Haemophilia B with Anti Factor IX

When the body’s immune system creates antibodies against the very treatment meant to help, managing haemophilia B becomes significantly more challenging.

Table of contents

• What is Haemophilia B
• Understanding Inhibitors: When Antibodies Develop
• Symptoms and Clinical Signs
• Causes and Risk Factors
• Diagnosis and Testing
• Treatment Approaches
• Possible Complications

What is Haemophilia B

Haemophilia B, also known as Christmas disease (named after Stephen Christmas, the first person diagnosed with this condition in 1952), is an inherited bleeding disorder that affects the body’s ability to form blood clots properly^[2]. This condition results from a defect in the F9 gene, which leads to insufficient production of factor IX, a protein essential for blood clotting^[2].

Factor IX is one of several special proteins called coagulation factors that work together in a series of reactions to help blood clots form^[3]. When you bleed, this process, known as the coagulation cascade, involves as many as 20 different clotting factors working together^[3]. Without enough factor IX, the blood cannot clot properly to control bleeding.

Haemophilia B is much less common than haemophilia A, constituting about 20% of all haemophilia cases^[4]. It is the second most prevalent form of haemophilia^[2]. The condition predominantly affects males because it is caused by an inherited X-linked recessive trait, with the variant gene located on the X chromosome^[3].

Understanding Inhibitors: When Antibodies Develop

A particularly challenging complication can occur when people with haemophilia B develop antibodies against factor IX^[3]. These antibodies are called inhibitors, and they represent a serious problem because they attack factor IX so that it no longer works properly^[3].

Some people who receive factor IX concentrate infusions may develop these inhibitors^[13]. Inhibitors make it more difficult to stop a bleeding episode because they prevent the treatment from working as intended^[13]. When inhibitors are present, the body’s immune system essentially fights against the very treatment designed to help control bleeding.

Inhibitors are seen in approximately 10 to 15% of haemophilia B patients who receive replacement therapy containing factor IX^[7]. The development of these antibodies occurs as the body becomes immunized against the infused factor IX, treating it as a foreign substance.

There is also a rare acquired form of haemophilia B with anti-factor IX antibodies that can occur in people who do not have inherited haemophilia^[7]. This acquired form is associated with the presence of antibodies directed against factor IX in non-haemophiliac subjects. It can occur particularly in women during or at the end of pregnancy, in patients with autoimmune disease, and in elderly subjects^[7].

Symptoms and Clinical Signs

The severity of symptoms can vary considerably^[3]. Prolonged bleeding is the main symptom, often first seen when an infant is circumcised^[3]. Other bleeding problems usually show up when the infant starts crawling and walking. Mild cases may go unnoticed until later in life, and symptoms may first occur after surgery or injury^[3].

People with mild forms of the condition may not have symptoms until they are adults^[5]. People with moderate or severe haemophilia B may first experience symptoms when they are babies. Males affected by the severe form may display spontaneous and severe bleeding at birth, while individuals with milder cases usually experience bleeding primarily after trauma or surgery^[2].

Common symptoms may include:

• Bleeding into joints with associated pain and swelling^[3]
• Blood in the urine or stool^[3]
• Bruising very easily^[3]
• Gastrointestinal tract and urinary tract bleeding^[3]
• Nosebleeds^[3]
• Prolonged bleeding from cuts, tooth extraction, and surgery^[3]
• Bleeding that starts without cause^[3]
• Big lumps if a baby bumps their head^[5]
• Blood pooling under the skin after having shots^[5]
• Difficulty breathing if bleeding makes the tongue swell^[5]

When inhibitors are present, the most common clinical sign is the presence of marked haematomas (blood collecting under the skin)^[7]. This condition may be life-threatening and requires appropriate therapy to be given quickly^[7].

Causes and Risk Factors

Haemophilia B typically happens when a person inherits a changed F9 gene^[5]. This gene carries the instruction manual for making clotting factor 9, and changes in the gene cause low or missing clotting factor 9 levels. The genetic defect can occur either through X-linked inheritance or a spontaneous de novo mutation (a new change that was not present in the parents)^[2].

The condition is inherited in an X-linked recessive manner. Females have two X chromosomes, inheriting one from their biological mother and one from their biological father^[5]. Males inherit one X chromosome from their biological mother and one Y chromosome from their biological father. A biological mother with a changed factor 9 gene on one chromosome can pass that chromosome on to a biological child.

A male child who inherits a chromosome carrying the changed factor 9 gene will have haemophilia B^[5]. A female child who inherits the changed gene will carry the disease, but they usually will not have haemophilia symptoms because the second chromosome does not carry the changed gene^[5]. Boys born to women who carry the variant gene have a 50% chance of having haemophilia B, and their daughters have a 50% chance of being a carrier^[3].

Although this condition predominantly affects males, carrier females may also occasionally experience more significant bleeding symptoms^[2]. Heterozygous women with the F9 genetic mutation may have varying levels of factor IX, and those with levels at or above 50% of normal are usually asymptomatic.

Risk factors for haemophilia B include family history of bleeding and being male^[3].

Diagnosis and Testing

If you are the first person in your family to have a suspected bleeding disorder, your healthcare provider will order a series of tests called a coagulation study^[3]. Once the specific variant has been identified, other people in your family will need tests to diagnose the disorder.

Healthcare providers will do a physical examination, checking for symptoms like bruising and swollen or painful joints^[5]. They will ask if anyone in your biological family has haemophilia or another blood disorder.

Tests to diagnose haemophilia B include:

• Partial thromboplastin time (PTT) – this test is increased in haemophilia B cases^[3][7]
• Prothrombin time (PT) – this test result is normal in haemophilia B^[3][7]
• Serum factor IX activity – this test determines the clotting activity of factor IX to establish the diagnosis and ascertain the severity of the disease^[3][7]
• Genetic tests to check for the genetic change that causes the condition^[5]

The assay may be performed on serial dilutions of the patient’s plasma to exclude any interference from circulating lupus anticoagulant antibodies^[7]. Healthcare providers classify haemophilia B by factor 9 levels, which are measured in international units per deciliter^[5]. Persons with less than 1% normal factor are considered to have severe haemophilia, persons with 1-5% normal factor are considered to have moderately severe haemophilia, and persons with more than 5% but no more than 40% normal factor are considered to have mild haemophilia^[4].

For diagnosis of inhibitors, screening for a specific inhibitor directed against factor IX is done using the Bethesda method or the Nijmegen method^[7]. This testing is important because the presence of inhibitors significantly affects treatment decisions.

Treatment Approaches

Treatment includes replacing the missing clotting factor^[3]. Patients receive factor IX concentrates, and the amount given depends on the severity of bleeding, the site of bleeding, and the patient’s weight and height. The standard way to treat haemophilia B is to replace the missing blood clotting factor so that the blood can clot properly^[13].

To prevent a bleeding crisis, people with haemophilia and their families can be taught to give factor IX concentrates at home at the first signs of bleeding^[3]. People with severe forms of the disease may need regular, preventive infusions. If a person has severe haemophilia, they may also need to take factor IX concentrate before surgery or certain types of dental work^[3].

Healthcare providers typically prescribe treatment products for episodic care (used to stop bleeding episodes) or prophylactic care (used to prevent bleeding episodes from occurring)^[13]. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints^[8].

The most common treatment for haemophilia B is called replacement therapy^[10]. Concentrates of clotting factor IX are the foundation of this treatment and are administered as an infusion to help replace the clotting factor that is missing or low in the blood. For people with haemophilia B, most preventative, or prophylactic, treatment involves infusions every 7 to 14 days^[10].

Two main types of clotting factor concentrates are available: plasma-derived factor concentrates (made from human plasma proteins) and recombinant factor concentrates (genetically engineered using DNA technology)^[13]. Commercially prepared factor concentrates are treated to remove or inactivate bloodborne viruses. Recombinant factors IX do not contain any plasma or albumin, and therefore cannot spread any bloodborne viruses^[13].

Treatment When Inhibitors Are Present

When people with haemophilia B develop antibodies to factor IX, these inhibitors create significant treatment challenges. In such cases, a man-made clotting factor called VIIa can be given^[3]. This alternative treatment approach is necessary because the inhibitors make standard factor IX replacement therapy ineffective.

Treatment of patients with haemophilia B who have developed inhibitors ideally should be provided through a comprehensive haemophilia care center^[8]. These centers follow a multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery, along with nurses, physiotherapists, social workers, and related allied health professionals. Patients treated at comprehensive care clinics have been shown to have better access to care, less morbidity, and better overall outcome^[8].

Home Treatment

Many people learn to infuse at home for their child or for themselves^[10]. Home treatment has several advantages: treatment can be given more quickly when bleeding happens, early treatment lowers the risk of complications, fewer visits to the healthcare provider or emergency room are needed, home treatment costs less than treatment in a medical care setting, and home treatment helps children accept treatment and take responsibility for their own health^[10].

Giving factor treatment products at home means that bleeds can be treated more quickly, resulting in less serious bleeding and fewer side effects^[13].

Possible Complications

Complications of haemophilia B may include:

• Long-term joint problems, which may require a joint replacement^[3]
• Bleeding that cannot be stopped or occurs in vital organs^[6]
• Chronic joint disease and pain from repeated bleeding within joints^[6]
• Bleeding in the head and sometimes in the brain, which can cause long-term problems such as seizures and paralysis^[6]
• Death, which can occur if bleeding cannot be stopped or if it occurs in a vital organ such as the brain^[6]

The development of inhibitors represents an additional serious complication. Since the disease may be life-threatening when inhibitors are present, appropriate therapy must be given quickly^[7]. Haemophilia B may also increase the risk of formation of abnormal blood clots in the body, especially if a person has risk factors for developing blood clots^[11].

People with haemophilia should have regular checkups with a hematologist (a doctor who specializes in blood disorders)^[3]. With treatment, most people with haemophilia B are able to lead a fairly normal life^[3].