Key Facts

Haemophilia is the most important inherited bleeding disorder characterised by deficiency of specific coagulation factors. It predominantly affects males and causes deep tissue bleeding rather than the mucocutaneous bleeding seen in platelet disorders.

Epidemiology

• Haemophilia A: 1 in 5,000 male births
• Haemophilia B: 1 in 25,000 male births
• Approximately 10,000 people with haemophilia in the UK
• ~30% of cases arise from de novo mutations (no family history)

Aetiology

• Haemophilia A: mutations in the F8 gene (Xq28) → FVIII deficiency
• Haemophilia B (Christmas disease): mutations in the F9 gene (Xq27) → FIX deficiency
• Inversion of intron 22 accounts for ~45% of severe haemophilia A
• Acquired haemophilia: autoantibodies against FVIII (elderly, post-partum, autoimmune)

Pathophysiology

• FVIII and FIX are essential components of the intrinsic coagulation pathway
• FVIII is a cofactor for FIXa in activating FX (tenase complex)
• Deficiency → impaired thrombin generation → inadequate fibrin clot formation
• Primary haemostasis (platelet plug) is intact → bleeding is delayed (hours after trauma)
• Bleeding pattern: deep tissues, joints (haemarthroses), muscles, post-surgical

Severe Haemophilia (Factor <1%)

• Spontaneous haemarthroses (knees, elbows, ankles most common)
• Muscle haematomas (iliopsoas – can mimic appendicitis)
• Intracranial haemorrhage (leading cause of death)
• Presents in infancy (excessive bruising, circumcision bleeding)

Moderate Haemophilia (Factor 1-5%)

• Bleeding after minor trauma
• Occasional spontaneous bleeding
• Haemarthroses less frequent

Mild Haemophilia (Factor 5-40%)

• Bleeding only after significant trauma or surgery
• May be diagnosed in adulthood
• Often detected after dental extraction or surgical procedure

Red Flags

• Head injury in known haemophilia → treat first, investigate second (CT head after factor replacement)
• Iliopsoas haematoma → groin pain, hip flexion deformity, femoral nerve palsy
• Compartment syndrome from muscle bleeding
• Tongue/floor of mouth haematoma → airway compromise

Bedside

• Joint examination: swollen, warm, restricted joint = haemarthrosis
• Family history: X-linked pattern (maternal uncles, brothers)

Bloods

• Coagulation screen: prolonged APTT; PT normal; thrombin time normal
• Mixing studies: APTT corrects with normal plasma (distinguishes from inhibitors)
• Factor VIII:C assay: low in haemophilia A
• Factor IX:C assay: low in haemophilia B
• vWF:Ag and vWF:RCo: normal (excludes vWD)
• Bethesda assay: quantifies inhibitors (antibodies against FVIII/FIX) – present in 20-30% of severe haemophilia A
• FBC: normal (platelet count normal)

Imaging

• Joint ultrasound/MRI: assess haemarthrosis, synovial hypertrophy, arthropathy
• CT head: for suspected intracranial haemorrhage (after factor replacement given)

Special Tests

• Genetic testing: identify specific mutation for carrier detection and prenatal diagnosis
• Carrier testing: for female relatives (factor levels and genetics)
• Thromboelastography (TEG/ROTEM): point-of-care assessment of clot formation

Non-pharmacological

• Comprehensive haemophilia centre (CCC) care – MDT approach
• Avoid intramuscular injections and aspirin/NSAIDs
• Joint physiotherapy to prevent and manage haemophilic arthropathy
• Medical alert bracelet
• Genetic counselling

Pharmacological

On-demand treatment (for acute bleeds):

• Haemophilia A: recombinant FVIII (e.g., octocog alfa) – dose based on target level and weight
  • Minor bleed: target FVIII 30-50% → 15-25 IU/kg
  • Major bleed/surgery: target 80-100% → 40-50 IU/kg
• Haemophilia B: recombinant FIX (e.g., nonacog alfa) – similar targets

Prophylaxis:

• Standard prophylaxis: FVIII 25-40 IU/kg 3× weekly (haemophilia A) or FIX 25-40 IU/kg 2× weekly (haemophilia B)
• Extended half-life products: efmoroctocog alfa (FVIII), eftrenonacog alfa (FIX) – less frequent dosing
• Emicizumab 1.5mg/kg SC weekly (or q2/q4 weekly): bispecific antibody mimicking FVIII cofactor function; effective in haemophilia A with or without inhibitors (HAVEN-1/2/3/4 trials)

Inhibitor management:

• Bypassing agents: rFVIIa (NovoSeven) 90-120 mcg/kg q2-3h; or FEIBA 50-100 U/kg
• Immune tolerance induction (ITI): high-dose FVIII to eradicate inhibitors
• Emicizumab for prophylaxis in inhibitor patients

Adjunctive:

• Desmopressin 0.3mcg/kg IV: for mild haemophilia A (raises FVIII 3-5 fold); ineffective in haemophilia B
• Tranexamic acid 1g TDS PO: for mucosal bleeding

Gene therapy:

• Valoctocogene roxaparvovec (Roctavian): AAV5-FVIII gene therapy for severe haemophilia A (EMA approved)
• Etranacogene dezaparvovec (Hemgenix): AAV5-FIX gene therapy for haemophilia B (HOPE-B trial)

Referral Criteria

• All suspected haemophilia → haemophilia centre
• Acute life-threatening bleed → treat immediately with factor replacement, then refer

• With modern treatment, near-normal life expectancy for patients without inhibitors or comorbidities
• Haemophilic arthropathy remains a major cause of morbidity (target joints)
• Inhibitor development: 20-30% of severe haemophilia A, 3-5% haemophilia B
• Legacy issues: HIV and hepatitis C from contaminated blood products (1970s-1980s) – Infected Blood Inquiry
• Gene therapy offers potential for functional cure
• Quality of life significantly improved with prophylaxis and emicizumab

Severity Classification

Target Factor Levels for Treatment

Landmark Trials