Hemophilia A is a rare hemorrhagic disease with an X-linked recessive inheritance pattern.
The prevalence of hemophilia is estimated to be about 1 in 6000 male individuals. As an X-linked disease, females are generally the carriers, while males are the ones who manifest and suffer from the disease due to the differential sex chromosome endowment in the human species. In affected families, males with the disease inherit a copy of the mutated F8 gene from their carrier mothers.
Despite preferentially affecting males, a symptomatic form of hemophilia A has also been described in female carriers, which generally presents with a mild clinical picture.
Hemophilia A is caused by a mutation in the clotting factor of the F8 gene, also called antihemophilic factor. This mutation in the clotting factor VIII gene results in low plasma factor VIII concentrations, leading to spontaneous bleeding events and joint damage (arthropathy) as a result of recurrent haemorrhages.
The severity of the clinical manifestations depends on the type and degree of clotting factor VIII deficiency in the blood. Symptoms range from mild to severe, depending on the degree of deficiency. Between 50 and 60% of hemophilia patients have moderate or mild hemophilia.
In patients with severe hemophilia A, the genetic underlying defects are detection of inversions of intron 22 (reported in 40–45% of severe patients) and point mutations in the F8 gene that encodes for the coagulation factor VIII.
Genetic testing in patients with hemophilia is recommended to determine the causative mutation. Knowing the bleeding phenotype of each individual may help to establish a treatment and prevention that will notably improve their quality of life.
Hemophilia is classified into three forms:
- Severe hemophilia: patients with a clotting factor level of less than 1 IU/dL (<1% of normal).
- Moderate hemophilia: defined as factor levels of 1-5 IU/dL (1-5% of normal).
- Mild hemophilia: defined as a factor level of 5-40 IU/dL (5-40% of normal).
Symptoms of hemophilia A and B are similar and include:
- Risk of bleeding (intracranial and extracranial) depending on the severity of the disease and the age of the patient.
- Non-traumatic intra-articular hemorrhages that increase with age and usually affect the same joint (i.e. ankle, elbow, and knee) and progressively damage the tissue leading to hemophilic arthropathy.
Severe hemophilia is mainly detected during the first years of life. Joint hemorrhages start at a much earlier age in patients with severe hemophilia than in moderate hemophilia. The distinction between mild and moderate hemophilia is more complicated.
Hemophilia A may influence the risk of cardiovascular damage, impact on brain function (due to possible cerebral hemorrhagic events), increased risk of hypertension, muscle bleeds and kidney disease.
The standard treatment of patients with severe hemophilia is regular replacement therapy with CFCs (clotting factor concentrates) as prophylactic that could help to maintain joint health and reduce the bleeding frequency. The major complication of replacement therapy is the development of neutralizing antibodies.
New therapies such as antibody, DNA and RNA therapies have emerged in recent years. For instance, Emicizumab is a drug based on a new coagulation therapy that uses a monoclonal antibody that mimics a key function of the activated factor VIII which was approved by the FDA (U.S. Food and Drug Administration) and EMA (European Medicines Agency) for hemophilia A treatment.
Gene therapy is one of the most promising therapeutic treatment innovations in the hemophilia field and is based on the bleeding protection of hemophilia A and B patients by the production of missing coagulation factors, VIII and IX, respectively. This approach is under study, and there are two possible methods: 1) Factor VIII and IX genes are transferred into hepatic cells using adenovirus vectors, or 2) genes are transferred with lentiviral vectors to stem cells, which are then delivered intravenously.
Nowadays, the survival of a patient with hemophilia is high due to the notorious advances in genetics and medicine, thanks to which people who suffer from this disease or have a family history that predisposes them to it can lead a completely normal life with proper treatment, therefore, it is essential to be able to detect this predisposition through tools such as genetic tests in order not to affect the quality of life.
Gene or region studied