Hemophilia is a rare X-linked recessive bleeding disorder primarily affecting males, yet its two most well-known forms.

Hemophilia A and Hemophilia B have distinct genetic foundations that influence both clinical presentation and treatment responses.

Despite their similar symptoms, their molecular origins differ in ways that are clinically and therapeutically significant.

The Genetic Roots: Factor VIII and Factor IX Deficiencies

Hemophilia A is caused by mutations in the F8 gene, which encodes coagulation Factor VIII. In contrast, Hemophilia B results from mutations in the F9 gene, responsible for producing Factor IX. Both factors are crucial in the intrinsic pathway of the coagulation cascade, but their respective genes differ markedly in size, mutation patterns, and inheritance behavior.

Recent genomic sequencing technologies have identified over 2,500 unique mutations in F8, many of which are large inversions, especially intron 22 inversions. In contrast, F9 mutations are often point mutations or small deletions. According to Dr. David Lillicrap, Professor of Pathology and Molecular Medicine at Queen's University, "Understanding the exact mutation not only confirms diagnosis but also predicts the likelihood of inhibitor development."

Phenotypic Similarities, Molecular Dissimilarities

Clinically, both types manifest with spontaneous joint bleeds, prolonged bleeding after trauma, and delayed wound healing. However, the genotype-phenotype correlation is tighter in Hemophilia B. Mild cases of Hemophilia A may present unpredictably depending on the type of F8 mutation, while in Hemophilia B, factor levels are more consistently aligned with bleeding risk.

A recent study published in Haematologica (2024) found that Hemophilia B patients with missense mutations often experience less severe bleeding compared to Hemophilia A patients with intron inversions, which disrupt the F8 gene more completely.

Inhibitor Formation Risk: A Clinical Dividing Line

One of the most clinically relevant distinctions between Hemophilia A and B lies in the development of inhibitors neutralizing antibodies against replacement clotting factors. Up to 30% of severe Hemophilia A patients develop inhibitors, particularly those with large deletions or intron inversions in F8. In contrast, inhibitor formation in Hemophilia B is rarer (~3%), but when it occurs, it's often accompanied by allergic reactions, posing additional treatment challenges.

Therapeutic Implications and Genetic Testing Advances

Treatment has historically involved factor replacement therapy, but recombinant extended half-life factors and non-factor therapies like emicizumab (effective only for Hemophilia A) have added layers of complexity to care. The introduction of gene therapy such as etranacogene dezaparvovec for Hemophilia B—further underscores the importance of precise genetic characterization.

Whole genome sequencing and next-generation sequencing (NGS) panels now allow for faster, more detailed differentiation between F8 and F9 mutations. Prenatal genetic screening and preimplantation diagnosis also enable informed reproductive decisions for carrier families.

Although Hemophilia A and B are united by their bleeding symptoms, their genetic divergence leads to critical differences in diagnosis, prognosis, and treatment. The ability to identify exact mutations not only enhances clinical care but also personalizes treatment strategies ushering in a genotype-driven era in hematology. With ongoing research and increasing access to gene editing tools, the once-blurred lines between Hemophilia A and B are now clearly defined at the molecular level.