Haemophilia

Haemophilia A (Factor VIII deficiency) is the more common form, affecting 1 in 5,000 males. Haemophilia B (Christmas disease, Factor IX deficiency) is clinically indistinguishable. Because they are X-linked, they primarily affect males while females are carriers. Severity is categorized by the level of factor activity: Severe (<1%), Moderate (1-5%), or Mild (>5%). Severe haemophilia typically presents in early childhood with spontaneous bleeds. The hallmark is bleeding into large joints (knees, elbows, ankles), leading to chronic haemophilic arthropathy and joint destruction. Bleeding after minor trauma or surgery is also characteristic. Modern management involves prophylactic factor replacement to prevent bleeds and maintaining a normal lifestyle. Complications include the development of 'inhibitors' (antibodies against replacement factor).

The intrinsic pathway of the coagulation cascade requires both Factor VIII and Factor IX to form the tenase complex, which activates Factor X. A deficiency in either leads to inadequate thrombin generation and poor clot stability. The genes for both factors are located on the X chromosome (Xq28 and Xq27). Common mutations include inversions (especially intron 22 in Haemophilia A), deletions, and point mutations. Since the extrinsic and common pathways are intact, the PT remains normal, but the APTT is prolonged as it measures the intrinsic pathway.

Neonatal: Prolonged bleeding after circumcision or heel pricks (though intracranial haemorrhage is rare). Infants: Easy bruising, 'goose eggs' on the head when crawling. Severe Haemophilia: Spontaneous haemarthrosis (joint starts with a 'tingle' followed by pain, swelling, and warmth). Muscle haematomas (e.g., psoas bleed causing hip pain and femoral nerve palsy). Haematuria and GI bleeding can occur. Prolonged bleeding after dental extractions or surgery is universal across all severities. Long-term, repeated bleeds into joints lead to synovial hypertrophy and cartilage destruction (haemophilic arthropathy).

Bloods: FBC (normal), PT (normal), APTT (Prolonged). Mixing Study: APTT corrects when patient plasma is mixed with normal plasma (suggests deficiency rather than inhibitor). Specific Factor Assays: Low Factor VIII (Haemophilia A) or Low Factor IX (Haemophilia B). von Willebrand factor: Checked to exclude vWD. Genetic testing: For carrier detection and prenatal diagnosis.

**Prophylaxis:**
- **Factor replacement:** Regular IV recombinant Factor VIII (Haemophilia A) or Factor IX (Haemophilia B) to maintain trough levels >1% (severe cases). Typically 2-3× weekly for FVIII, 2× weekly for FIX.
- **Emicizumab (Hemlibra):** Subcutaneous bispecific antibody that bridges Factor IXa and Factor X, mimicking FVIII function. NICE-approved for Haemophilia A (with and without inhibitors). Administered weekly, fortnightly, or monthly SC. Now widely used as standard prophylaxis for moderate-severe Haemophilia A — significantly reduces bleed frequency. Does not work for Haemophilia B.

**Acute Bleeds:**
Immediate factor replacement — target 50-100% activity depending on bleed site/severity. 'If in doubt, treat.' If on emicizumab with inhibitors: use activated bypassing agents (aPCC — FEIBA; or rFVIIa — NovoSeven). Caution: aPCC + emicizumab combination carries thrombotic risk — use rFVIIa in preference.

**Mild Haemophilia A:** Desmopressin (DDAVP) can transiently raise Factor VIII by releasing endothelial stores. Effective for minor bleeds/procedures in mild disease.

**Adjuvant:** Tranexamic acid (antifibrinolytic) for mucosal bleeds — do not use for haematuria.

**Inhibitors:** If inhibitory antibodies develop, bypassing agents are used (rFVIIa or aPCC). Immune tolerance induction (ITI) to eradicate inhibitors. Emicizumab remains effective for prophylaxis regardless of inhibitor status.