Haemophilia A ✅

Related Subjects: |Haemophilia A |Haemophilia B |Haemolytic anaemia |Heme |Globins |Red blood cells |White blood cells |Lymphocytes |Platelets |Cryoprecipitate |Fresh Frozen Plasma |Blood Cell Maturation |Blood film interpretation |Reticulocytes

A classic X-linked bleeding disorder, six times more common than Haemophilia B.

📖 About

• Haemophilia A: X-linked recessive genetic disorder due to defective clotting factor VIII, almost exclusively affecting males 👨.
• ~30–50% of cases arise from de novo (new) mutations 🧬.
• History: Queen Victoria was a carrier and passed the gene into European royalty 👑.
• 1980s: many patients acquired HIV and hepatitis C from contaminated blood products 💉 (now prevented with recombinant/safe products).

🧬 Aetiology

• Inherited deficiency of factor VIII:C due to mutations on the X chromosome (F8 gene).
• >2000 mutations identified; ~45–50% due to inversion of intron 22.

📊 Background

• Prevalence: ~1 in 5,000–6,000 male births; UK registrations ~6,900 males (UKHCDO 2024/25).
• Males affected; females carriers (except rare cases e.g. Turner syndrome XO or skewed lyonisation).
• Carriers may have reduced factor VIII (~30–60% average) due to X-inactivation; some symptomatic ♀️.
• Haemophilia A is ~6× more common than Haemophilia B.

📉 Grading by Factor VIII Levels (WFH/ISTH standard)

• Severe: <1% → spontaneous haemarthroses 🤕, muscle haematomas, frequent bleeds.
• Moderate: 1–5% → bleeding after minor trauma/surgery 🩸.
• Mild: 5–40% → excessive bleeding only after major surgery/trauma 🏥.

⚡ Clinical Features

• Bleeding rarely evident in newborn period; problems arise with mobility 🍼➡️🚶.
• Bleeding after procedures (e.g., circumcision ✂️).
• Haematomas appear after ~6 months of age.
• Recurrent haemarthroses → chronic arthropathy and joint deformity 🦵 (preventable with prophylaxis).
• Risk of intracranial haemorrhage, especially post-head injury 🧠.
• Minor cuts/abrasions not a problem (platelets normal ✅).

🔬 Investigations

• APTT: prolonged ⏱️.
• Factor VIII:C: reduced 📉 (chromogenic assay preferred).
• VWF: normal ✅ (distinguishes from von Willebrand disease).
• PT, bleeding time, platelet count: normal 📊.
• Female carriers: factor VIII ~30–60% of normal (variable).

👶 Prenatal Diagnosis

• Possible via chorionic villus sampling (CVS) at ~11 weeks or amniocentesis if mutation known 🧬; pre-implantation genetic diagnosis available.

🩺 Management (per UKHCDO/BSH/WFH/ISTH; involve Haemophilia Centre)

• Avoid aspirin, NSAIDs, intramuscular injections, contact sports/high-risk activities 🚫.
• Mild disease: Desmopressin (DDAVP; IV/SC/intranasal) → 2–6× ↑ in Factor VIII (test response first) 💉.
• IV Factor VIII replacement = mainstay; recombinant/extended half-life (EHL) products preferred 🌱.
• Home therapy: self-infusion of factor concentrate for early bleed treatment 🏠.
• Half-life of standard FVIII ~8–12 hours ⏳ (EHL longer); dosing often 2–3× weekly for prophylaxis.
• Severe disease: regular prophylaxis (e.g., 3× weekly or more) prevents spontaneous bleeds and arthropathy; emicizumab (subcutaneous) alternative for many (NICE-approved).

💉 Replacement Therapy Targets

• Joint/muscle bleed → raise FVIII to 30–50% 🦵.
• Life-threatening bleed (e.g., intracranial) → raise FVIII to 80–100% ⚠️ (then maintain).
• Prophylaxis: prevents spontaneous bleeds; modern goal zero bleeds.
• FVIII: plasma-derived (rare now) or recombinant (standard/EHL) 🧪.

⚠️ Complications

• Historical blood-borne infections (HIV, Hep B/C) from contaminated products 🦠 (now negligible risk).
• Development of inhibitors (antibodies) to factor VIII (~20–30% in severe) → refractory bleeding; manage with emicizumab, bypassing agents (rFVIIa, FEIBA), or immune tolerance induction 💉.

📚 References

• NICE TA1051: Efanesoctocog alfa for haemophilia A (2025 – prophylaxis/treatment ≥2 years).
• NICE TA1073: Marstacimab for severe haemophilia A/B (2025 – ≥12 years without inhibitors).
• UKHCDO Annual Report 2024/25; WFH Guidelines (2020 + 2025 gene therapy addendum); ISTH 2024 CPG for congenital haemophilia A/B.

Cases - Haemophilia A

• Case 1 - Child with Spontaneous Joint Bleed: A 7-year-old boy is brought to A&E with a painful swollen right knee after minor trauma. He has recurrent episodes of joint swelling since age 2. FBC is normal, PT normal, but APTT prolonged. Factor VIII level <1%. Diagnosis: Severe Haemophilia A with haemarthrosis.
• Case 2 - Post-Surgical Bleeding: A 22-year-old man develops persistent bleeding 12 hours after a dental extraction. Past history includes prolonged bleeding after circumcision. Coagulation studies: PT normal, APTT prolonged, low Factor VIII activity (12%). Diagnosis: Moderate Haemophilia A, presenting with excessive surgical bleeding.
• Case 3 - Inhibitor Development: A 30-year-old man with known severe Haemophilia A is admitted with persistent thigh haematoma after intramuscular injection. He has had multiple prior Factor VIII infusions. Factor VIII levels do not correct as expected after treatment; Bethesda assay confirms inhibitors. Diagnosis: Haemophilia A with inhibitor antibodies.

Teaching Commentary 🩸

Haemophilia A is an X-linked recessive deficiency of Factor VIII, the most common inherited bleeding disorder after von Willebrand disease. Severity depends on Factor VIII activity: - <1% = severe (spontaneous joint/muscle bleeds), - 1–5% = moderate (bleeding after minor trauma), - 5–40% = mild (bleeding after surgery/dental work). Key labs: prolonged APTT, normal PT and platelets. Mainstay treatment is recombinant Factor VIII replacement (prophylaxis in severe) or, in some mild cases, desmopressin (DDAVP). Non-factor options like emicizumab increasingly used for prophylaxis. A major complication is development of inhibitor antibodies against Factor VIII, requiring bypassing agents (e.g., recombinant Factor VIIa) or emicizumab. Long-term, recurrent haemarthroses can cause chronic arthropathy (preventable with early prophylaxis).