity along with normal von Willebrand factor levels, per GeneReviews for hemophilia A. Severity is defined by factor activity levels: severe (less than 1%), moderate (1–5%), and mild (5–40%). Molecular genetic testing of the relevant causative gene aids in predicting disease severity and the likelihood of inhibitor development, and facilitates carrier testing in family members. Hemophilia is suspected in males presenting with hemarthrosis following mild or absent trauma, deep-muscle hematomas, intracranial bleeding, prolonged bleeding after dental or surgical procedures, unexplained gastrointestinal bleeding, or a family history consistent with X-linked inheritance. Affected females with low factor activity may present similarly. Newborn males with a known family history are typically evaluated by factor assay before any invasive procedures. Differential diagnosis includes von Willebrand disease and other inherited or acquired bleeding disorders, which are distinguished by specific factor activity assays and molecular testing. Evaluation and confirmation of diagnosis at a comprehensive hemophilia treatment center is described by GeneReviews as standard practice in disease management.

Treatment of hemophilia targets prevention and management of bleeding episodes. The FDA-approved treatments in this packet's approved_treatments field for hemophilia are tranexamic acid formulations: TRANEXAMIC ACID IN SODIUM CHLORIDE (approved 2019) and CYKLOKAPRON (tranexamic acid, approved 1986), both antifibrinolytic agents that reduce bleeding by inhibiting fibrinolysis. The GeneReviews chapter for hemophilia A describes the clinical management landscape more broadly: prophylactic intravenous infusion of plasma-derived or recombinant factor VIII concentrate is described by the National Hemophilia Foundation and World Federation of Hemophilia as standard practice for individuals with severe and frequently bleeding moderate hemophilia A. The bispecific antibody emicizumab, which mimics factor VIII function and is administered subcutaneously, is described in GeneReviews as providing effective prophylaxis in individuals with and without inhibitors. GeneReviews also describes 'rebalancing agents'—including marstacimab, concizumab, and fitusiran—as more recently introduced approaches. Treatment is coordinated through hemophilia treatment centers, where multidisciplinary teams provide clinical evaluation, home therapy training, and family support. Long-term surveillance encompasses bleeding episode frequency, joint and muscle status, inhibitor development testing, and relevant infectious disease testing. Children with severe or moderate hemophilia are evaluated at intervals of six to twelve months, per GeneReviews.

The prognosis of hemophilia is substantially influenced by disease severity, subtype, access to treatment, and the development of inhibitors. Individuals with severe hemophilia A who begin prophylactic therapy before or shortly after first joint bleeding events can nearly eliminate spontaneous bleeding and prevent chronic joint disease, per GeneReviews. The greatest benefit of prophylaxis is seen when initiated before age two to three years. Long-term data indicate that early-onset prophylaxis significantly reduces joint damage and associated disability. Inhibitor development, occurring in approximately 20–30% of individuals with the most severe genotypes who receive factor concentrate, complicates management and is associated with reduced treatment efficacy and greater morbidity. Individuals followed at hemophilia treatment centers have demonstrated lower mortality rates than those not receiving center-based care, per GeneReviews. The clinical trajectory of hemophilia continues to evolve with the availability of extended half-life products, non-factor therapies, and gene therapy approaches.

Hemophilia is an active area of clinical research, with numerous trials listed in this packet's clinical_trial_details field and on ClinicalTrials.gov. Gene therapy trials using adeno-associated viral vectors to achieve durable factor expression are in advanced-phase clinical development for both hemophilia A and B; per GeneReviews, one gene therapy product received conditional marketing authorization from the European Medicines Agency in 2022 and FDA approval in 2023 for hemophilia A, with clinical trials demonstrating sustained factor activity and reduction in annual bleed rates. Additional investigational approaches include bispecific antibodies mimicking factor VIII function, rebalancing coagulation inhibitors, and extended half-life factor products. Individuals interested in research participation can search ClinicalTrials.gov for current hemophilia studies.