Haemophilia

Haemophilia is an inherited bleeding disorder characterised by a deficiency or dysfunction of specific clotting factors essential for normal blood coagulation. Individuals with the condition experience prolonged bleeding after injuries, surgical procedures, or spontaneously within muscles and joints. As a lifelong condition, haemophilia requires continuous clinical management and careful monitoring to prevent complications arising from repeated bleeding episodes. Although rare, it is one of the most widely studied genetic disorders due to its clear hereditary pattern and significant impact on quality of life.

Genetic background and inheritance

Haemophilia is primarily caused by mutations in the genes responsible for producing clotting Factor VIII or Factor IX. These genes are located on the X chromosome, making haemophilia an X-linked recessive disorder. Males are predominantly affected, while females generally act as carriers, although some may display mild symptoms due to lyonisation or skewed X-chromosome inactivation.
There are two major forms:

• Haemophilia A, resulting from Factor VIII deficiency, is the more common variant.
• Haemophilia B, caused by Factor IX deficiency, is less common but clinically similar.

The severity of symptoms depends on the circulating level of the deficient factor:

• Severe: <1% of normal activity, leading to frequent spontaneous bleeds.
• Moderate: 1–5% of normal activity, causing bleeding after minor injuries.
• Mild: 5–40% of normal activity, with bleeding typically occurring only after significant trauma or surgery.

Occasionally, haemophilia arises from spontaneous mutation with no prior family history.

Clinical features and symptoms

The clinical presentation varies, but specific features are characteristic of clotting factor deficiency. The hallmark symptom is prolonged bleeding, though the patterns differ depending on severity.
Typical manifestations include:

• Haemarthrosis (joint bleeding), especially affecting knees, elbows, and ankles. Recurrent episodes may cause chronic synovitis and long-term joint damage.
• Intramuscular bleeding, causing swelling, pain, and reduced mobility.
• Prolonged bleeding from cuts, dental extractions, or surgical procedures.
• Easy bruising, disproportionate to the degree of trauma.
• Internal bleeding, including gastrointestinal or intracranial haemorrhage, which may occur spontaneously in severe cases.

Children with haemophilia often present symptoms when they begin crawling or walking, as increased mobility exposes them to minor injuries.

Diagnosis and laboratory evaluation

Diagnosis is based on a combination of clinical suspicion, family history, and laboratory testing. Standard tests reveal a normal platelet count and normal prothrombin time (PT), but a prolonged activated partial thromboplastin time (aPTT), reflecting intrinsic pathway deficiency.
Confirmatory tests include:

• Factor VIII activity assay for diagnosing haemophilia A.
• Factor IX activity assay for haemophilia B.
• Genetic testing to identify causative mutations, vital for prenatal diagnosis and carrier detection.

In newborns, early diagnosis is particularly important if there is a family history, enabling prompt intervention and prevention of bleeding complications.

Treatment and management strategies

Modern haemophilia management focuses on replacing the missing clotting factor and preventing recurrent bleeds. Treatment differs according to severity and availability of therapeutic products.
Key approaches include:

• Replacement therapy: Intravenous infusion of recombinant or plasma-derived Factor VIII or Factor IX concentrates. This can be administered on demand (during a bleed) or prophylactically to prevent bleeds.
• Extended half-life products: Modified factor concentrates offering longer duration in circulation, reducing infusion frequency.
• Non-factor replacement therapies: Agents such as monoclonal antibodies that mimic or support coagulation pathways, particularly beneficial for haemophilia A.
• Management of inhibitors: Some individuals develop antibodies against replacement factors. Bypassing agents or immune tolerance induction therapies may be required.
• Physiotherapy: Essential for managing joint health and restoring function after haemarthrosis.
• Comprehensive care centres: Multidisciplinary teams provide coordinated care, including haematologists, physiotherapists, and genetic counsellors.

Vaccinations against hepatitis viruses and careful monitoring for blood-borne infections are crucial for those using plasma-derived products, although modern processing methods have significantly improved safety.

Complications and long-term implications

Without effective management, haemophilia can lead to several serious complications:

• Chronic arthropathy due to repeated joint bleeding, potentially resulting in disability.
• Muscle contractures from soft-tissue haemorrhage.
• Neurological impairment following intracranial bleeding.
• Anaemia due to recurrent blood loss.
• Inhibitor development, a major treatment complication requiring specialised therapy.

Advances in therapy have markedly reduced mortality and improved life expectancy; however, lifelong vigilance is required to manage risks associated with bleeding episodes.

Social, psychological, and economic considerations

Living with haemophilia involves navigating medical, social, and psychological challenges. Regular treatment schedules, physical limitations, and risk of complications influence educational, occupational, and recreational choices. Support networks, counselling, and patient education play crucial roles in fostering independence and long-term wellbeing.
Economic impacts arise from treatment costs, particularly for advanced recombinant products. Many national health systems provide specialised funding or reimbursement programmes to ensure access to essential therapies.

Advances in research and future directions

Research continues to transform haemophilia treatment. Key developments include:

• Gene therapy, aiming for long-lasting or permanent correction of clotting factor deficiency through targeted genetic modification.
• Improved recombinant technologies, reducing immunogenicity and enhancing factor stability.
• Global health initiatives, supporting improved diagnosis and treatment access in low-resource settings.