The packet lists F8 as the associated gene, with ClinGen gene-disease validity of definitive, located on the X chromosome. GeneReviews states that hemophilia A is inherited in an X-linked manner. According to GeneReviews, all males with an F8 pathogenic variant are affected with approximately the same severity as other affected males in the family, though other genetic and environmental effects may modify severity to some extent. Approximately 30% of heterozygous females are described as having factor VIII clotting activity below 40%. GeneReviews describes genotype-phenotype correlations: F8 intron 22 inversions are associated with severe disease and account for 45% of individuals with severe hemophilia A, while single-nucleotide variants creating new stop codons and most frameshift variants are associated with a severe phenotype. Missense variants are found in nearly all of those with mild or moderate disease. GeneReviews states that approximately 30% of affected males have no family history.

GeneReviews lists clinical features that raise suspicion of hemophilia A, including hemarthrosis with mild or no antecedent trauma, deep-muscle hematomas, intracranial bleeding without major trauma, neonatal cephalohematoma, prolonged bleeding after tooth extraction or circumcision, unexplained gastrointestinal bleeding or hematuria, heavy menstrual bleeding, prolonged nosebleeds, and excessive bruising. Laboratory features listed are a normal platelet count, a prolonged activated partial thromboplastin time, and a normal prothrombin time. According to GeneReviews, the diagnosis is established in a male proband by decreased factor VIII clotting activity together with a normal, functional von Willebrand factor level. In a female proband, the diagnosis may be established by bleeding symptoms with decreased factor VIII clotting activity, and/or by identification of a heterozygous F8 pathogenic variant; GeneReviews notes that clotting activity does not reliably identify heterozygous females. GeneReviews states that identification of a hemizygous F8 pathogenic variant can help predict the clinical phenotype, assess inhibitor risk, and allow family studies. GeneReviews also lists other inherited bleeding disorders with low factor VIII clotting activity, including von Willebrand disease, and notes that von Willebrand factor levels can differentiate mild hemophilia A from it. The packet lists no newborn screening information for this condition.

The packet lists active FDA records for fitusiran (Qfitlia, March 2025), concizumab (Alhemo, December 2024), marstacimab (Hympavzi, October 2024), valoctocogene roxaparvovec (Roctavian, June 2023), antihemophilic factor Fc-VWF-XTEN fusion protein (Altuviiio, February 2023), emicizumab (Hemlibra, November 2017), and antihemophilic factor Fc fusion protein (Eloctate, June 2014). GeneReviews states that the World Federation of Hemophilia has published treatment guidelines, and that treatment is coordinated through a hemophilia treatment center, with hemophilia nurse specialists contributing education, home infusion and injection training, and family support. GeneReviews describes prophylactic intravenous infusion of plasma-derived or recombinant factor VIII, or subcutaneous emicizumab, as considered the standard of care by the National Hemophilia Foundation and the World Federation of Hemophilia for severe hemophilia A and for moderate disease with frequent bleeding. It states that prophylaxis may also be achieved with the rebalancing agents marstacimab, concizumab, and fitusiran, that the greatest benefit of prophylaxis is seen in those who begin before age 2.5 to three years, and that routine prophylaxis begun later significantly decreases bleeding episodes. Factor VIII concentrate infusions are also described for bleeding episodes. It also describes a section of agents and circumstances of concern, which includes medications affecting platelet function and activities carrying a risk of trauma. Patient assistance programs may be available for some therapies. Orphan designations in the packet, which are not approvals, include numerous gene therapy vectors and other investigational products.

The packet does not provide a structured natural history field, so the following is drawn from GeneReviews. GeneReviews states that persons with hemophilia who are followed at a hemophilia treatment center have lower mortality than those who are not. It describes the age of diagnosis and frequency of bleeding in untreated individuals as related to factor VIII clotting activity: severe disease is usually diagnosed in the neonatal period or first year of life, moderate disease usually before age five to six years, and mild disease often later in life. GeneReviews states that prophylaxis given to young children before or just after their first few joint bleeds can nearly eliminate spontaneous bleeding and prevent chronic joint disease. It also describes alloimmune inhibitors, which develop in 20% to 30% of individuals with severe disease caused by intron 22 inversions. Outcomes for any individual are not certified in this packet.

ClinicalTrials.gov records in the packet include studies that are recruiting, not yet recruiting, and active but not recruiting. Records relevant to hemophilia A include a phase 1 lentiviral factor VIII gene therapy study, a first-in-human study of an investigational agent in healthy volunteers and people with hemophilia A, a phase 3 fitusiran prophylaxis study in boys with hemophilia A or B, an open-label extension study of marstacimab, an observational study of damoctocog alfa pegol in previously treated children, a phase 3 comparison of an investigational agent with factor VIII prophylaxis, a real-world fitusiran experience study, and a liver biopsy study following gene therapy. The GeneReviews chapter describes gene therapy trials using liver-targeted adeno-associated vectors, additional approaches with lentiviral vectors, and rebalancing and bispecific antibody approaches as under investigation, and states that long-term durability and safety of gene therapy need further study. The packet's trial summary lists drug therapy, biologic therapy, gene therapy, and other interventions. Its publication landscape summary classifies reviews and meta-analyses as the dominant research type.