Hemophilia Genetics, Diagnostics, and Therapeutics
Hemophilia A and B are X-linked recessive bleeding disorders caused by mutations in the F8 and F9 genes, which encode coagulation factors VIII and IX respectively[^c1]. Hemophilia A affects approximately one in 5,000 male live births, while hemophilia B is less common at approximately one in 30,000 worldwide (about one in 25,000 in the United States). The F8 gene at Xq28 spans roughly 180 kb with 26 exons and contains large inverted repeat sequences that make it susceptible to recurrent inversions, particularly the intron 22 and intron 1 inversions that together account for approximately half of severe hemophilia A cases[^c2]. The F9 gene similarly harbors a diverse range of pathogenic variants, with large deletions and nonsense mutations carrying elevated risk of inhibitor development — the most significant complication of replacement therapy. Sporadic hemophilia, arising from de novo mutations in families with no prior history, accounts for approximately 30 to 60 percent of hemophilia A cases[^c17]. Advances in molecular genetics have defined a highly heterogeneous mutational spectrum in both genes, including recurrent inversions, point mutations, small insertions or deletions, and large rearrangements, and these variants underlie genotype-phenotype correlations[^c22].
Severity is classified by residual factor activity: severe (<1 percent), moderate (1–5 percent), and mild (>5 to 40 percent) as standardized by the ISTH and WFH. Diagnostic testing follows a stepwise cascade from factor activity assays through inversion screening and sequencing, and universal genotyping is recommended for all individuals with hemophilia[^c5]. The Nijmegen-Bethesda assay is the standard method for inhibitor quantification. Female carriers of F8 or F9 mutations are increasingly recognized as experiencing clinically significant bleeding; although 55 percent of confirmed carriers have abnormal bleeding, only 19 percent have low factor activity, and integrative models incorporating X-chromosome inactivation and factor antigen levels achieve superior risk stratification[^c18][^c15]. Emicizumab, a bispecific antibody mimicking FVIII, interferes with standard coagulation assays and requires specialized monitoring using bovine chromogenic assays[^c12]; the NBDF MASAC has published updated guidelines on valid and invalid assays for patients receiving emicizumab[^c16].
Von Willebrand disease (VWD) is the most common inherited bleeding disorder worldwide, affecting approximately 1 per 1,000 in the general population (symptomatic prevalence), with a substantially higher rate of laboratory-detected low VWF levels in population screening[^c20][^c21]. This wiki covers VWD alongside hemophilia — see [[diagnostics/von-willebrand-disease|Von Willebrand Disease]] for ISTH classification (types 1, 2A, 2B, 2M, 2N, 3, and 1C), the 2024 BSH/UKHCDO tiered diagnostic algorithm, population genetics from gnomAD, and clinical management protocols; see [[treatment/von-willebrand-disease-therapy|Von Willebrand Disease Therapy]] for replacement therapy (recombinant VWF), emerging subcutaneous options, and FVIII-mimetic approaches under investigation.
The treatment landscape has evolved from on-demand plasma-derived factor replacement to individualized prophylaxis with standard and extended half-life concentrates[^c23], and now includes non-factor rebalancing therapies (concizumab, fitusiran, and the anti-TFPI agent marstacimab) and AAV-based gene therapy. Liver-directed adeno-associated viral gene therapy has enabled sustained endogenous expression of FVIII and FIX following a single infusion, with marked reductions in annualized bleeding rates and factor use[^c24]; approved and investigational agents such as valoctocogene roxaparvovec (Roctavian) and GS001 have demonstrated durable FVIII expression, and a 6-year follow-up of one treated patient showed sustained FVIII activity within the normal range[^c4]. Marstacimab (Hympavzi) received FDA approval expansion in June 2026 as a once-weekly subcutaneous prophylaxis for all individuals aged 6 years and older with hemophilia A or B, with or without inhibitors[^c13]. Concizumab, evaluated in the Phase 3 explorer8 study, demonstrated sustained efficacy at 56 weeks with median annualized bleeding rates of 1.7 in hemophilia A and 2.8 in hemophilia B patients without inhibitors, and was considered safe and well tolerated[^c19]. Next-generation FVIIIa mimetics — denecimig (Mim8) and NXT007 — are in late-stage clinical development and aim to achieve normal-range coagulation activity, surpassing the efficacy ceiling of first-generation agents[^c9][^c10]. Gene editing approaches are advancing toward the clinic, with Metagenomi's MGX-001 planning IND submission in Q4 2026 with a curative benchmark of FVIII activity above 50 IU/dL[^c14][^c7]. The PedNet Registry, a prospective birth cohort spanning 34 centers in 19 countries, provides long-term epidemiological data on 2,993 children with hemophilia, with gene mutation data available for 87 percent of patients[^c11].