Hemophilia A

Other Names: Hemophilia, classic; HEM A; Classic hemophilia; Factor 8 deficiency; Factor VIII deficiency; Classical hemophilia; Haemophilia A; Hemophilia A, congenital

Hemophilia A is an inherited bleeding disorder in which the blood does not clot normally.People with hemophilia A will bleed more than normal after an injury, surgery, or dental procedure. This disorder can be severe, moderate, or mild. In severe cases, heavy bleeding occurs after minor injury or even when there is no injury (spontaneous bleeding).

Bleeding into the joints, muscles, brain, or organs can cause pain and other serious complications. In milder forms, there is no spontaneous bleeding, and the disorder might only be diagnosed after a surgery or serious injury.

Cause

Hemophilia A is caused by having low levels of a protein called factor VIII. Factor VIII is needed to form blood clots.

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.

Inheritance

X-linked recessive inheritance

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.

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.

Symptoms

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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Arthralgia(Joint pain)
• Bleeding with minor or no trauma(Easy bleeding)
• Joint swelling
• Reduced factor VIII activity

30%-79% of people have these symptoms

• Oral cavity bleeding(Bleeding from mouth)
• Spontaneous hematomas
• Thromboembolism

5%-29% of people have these symptoms

• Abnormality of the elbow(Abnormality of the elbows)
• Gastrointestinal hemorrhage(Gastrointestinal bleeding)
• Intramuscular hematoma
• Intraventricular hemorrhage
• Joint hemorrhage(Bleeding within a joint)

1%-4% of people have these symptoms

• Splenic rupture(Ruptured spleen)

Diagnosis

The diagnosis of hemophilia A is made through clinical symptoms and specific laboratory tests to measure the amount of clotting factors in the blood.

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.

PTT partial thromboplastin time (PTT) tests are the first blood test done when haemophilia is indicated.

Treatment

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.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Antihemophilic factor (recombinant), Fc fusion protein (Brand name: Eloctate)was approved for the treatment of adults and children with Hemophilia A (congenital Factor VIII deficiency) for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

• Emicizumab-kxwh (Brand name: Hemlibra) received expanded approval for the routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older with hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors.

• Antihemophilic factor (recombinant) (Brand name: Kogenate FS) Kogenate FS was approved for the treatment and prophylaxis of bleeding in patients with hemophilia A (not von Willebrand's disease).
• Coagulation Factor VIIa (Recombinant) (Brand name: NovoSeven RT)

Moroctocog alfa (Brand name: ReFacto)moroctocog alfa (ReFacto) was approved for the control and prevention of hemorrhagic episodes and for surgical prophylaxis in patients with hemophilia A

• Desmopressin acetate (Brand name: Stimate) desmopressin acetate (Stimate) was approved for the treatment of patients with hemophilia A or von Willebrand's disease (type I) whose factor VIII coagulant activity level is greater than 5%.

Prognosis

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.

Epidemiology

About 1/5000 -1/6000 people in the US are born with hemophilia A. This disorder affects males more than females, and occurs equally in all races and ethnic groups.