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Haemophilia B
This condition primarily affects males, leading to prolonged bleeding after injury or surgery, and sometimes spontaneous bleeding. It is caused by genetic changes in the F9 gene, which plays a crucial role in blood clotting.
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Overview
Haemophilia B is a rare, inherited bleeding disorder that impacts the body's ability to form blood clots effectively. This condition is caused by a deficiency or malfunction of coagulation factor IX, a protein essential for the blood clotting cascade [PMID:32619420]. When a blood vessel is injured, a series of complex reactions involving various clotting factors normally occurs to stop the bleeding. In individuals with haemophilia B, the reduced or absent activity of factor IX disrupts this process, leading to prolonged bleeding episodes.
Haemophilia B is significantly less common than Haemophilia A, another type of haemophilia caused by a deficiency in factor VIII. It primarily affects males, with an estimated prevalence of about 1 in 25,000 male births globally. Females are typically carriers and usually do not experience severe bleeding symptoms, though some may have milder bleeding tendencies [PMID:32619420].
Symptoms & clinical features
The main symptom of haemophilia B is excessive bleeding. The severity of bleeding can vary widely among individuals, depending on the level of functional factor IX in their blood. Those with very low factor IX levels may experience severe bleeding episodes, while individuals with higher, but still deficient, levels might have milder symptoms.
Bleeding can occur in various forms. Common manifestations include prolonged bleeding after minor cuts, dental procedures, or surgery. More significantly, internal bleeding can occur, often into joints (haemarthrosis) and muscles (haematoma). Joint bleeds can cause pain, swelling, and over time, lead to chronic joint damage and arthritis. Bleeding into muscles can also cause pain, swelling, and nerve compression. In severe cases, bleeding in critical areas like the brain (intracranial haemorrhage) can be life-threatening [PMID:32619420]. Infants with severe haemophilia B may first present with excessive bleeding after circumcision or easy bruising as they start to become mobile.
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Affected organs
Haemophilia B primarily affects the circulatory system, specifically the blood and blood vessels, due to the impaired clotting mechanism. However, the consequences of uncontrolled bleeding can impact many other organ systems. The musculoskeletal system is frequently affected, as recurrent bleeding into joints, particularly knees, ankles, and elbows, can lead to chronic joint inflammation, pain, and degenerative joint disease known as haemophilic arthropathy. Muscle bleeds can cause significant pain and may sometimes lead to nerve damage if a major nerve is compressed.
While less common, bleeding can also affect the gastrointestinal tract, leading to blood in stools, or the urinary tract, causing blood in urine. The most serious complication is intracranial haemorrhage, bleeding within the brain, which can lead to neurological damage or even be fatal. Therefore, while the primary defect lies in the blood's clotting ability, the effects of haemophilia B can be widespread across the body.
Risks & severity
The severity of haemophilia B is directly related to the activity level of factor IX in the blood. Severe haemophilia B is diagnosed when factor IX activity is less than 1% of normal, leading to frequent spontaneous bleeding episodes, particularly into joints and muscles. Moderate haemophilia B involves factor IX activity between 1% and 5%, typically resulting in bleeding after minor injuries or surgery, with spontaneous bleeds being less common. Mild haemophilia B, with factor IX activity between 5% and 40%, often only presents with bleeding after significant trauma or surgery, and spontaneous bleeding is rare [PMID:32619420].
Individuals with haemophilia B face a lifelong risk of bleeding complications. Without appropriate treatment, recurrent joint bleeds can lead to progressive and irreversible joint damage, significantly impacting mobility and quality of life. The risk of life-threatening bleeds, such as intracranial haemorrhages, though rare, necessitates careful management and prompt treatment of bleeding episodes. Modern treatments, particularly prophylactic factor IX replacement, have significantly improved the prognosis and life expectancy for individuals with haemophilia B, allowing many to lead full and active lives.
Genetic causes
Haemophilia B is caused by pathogenic variants in the F9 gene. This gene provides instructions for making coagulation factor IX, a protein that plays a critical role in the blood clotting process. Factor IX is part of a complex cascade of proteins that work together to form a stable blood clot at the site of an injury.
Pathogenic variants in F9 can lead to either a reduced amount of factor IX being produced or the production of a dysfunctional factor IX protein. In either case, the efficiency of the clotting cascade is impaired, leading to prolonged bleeding. Hundreds of different pathogenic variants have been identified in the F9 gene, including point mutations, small deletions, and insertions, each affecting the factor IX protein in various ways [PMID:33994348]. The specific genetic change can sometimes correlate with the severity of the condition, though this is not always a direct relationship.
- F9 coagulation factor IX
Inheritance pattern
Haemophilia B is inherited in an X-linked recessive pattern. This means the F9 gene is located on the X chromosome, one of the two sex chromosomes. Males have one X and one Y chromosome, while females have two X chromosomes.
Because males have only one X chromosome, if their single X chromosome carries a pathogenic variant in F9, they will develop haemophilia B. Females with one affected X chromosome and one unaffected X chromosome are typically carriers. They usually do not show symptoms because their unaffected X chromosome can produce enough functional factor IX. However, some female carriers can have lower-than-normal factor IX levels and experience mild bleeding symptoms. A carrier mother has a 50% chance of passing the variant to each son (who would be affected) and a 50% chance of passing it to each daughter (who would be a carrier). Affected fathers will pass the variant to all their daughters, making them carriers, but will not pass it to their sons. Genetic counselling can provide detailed information about inheritance patterns and risks for family members.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
Diagnosis & testing
The diagnosis of haemophilia B is typically suspected based on a person's bleeding history, especially if there is a family history of the condition. Initial laboratory tests usually include a prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and platelet count. In haemophilia B, the APTT is usually prolonged, while the PT, TT, and platelet count are typically normal.
Confirmation of haemophilia B requires specific measurement of factor IX activity in the blood. If factor IX activity is found to be low, genetic testing of the F9 gene is performed to identify the underlying pathogenic variant. This genetic confirmation is important for precise diagnosis, family planning, and sometimes to predict the response to certain treatments. In the UK, genetic testing for haemophilia B is available through the NHS Genomic Medicine Service, often following referral to a clinical haematology or genetics service. The relevant NHS R-code for testing for inherited bleeding disorders including Haemophilia B is R168 Inherited bleeding, thrombotic and platelet disorders.
Management & lifestyle
Management of haemophilia B focuses on preventing and treating bleeding episodes, aiming to minimise complications and improve quality of life. The cornerstone of treatment is factor IX replacement therapy, where the deficient factor IX protein is infused into the bloodstream. This can be given on demand to treat active bleeds, or regularly as prophylaxis to prevent bleeds, especially in individuals with severe haemophilia B. Prophylactic treatment is particularly effective in preventing joint damage.
Treatment also involves managing joint health, which may include physiotherapy and, in some cases, orthopaedic surgery. Patients are advised to avoid medications that interfere with clotting, such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). Regular follow-up with a specialist haemophilia treatment centre is crucial for monitoring, treatment adjustments, and education. Access to a multidisciplinary team including haematologists, physiotherapists, nurses, and genetic counsellors is a key component of comprehensive care within the NHS.
UK care pathway
In the UK, individuals with suspected or diagnosed haemophilia B are managed through specialised NHS Haemophilia Comprehensive Care Centres. These centres provide multidisciplinary care, including diagnosis, treatment, and ongoing support. Referral to a clinical genetics service is common for diagnostic confirmation via genetic testing and for genetic counselling. The NHS Genomic Medicine Service facilitates genetic testing, often using national testing directories such as PanelApp, under relevant R-codes like R168 for inherited bleeding disorders. Genetic counsellors play a vital role in explaining inheritance patterns, recurrence risks, and implications for family members.
Frequently asked questions
What is the difference between Haemophilia A and Haemophilia B?
Both Haemophilia A and B are bleeding disorders caused by deficiencies in specific clotting factors. Haemophilia A is due to a lack of factor VIII, while Haemophilia B is due to a lack of factor IX. While their symptoms are very similar, they are caused by different gene changes and require different factor replacement treatments.
Can females get Haemophilia B?
Haemophilia B primarily affects males. Females are typically carriers and usually do not experience significant bleeding symptoms. However, some female carriers can have lower than normal factor IX levels and may experience milder bleeding tendencies, such as heavy menstrual periods or prolonged bleeding after surgery.
Is Haemophilia B curable?
Currently, there is no cure for haemophilia B. However, treatments involving regular infusions of factor IX replacement therapy are very effective in preventing and controlling bleeding episodes, allowing individuals to lead healthy lives. Gene therapy research is ongoing and shows promise for future treatments.
What should someone with Haemophilia B avoid?
Individuals with haemophilia B should generally avoid medications that interfere with blood clotting, such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), unless specifically advised by their doctor. They should also be careful with activities that carry a high risk of injury, though many can participate in regular sports with appropriate precautions and medical management.
How is Haemophilia B diagnosed?
Diagnosis typically begins with blood tests that check how long blood takes to clot, such as the activated partial thromboplastin time (APTT). If these tests are abnormal, specific tests to measure factor IX activity levels are performed. A definitive diagnosis is then made by genetic testing of the F9 gene to identify the specific pathogenic variant.
References
- Dolan G, Benson G, Duffy A. Haemophilia B: Where are we now and what does the future hold? Blood reviews. 2018. PMID: 28826659
- Fassel H, McGuinn C. Haemophilia: factoring in new therapies. British journal of haematology. 2021. PMID: 34322873
- Nekkal MS, Mesli N, Grifi F. Haemophilia B in Algeria: Realities and therapeutic perspectives. Haemophilia : the official journal of the World Federation of Hemophilia. 2023. PMID: 37467156
- Gater A, Thomson TA, Strandberg-Larsen M. Haemophilia B: impact on patients and economic burden of disease. Thrombosis and haemostasis. 2011. PMID: 21833450
- Neufeld EJ, Solimeno L, Quon D. Perioperative management of haemophilia B: A critical appraisal of the evidence and current practices. Haemophilia : the official journal of the World Federation of Hemophilia. 2017. PMID: 28752639
- Miller CH, Bean CJ. Genetic causes of haemophilia in women and girls. Haemophilia : the official journal of the World Federation of Hemophilia. 2021. PMID: 33314404
- Franchini M, Mannucci PM. Haemophilia B is clinically less severe than haemophilia A: further evidence. Blood transfusion = Trasfusione del sangue. 2018. PMID: 27723453
- Staber J, Croteau SE, Davis J. The spectrum of bleeding in women and girls with haemophilia B. Haemophilia : the official journal of the World Federation of Hemophilia. 2018. PMID: 29178325