Hemophilia B

 

Hemophilia B is a rare genetic bleeding disorder that impairs the blood’s ability to clot properly.

The condition is also known as Christmas disease, named after Stephen Christmas, who was a 5-year-old boy and the first person diagnosed with this disease type in 1952.

Hemophilia B is caused by a mutation in the F9 gene, which creates a deficiency in a blood clotting protein called factor IX (FIX).

Estimated to occur in nearly 1 in 25,000 male births, hemophilia B prevalence is about 15% to 20% of all hemophilia cases in the U.S. One subtype, hemophilia B Leyden, accounts for approximately 3% of all type B cases. Although the disease is more common in men, women can also have hemophilia B.

In contrast, hemophilia A accounts for about 80% of cases and is caused by a mutation in the F8 gene that results in a deficiency of clotting factor VIII.

Hemophilia B symptoms include spontaneous bleeding episodes, along with joint and muscle bleeding. Treatment includes factor replacement therapy to control and prevent bleeding, along with hemophilia B gene therapy.

Hemophilia B genetics and inheritance

What causes hemophilia B is a mutation in the F9 gene, which is located on the X chromosome, one of the two sex-determining chromosomes in humans.

This gene provides instructions for producing FIX, a clotting protein essential for blood coagulation that stops bleeding.

Hemophilia B inheritance follows an X-linked recessive pattern, so the disease is more common in boys than girls. Because boys have only one X chromosome, if they inherit a mutated F9 gene, they will have hemophilia B.

Girls receive two X chromosomes, one from each parent. If a girl inherits one X chromosome with a faulty F9 gene and one X chromosome with a healthy F9 gene, she is considered to be a carrier.

Carriers do not usually have symptoms, but they can pass the affected F9 gene on to their children. In certain cases, female carriers may have hemophilia and present similar symptoms to men, as their factor IX levels are low.

In some cases, hemophilia B may occur without any family history of the condition, due to spontaneous mutations in the F9 gene.

Leyden inheritance

The mutations causing this subtype of hemophilia B occur in the promoter region of the F9 gene. The promoter region is a specific area in the DNA code that controls when a certain gene is turned on (activated) or off (inactivated).

Hormonal changes during puberty can activate this promoter region to a certain degree, leading to an increase in FIX levels, which can decrease bleeding episodes.

By midlife, people with this subtype often have somewhat normal FIX levels and may no longer need hemophilia B medications.

Hemophilia B symptoms

Hemophilia B can be considered mild, moderate, or severe, depending on FIX activity levels.

Mild

People with mild hemophilia B typically have FIX activity levels ranging from 5% to 40% of normal. This means they may remain undiagnosed until a surgical procedure results in prolonged bleeding, and there may be many years between episodes.

In mild hemophilia B, significant trauma or injury, as well as surgery or dental procedures, may cause bruising and bleeding. These bleeding episodes usually last longer and are more severe compared to people without hemophilia. Spontaneous bleeding is relatively rare.

Moderate

People with moderate hemophilia B typically have FIX activity levels ranging from 1% to 5% of normal. They are usually diagnosed by 5 or 6 years of age, and the frequency of spontaneous bleeding episodes is highly variable.

In moderate hemophilia B, bleeding may follow minor injuries or occur without apparent cause (spontaneous bleeding). Prolonged bleeding may happen after trauma, surgeries, or dental procedures.

Symptoms may include:

• easy bruising
• prolonged nosebleeds
• hematomas (blood-filled bumps under the skin) after minor injuries
• joint and muscle bleeds that cause complications such as pain and immobility.

Severe

People with the severe form of hemophilia B typically have FIX activity levels of less than 1%. Severe forms are usually identified early during infancy or childhood.

Severe hemophilia B poses the highest risk of spontaneous and severe bleeding, triggered by even minor trauma.

Symptoms may include:

• internal bleeding in the joints, muscles, or other internal organs
• significant pain, swelling, and potential long-term joint damage
• bleeds in the gastrointestinal tract
• bleeding into the brain, although rare, that can cause symptoms of severe headache, vomiting, seizures, and neurological changes.

Hemophilia B treatment

The standard approach to prevent and manage bleeding episodes in a person with hemophilia B is replacement therapies that provide functional FIX protein.

Replacement therapy can be used on demand to manage acute bleeding episodes, or serve as a regular preventive measure (prophylaxis) to reduce the risk of bleeding. Prophylaxis is typically advised for the more severe forms of the disease.

Additionally, some patients may receive antifibrinolytics, which are medications that help slow the natural process of breaking down blood clots within the body.

Gene therapy

More recently, researchers have developed hemophilia B gene therapies that introduce a healthy copy of the F9 gene into patients. In late 2022, Hemgenix was approved in the U.S. for certain adults with hemophilia B. Hemgenix’s approval was followed by that of Beqvez in 2024 for a similar patient population. Both are given via a one-time intravenous (into-the-vein) infusion that is expected to help keep bleeding in check over the long term.

People with hemophilia B are encouraged to stay up to date on the latest developments in treatment and discuss any concerns with their healthcare providers.

Hemophilia B diagnosis

Hemophilia B is diagnosed through a combination of clinical evaluation, medical history, and laboratory tests.

A healthcare provider will review the person’s medical history and ask about bleeding symptoms or a family history of bleeding disorders. A physical exam will look for signs such as bruises, swollen joints, or external bleeding.

Lab tests are crucial for a definitive hemophilia B diagnosis. The primary tests include:

• factor IX assay: measures the activity level of FIX in the blood, as hemophilia B causes this level to be significantly reduced. This test can also determine the severity of the disease
• blood tests: assesses clotting ability and general blood health
• genetic testing: identifies the specific gene mutation responsible for hemophilia B
• specialized coagulation tests: helps determine whether the disease is hemophilia A or B, since symptoms are similar.

Living with hemophilia B

People living with hemophilia B can manage their symptoms with treatment and lifestyle changes. Some suggestions include:

• Set up regular appointments to be treated at a specialized hemophilia treatment center. More than 140 hemophilia treatment centers are located in the U.S. and at least 25 treatment centers in Canada.
• Learn how to self-administer the factor replacement therapy at home, which can offer more control and independence in managing the condition.
• Write an emergency treatment plan, including contact information for the local hemophilia treatment center, and carry medical ID that indicates hemophilia B.
• Learn how to treat the disease in an emergency, such as applying pressure to the site, calling for emergency help, and, if trained, administering FIX replacement therapy. You may want to consider asking close family and friends if they also want to be trained.
• Avoid high-impact activities and take safety precautions to reduce the risk of bleeding. Maintain joint health with regular exercise, such as swimming and low-impact sports.
• Stay up to date with vaccinations, especially for hepatitis A and B, to protect the liver, which may be affected by hemophilia treatments.
• Eat a balanced diet and maintain a healthy weight to help reduce the strain on joints and improve overall health.
• Avoid excessive alcohol and non-prescription medications that can interfere with blood clotting.
• Seek emotional and mental health support as needed, by connecting with support groups and mental health counselors, or talking with family and friends.

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