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Haemophilia A
This condition primarily affects males and causes prolonged bleeding due to the blood's inability to clot properly. It can lead to spontaneous bleeding episodes, particularly into joints and muscles, impacting quality of life and requiring lifelong management.
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Overview
Haemophilia A is a genetic bleeding disorder where the blood does not clot as it should. This is due to a problem with a specific protein called factor VIII, which is one of many proteins involved in the complex process of blood clotting [PMID:33604077]. Without enough functional factor VIII, bleeding can continue for longer than usual after an injury, or sometimes even occur spontaneously without any clear cause. This condition is significantly more common in males.
The severity of haemophilia A can vary widely, from mild to severe, depending on the amount of functional factor VIII present in the blood. Individuals with severe haemophilia A typically experience more frequent and serious bleeding episodes, often beginning in early childhood. Those with milder forms may only notice bleeding problems after surgery, injury, or tooth extraction [PMID:20301323].
Effective treatments are available in the UK, helping individuals with haemophilia A to manage their condition and lead full lives. Management often involves replacing the missing factor VIII to prevent or stop bleeding. Regular monitoring and specialised care are key components of the NHS care pathway.
Symptoms & clinical features
The main symptom of haemophilia A is prolonged or excessive bleeding. This bleeding can occur externally, such as from cuts or after dental procedures, or internally within the body. A common and characteristic symptom is bleeding into joints, most frequently the knees, ankles, and elbows. This can cause pain, swelling, and a warm sensation in the affected joint, and repeated bleeds can eventually lead to joint damage and chronic arthritis [PMID:34423450].
Bleeding into muscles is another frequent occurrence, which can result in deep bruising, pain, and swelling. More serious bleeding can include haemorrhages in the brain, which are rare but life-threatening, or bleeding in the gastrointestinal tract. For infants with severe haemophilia A, symptoms might first be noticed as prolonged bleeding after circumcision or excessive bruising as they start to crawl and walk.
The severity of bleeding symptoms often correlates with the level of functional factor VIII in the blood. Individuals with very low levels (less than 1% of normal) usually have severe symptoms, experiencing spontaneous bleeding episodes. Those with 1-5% activity may have moderate symptoms, bleeding after minor trauma, while individuals with 5-40% activity might only experience bleeding after significant injury or surgery.
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Affected organs
Haemophilia A primarily affects the blood clotting system, which has widespread effects throughout the body due to the risk of bleeding. The organs most commonly affected by bleeding complications are the joints, particularly weight-bearing joints like the knees and ankles, and also the elbows. Repeated bleeding into these joints can cause progressive damage, leading to chronic pain, stiffness, and reduced mobility over time, a condition known as haemophilic arthropathy.
Muscles are also frequently affected, with deep muscle bleeds causing pain, swelling, and sometimes nerve damage if a haematoma compresses a nerve. While less common, bleeding can occur in other vital organs. For example, intracranial haemorrhage (bleeding in the brain) is a serious complication, especially in severe haemophilia A, and can lead to neurological damage or be life-threatening. Bleeding in the gastrointestinal tract can also occur, sometimes requiring medical intervention. The impact of haemophilia A is therefore systemic, affecting various body systems through its core effect on blood clotting.
Risks & severity
The severity of haemophilia A is directly related to the amount of functional factor VIII in a person's blood. Individuals with less than 1% of normal factor VIII activity typically have severe haemophilia, experiencing frequent spontaneous bleeding into joints and muscles, often several times a month. Those with 1% to 5% factor VIII activity have moderate haemophilia, where bleeding episodes are less frequent and usually occur after injury or surgery. Mild haemophilia, defined as 5% to 40% factor VIII activity, may only manifest with bleeding problems after significant trauma or invasive procedures.
The lifetime risks associated with haemophilia A include chronic joint disease, which can develop from recurrent joint bleeds. While spontaneous brain bleeds are a significant risk for those with severe haemophilia, especially in early life, advancements in treatment have significantly reduced this risk. There is also a risk of developing inhibitors, which are antibodies that neutralise factor VIII replacement therapy, making treatment more challenging. Age of onset for symptoms often occurs in infancy or early childhood for severe cases, whereas mild cases might not be diagnosed until later in life following a surgical procedure or significant injury.
Genetic causes
Haemophilia A is caused by pathogenic variants (sometimes called mutations) in the F8 gene, which provides instructions for making coagulation factor VIII. Factor VIII is a vital protein that plays a crucial role in the blood clotting cascade, a series of steps that stop bleeding by forming a blood clot. Specifically, factor VIII acts as a cofactor for factor IXa, enabling the activation of factor X, which is a key step in forming a stable clot.
When there is a pathogenic variant in the F8 gene, it can lead to either a reduced amount of factor VIII protein being produced, or the production of a faulty factor VIII protein that does not function correctly. Both scenarios result in insufficient functional factor VIII in the blood, impairing the body's ability to form a clot and leading to the characteristic prolonged bleeding seen in haemophilia A.
The F8 gene is located on the X chromosome. The specific type of pathogenic variant can influence the severity of the condition. For example, large inversions (where a segment of DNA is reversed) within the F8 gene are a common cause of severe haemophilia A, particularly Intron 22 and Intron 1 inversions [PMID:33604077].
- F8 coagulation factor VIII
Inheritance pattern
Haemophilia A follows an X-linked recessive inheritance pattern. This means the F8 gene, which causes the condition, is located on the X chromosome. Males have one X and one Y chromosome, so if their single X chromosome carries a pathogenic variant in the F8 gene, they will develop haemophilia A. Females have two X chromosomes; if one X chromosome has a pathogenic variant, they are typically carriers and usually do not experience severe symptoms because their other, unaffected X chromosome can produce enough functional factor VIII.
A female carrier has a 50% chance in each pregnancy of passing the affected X chromosome to her children. If she has a son, there is a 50% chance he will inherit the pathogenic variant and develop haemophilia A. If she has a daughter, there is a 50% chance the daughter will be a carrier like her mother. Males with haemophilia A cannot pass the condition to their sons (as they pass a Y chromosome), but all their daughters will be carriers (as they pass their single X chromosome to all daughters). Sometimes, haemophilia A can also arise from a new pathogenic variant in the F8 gene, meaning there is no family history of the condition.
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 A typically begins when a person experiences unusual bleeding episodes, often referred by a GP or other healthcare professional to a haematologist. A series of blood tests are performed to evaluate the blood's clotting ability. These tests include a prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time, and fibrinogen levels. In haemophilia A, the APTT is usually prolonged, while other tests are generally normal.
The definitive diagnosis is made by measuring the level of factor VIII activity in the blood. A significantly reduced level of factor VIII confirms the diagnosis. Following this, genetic testing of the F8 gene is usually offered to identify the specific pathogenic variant. This is important for confirming the diagnosis, determining carrier status in family members, and for future family planning. Genetic testing for haemophilia A falls under the NHS Genomic Medicine Service (GMS) pathways, often initiated by a clinical genetics service referral (R-code R115, R116, R117, R118 for specific gene testing panels related to bleeding disorders).
Management & lifestyle
The management of haemophilia A in the UK is primarily focused on preventing and treating bleeding episodes and is coordinated through NHS Haemophilia Centres, which offer multidisciplinary care. The main treatment involves replacing the missing factor VIII protein. This can be achieved using factor VIII concentrates, which are administered intravenously. For individuals with severe haemophilia, regular prophylactic (preventative) infusions of factor VIII are common, aiming to maintain factor VIII levels and prevent spontaneous bleeding, especially into joints. This approach has significantly improved outcomes and quality of life.
For mild haemophilia, treatment might involve administering desmopressin (DDAVP), which can stimulate the release of stored factor VIII, or antifibrinolytic agents like tranexamic acid, which help stabilise blood clots. In cases of bleeding, factor VIII is given as treatment. Individuals with haemophilia are also advised to avoid medications that can increase bleeding risk, such as aspirin and NSAIDs. Regular follow-up appointments at a Haemophilia Centre, access to a specialist physiotherapist for joint health, and genetic counselling are also key components of care. Lifestyle adjustments, such as avoiding high-impact sports, are often recommended to minimise injury risk.
UK care pathway
In the UK, individuals with suspected or diagnosed haemophilia A are managed within the NHS Genomic Medicine Service (GMS) framework. Initial clinical assessment and blood clotting tests are often performed by a haematologist, who can then refer for genetic testing if haemophilia is suspected. Genetic testing for F8 variants falls under various NHS national genomic testing directories, such as specific R-codes for inherited bleeding disorders (e.g., R115 for primary haemostasis and coagulation disorders). These tests are typically arranged through a regional Genomic Medicine Centre.
Once a genetic diagnosis is confirmed, individuals and their families are often referred to a clinical genetics service for further counselling and support. Genetic counsellors play a vital role in explaining the inheritance pattern, discussing risks for other family members, and exploring reproductive options. Ongoing care and management of haemophilia A are provided by specialist NHS Haemophilia Centres, which bring together haematologists, specialist nurses, physiotherapists, and other healthcare professionals to deliver comprehensive, coordinated care.
Frequently asked questions
What does it mean for me if I am a carrier of haemophilia A?
As a carrier, you have one X chromosome with an F8 pathogenic variant and one unaffected X chromosome. Most carriers do not have severe bleeding symptoms, but some may experience milder bleeding, such as heavy periods or prolonged bleeding after surgery. You also have a 50% chance of passing the variant to each of your children.
Can haemophilia A be cured?
Currently, there is no cure for haemophilia A, but treatments are highly effective at managing the condition. Gene therapy is a promising area of research that aims to introduce a healthy F8 gene into the body, potentially offering a long-term solution or even a functional cure in the future.
How does haemophilia A affect daily life?
With modern treatments, many individuals with haemophilia A can lead active and fulfilling lives. Regular preventative treatment (prophylaxis) helps minimise bleeding episodes. However, careful management, awareness of potential risks, and adjustments to activities to avoid injury are often necessary.
What is the risk of my child developing inhibitors?
Developing inhibitors is a significant complication where the immune system recognises the infused factor VIII as foreign and produces antibodies against it. This occurs in approximately 25-30% of individuals with severe haemophilia A, typically within the first 50 exposure days to factor VIII concentrate. Your medical team will monitor for this closely.
Are there any specific precautions I should take before surgery or dental work?
Yes, it is crucial to inform your surgeon or dentist that you have haemophilia A. They will need to coordinate with your Haemophilia Centre team to ensure you receive appropriate factor VIII replacement therapy or other treatments before and after the procedure to prevent excessive bleeding.
References
- Khair K. Haemophilia. Professional nurse (London, England). 2002. PMID: 11997958
- The Lancet Haematology. Bittersweet progress for haemophilia A. The Lancet. Haematology. 2018. PMID: 29602354
- Emicizumab for haemophilia A. Australian prescriber. 2019. PMID: 30765913
- Jayaraman D, S R AK, G MS. Hyphaema unmasking the underlying haemophilia-A. Pediatric blood & cancer. 2023. PMID: 36519556
- Ter-Zakarian A, Al Banaa K, Barnes R. Hypertension in haemophilia: A meta-analysis. Haemophilia : the official journal of the World Federation of Hemophilia. 2023. PMID: 36413602
- Gatt A, Vella K. Teaching an old dog new tricks? British journal of haematology. 2019. PMID: 31364157
- Berntorp E, Hermans C, Solms A. Optimising prophylaxis in haemophilia A: The ups and downs of treatment. Blood reviews. 2021. PMID: 34243987
- Santana MAP, Chaves DG, Camelo RM. Prevalence of sporadic haemophilia A. Haemophilia : the official journal of the World Federation of Hemophilia. 2023. PMID: 36706366