Hemophilia A is caused by genetic changes (mutations) in the F8 gene. This gene is responsible for making the Factor VIII protein, an important protein that helps start the formation of blood clots. Mutations in the F8 gene lead to reduced or absent levels of Factor VIII in the blood, making it hard for the body to form blood clots.

Normal Function

The F8 gene provides instructions for making a protein called coagulation factor VIII. Coagulation factors are a group of related proteins that are essential for the formation of blood clots. After an injury, clots protect the body by sealing off damaged blood vessels and preventing further blood loss.

Coagulation factor VIII is made chiefly by cells in the liver. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein (sometimes written as coagulation factor VIIIa) interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.

Health Conditions Related to Genetic Changes

Hemophilia

Mutations in the F8 gene cause hemophilia A, the most common form of this bleeding disorder. More than 1,300 alterations in this gene have been identified. Some of these mutations change single DNA building blocks (base pairs) in the gene, while others delete or insert multiple base pairs. The most common mutation in people with severe hemophilia A is a rearrangement of genetic material called an inversion. This inversion involves a large segment of the F8 gene.

Mutations in the F8 gene lead to the production of an abnormal version of coagulation factor VIII or reduce the amount of this protein. The altered or missing protein cannot participate effectively in the blood clotting process. As a result, blood clots cannot form properly in response to injury. These problems with blood clotting lead to excessive bleeding that can be difficult to control. Some mutations, such as the large inversion described above, almost completely eliminate the activity of coagulation factor VIII and result in severe hemophilia. Other mutations reduce but do not eliminate the protein's activity, resulting in mild or moderate hemophilia.

Other Names for This Gene

• AHF
• antihemophilic factor
• coagulation factor VIII, procoagulant component
• coagulation factor VIII, procoagulant component (hemophilia A)
• DXS1253E
• FA8_HUMAN
• Factor VIIIF8B
• FVIII
• HEMA
• procoagulant component

Genomic Location

The F8 gene is located on the X-chromosome. Therefore, hemophilia A is inherited in an X-linked recessive pattern. In males (who have only one X chromosome), one mutated copy of the F8 gene in each cell is enough to cause hemophilia A. In females (who have two X chromosomes), a mutation needs to occur in both copies of the F8 gene to cause the disorder. Because it is unlikely that females will have two mutated copies of this gene, hemophilia A, like other X-linked recessive disorders, affects males much more frequently than females. Females who have a mutation in one copy of the F8 gene are called carriers. Most carriers have no signs or symptoms, however about 10% of female carriers of hemophilia A will experience some abnormal bleeding.

A female who carries one F8 gene mutation has a 50% or 1 in 2 chance of having a son with hemophilia A. A male with hemophilia A cannot pass on the disorder to his sons, but all of his daughters will be carriers for hemophilia A.

When a male child is the first person in a family with hemophilia A, further testing may be needed to determine if the child inherited the disorder from his mother, or if the mutation occurred by chance for the first time in the child.

The symptoms of hemophilia A and the age symptoms appear vary depending on the amount of factor VIII a person’s body makes. Infants with the severe form may bleed abnormally from their mouth and develop ‘goose eggs’ on their heads (collections of blood under the scalp). Other symptoms of the severe form include bleeding without any known cause (spontaneous bleeding) into the muscles, joints, and organs. Children with the moderate form may bruise easily and bleed too much after minor injuries, dental work, or surgery. People with the mild form of hemophilia A may not be diagnosed until they bleed more than normal after a major injury or surgery. With the mild form, there are no episodes of spontaneous bleeds.

The diagnosis of hemophilia A is made through the clinical symptoms and confirmed by laboratory testing. Blood tests are done to measure the time it takes the blood to clot and the amount of clotting factors found in the blood. Genetic testing can also help determine the exact change in the F8 gene and can be helpful for identifying other family members at risk for hemophilia A.

People with inherited hemophilia A require life-long care, preferably through a specialized hemophilia treatment center.

There is no cure for hemophilia A, but current treatments can prevent many of the symptoms of hemophilia A. Treatment may include medications and replacing the missing clotting factor (replacement therapy). This type of replacement therapy is done by slowly injecting or dripping concentrated factor VIII into a vein (intravenous infusion). The type and frequency of treatment often depends on the severity of the disorder in each person.

People with mild or moderate hemophilia A may be treated with replacement therapy as needed (for example, when a bleeding episode occurs). This is called ‘on-demand’ therapy. Some people with mild hemophilia A may be treated with desmopressin (DDAVP). Desmopressin raises the levels of factor VIII in the blood and may be given directly into a vein or through a nasal spray. Drugs known as antifibrinolytics, which slow the breakdown of clotting factors in the blood, can also be used to treat a mild form of the disorder.

Some people with severe hemophilia A may receive regular factor VIII replacement therapy to prevent bleeding episodes and other complications such as joint damage. This is referred to as prophylactic or preventative therapy. These factor VIII infusions may be done as often as necessary depending on the severity. The immune system of some people with the severe form of hemophilia A may start to make antibodies (inhibitors) that prevent the replacement factor VIII from working. Treatment for these people includes larger doses of replacement factor VIII and/or medications that may help block the inhibitors.

Infusions of replacement Factor VIII can be given at home. This is especially important for people with severe disease because the infusion works the best within one hour of a bleeding episode. In general, prompt treatment is important because it reduces pain and damage to the joints, muscles, or other affected tissues or organs.

Hemophilia A can be mild, moderate, or severe, depending on how much clotting factor VIII is in a person's blood. About 50-60% of people with hemophilia A have the severe form of the disorder.

With education and treatment, people with hemophilia A can live healthy and active lives. Life expectancy may depend on the response to treatment and the presence of other health conditions. Life-threatening complications of hemophilia A include bleeding within the skull (intracranial hemorrhage) and bleeding into the soft tissue around important organs. Chronic, debilitating joint disease may also develop.