Hemophilia As an Inherited Disorder
Written by Margaret Anne Rockwood | Last updated August 7th, 2026
Medically reviewed by Shannon Walker, MD
Â
An inherited bleeding disorder caused by genetic mutations, hemophilia leads to deficiencies of clotting factor VIII (hemophilia A) or factor IX (hemophilia B). While treatment advances have dramatically improved patient outcomes, the genetic nature of hemophilia continues to shape risk assessment and decision-making.
The Genetic Basis of Hemophilia
Hemophilia A results from mutations in the F8 gene, while hemophilia B is caused by mutations in the F9 gene. These genes provide instructions for producing clotting factors VIII and IX, proteins that are essential for normal blood coagulation.
When one of these genes contains a pathogenic variant, clot formation becomes impaired, increasing the risk of prolonged bleeding after injury and, in severe cases, spontaneous bleeding into joints and muscles.
Hemophilia A
Hemophilia A results from pathogenic variants in the F8 gene located on Xq28, while hemophilia B arises from variants in the F9 gene located on Xq27. Both disorders are inherited in an X-linked pattern, which explains their predominance among males.
Hemophilia A accounts for approximately 80% to 85% of cases and demonstrates remarkable genetic heterogeneity. More than 2,000 different pathogenic F8 variants have been described.
Among patients with severe hemophilia A, intron 22 inversion is the most common molecular defect, accounting for approximately 40% to 50% of severe cases. Intron 1 inversions account for an additional 2% to 5%.
Other pathogenic variants include:
- missense mutations
• nonsense mutations
• small insertions and deletions
• splice-site variants
• large genomic deletions
Hemophilia B
Hemophilia B exhibits similar genetic diversity but has no common recurrent inversion variants comparable to the intron 22 and intron 1 inversions of F8. Most identified F9 variants are single-nucleotide variants, particularly missense variants.
Common Genetic Defects by Hemophilia Type
Scroll horizontally to view all columns -->
| Mutation Type | Hemophilia A | Hemophilia B | Typical Severity |
| Intron 22 inversion | Common | No common equiv. | Severe |
| Intron 1 inversion | Less common | No common equiv. | Usually severe |
| Missense mutation | Common | Common | Variable |
| Nonsense mutation | Common | Common | Often severe |
| Large deletion | Uncommon | Uncommon | Usually severe |
X-Linked Inheritance
Both hemophilia A and B are inherited in an X-linked recessive pattern. Because males have one X chromosome and one Y chromosome, a single altered copy of the F8 or F9 gene on the X chromosome is sufficient to cause disease. Because females have two X chromosomes, they often retain adequate clotting factor production from the unaffected gene copy. Females who have the affected gene are known as carriers.
When a mother carries a hemophilia-associated mutation, each son has a 50% chance of inheriting hemophilia while each daughter has a 50% chance of being a carrier.
When a father has hemophilia, all daughters inherit the altered X chromosome and become carriers (and about 40% have some level of symptoms themselves). Yet, none of his sons inherit the mutation because sons receive their father’s Y chromosome rather than his X chromosome. As a result, the father’s altered F8 or F9 gene cannot be transmitted to his sons.
De Novo Mutations
Although hemophilia most often runs in families, a negative family history does not exclude the diagnosis. Approximately one-third of people newly diagnosed with hemophilia have no known family history. In some cases, the pathogenic variant arose de novo in the affected individual; in others, the mother may carry the variant despite the absence of previously recognized hemophilia in the family. These new mutations may be discovered only after a child develops unusual bleeding or abnormal coagulation test results. Once identified, family members may benefit from genetic evaluation and counseling.
The most common cause of severe hemophilia A is an inversion involving intron 22 of the F8 gene, accounting for approximately 40% to 50% of severe cases. Intron 1 inversions and point mutations are also common.
Hemophilia B is more often caused by point mutations within the F9 gene.
Female Carriers and Symptomatic Disease
Female carriers of hemophilia have variable levels of factor expression, which can range from the normal range to lower-than-expected levels of factor VIII or factor IX, and can be low enough to meet criteria for mild, moderate, or even severe hemophilia.
Historically, female carriers were often assumed to be unaffected, but today it is known that many carriers experience clinically significant bleeding symptoms, both with normal and low factor levels. Current guidance from organizations such as the World Federation of Hemophilia and the International Society on Thrombosis and Haemostasis recognizes that females with low factor levels should appropriately be diagnosed as having hemophilia and managed according to their factor levels and bleeding phenotype.
Symptoms in female carriers and women with hemophilia may include:
- heavy menstrual bleeding
- easy bruising
- excessive bleeding after surgery or dental procedures
- postpartum hemorrhage
- recurrent iron deficiency anemia (typically from chronic menstrual bleeding)
The classic teaching is that a female with hemophilia would need to inherit:
- an affected X chromosome from her father (who has hemophilia), and
- a mutated X chromosome from her mother (who is a carrier or has hemophilia herself)
However, the medical community now recognizes several ways that females can have clinically significant hemophilia, as described below:
- Father affected plus mother carrier: The daughter may have two affected X chromosomes. Factor levels can be in the severe, moderate, or mild range depending on the specific mutations (rare).
- Skewed X-chromosome inactivation (lyonization): A carrier female experiences unequal inactivation of her normal X chromosome, and thus factor VIII or IX levels can fall into the mild, moderate, or even severe hemophilia range. These females develop hemophilia early in fetal development. Randomly, the female cells inactivate one of their two X chromosomes, a process known as lyonization or X-chromosome inactivation. If a large proportion of cells inactivate the X chromosome carrying the normal F8 or F9 gene, clotting factor levels may fall significantly, resulting in bleeding symptoms.
- Turner syndrome (45,X): If the single X chromosome carries a hemophilia mutation, the female can have hemophilia because there is no second normal X chromosome to compensate.
- De novo variant: A new F8 or F9 pathogenic variant may arise in a female. If it occurs on one X chromosome, her factor level will also depend on the pattern of X-chromosome inactivation and whether the other X chromosome functions normally.
The likelihood of developing hemophilia A versus B follows the same pattern as in males, and the potential severity spectrum is the same for both.
Scroll horizontally to view all columns -->
| Â
Severity  |
Â
Factor VIII or IX Activity  |
| Severe | <1% of normal |
| Moderate | 1 to 5% |
| Mild | >5% to <40% |
Â
Emotional and Practical Challenges
The hereditary nature of hemophilia naturally creates emotional stress for not only the family member with hemophilia, but also a potential carrier parent. Carriers also face concerns over future pregnancies.
Families may face practical concerns as well, involving the nature and cost of testing, disclosure of genetic risk to relatives, and long-term medical planning. Clinicians can guide families to comprehensive care centers and genetic counselors as appropriate.
Sources
- Abdulqader AMR, et al. Identification of the intron 22 and intron 1 inversions of the factor VIII gene in patients with severe hemophilia A. Mol Genet Genomic Med. 2020.
- Bolton-Maggs PHB, Pasi KJ. Haemophilias A and B. Lancet. 2003;361(9371):1801-1809. doi:10.1016/S0140-6736(03)13405-8
- Goodeve AC. Hemophilia B: molecular pathogenesis and mutation analysis. J Thromb Haemost. 2015;13(7):1184-1195. doi:10.1111/jth.12940
- Srivastava A, et al. WFH guidelines for the management of hemophilia. 3rd ed. Haemophilia. 2020;26(suppl 6):1-158. doi:10.1111/hae.14046
- Konkle BA, et al. Hemophilia A. In: Adam MP, Feldman J, Mirzaa GM, et al, eds. GeneReviews®. University of Washington, Seattle; updated 2025. Accessed August 3, 2026. https://www.ncbi.nlm.nih.gov/books/
- Konkle BA, et al. Hemophilia B. In: Adam MP, Feldman J, Mirzaa GM, et al, eds. GeneReviews®. University of Washington, Seattle. Accessed August 3, 2026. https://www.ncbi.nlm.nih.gov/books/
- Li T, et al. The CDC Hemophilia B Mutation Project mutation list: a new online resource. Mol Genet Genomic Med. 2013.
- Li T, et al. Mutation analysis of a cohort of US patients with hemophilia B. Am J Hematol. 2014.
- Ljung R. Prenatal diagnosis of haemophilia. Haemophilia. 1996;2(1):7-12. doi:10.1111/j.1365-2516.1996.tb00144.x
- Peyvandi F, et al. The past and future of hemophilia: diagnosis, treatments, and its complications. Lancet. 2016;388(10040):187-197. doi:10.1016/S0140-6736(15)01123-X
- van Galen KPM, et al. A new hemophilia carrier nomenclature to define hemophilia in women and girls: communication from the SSC of the ISTH. J Thromb Haemost. 2021;19(8):1883-1887. doi:10.1111/jth.15397
- World Federation of Hemophilia. Genetic assessment. In: WFH Guidelines for the Management of Hemophilia. 3rd ed. World Federation of Hemophilia; 2020.
- World Federation of Hemophilia. Women and Girls With Hemophilia. World Federation of Hemophilia; 2024.