Hemophilia — Types A & B, Factor Replacement, Emicizumab & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Haemophilia is an X-linked recessive inherited bleeding disorder caused by deficiency or dysfunction of clotting factors in the coagulation cascade. Haemophilia A (the most common form, affecting approximately 1 in 5,000 male births) is caused by deficiency of factor VIII (FVIII). Haemophilia B (Christmas disease, affecting approximately 1 in 25,000 male births) is caused by deficiency of factor IX (FIX). Because the gene encoding FVIII and FIX is located on the X chromosome, haemophilia predominantly affects males — who have only one X chromosome (hemizygous). Females with one defective copy are carriers and generally have around 50% factor activity; most have no symptoms but some (manifesting carriers) experience mild bleeding, particularly heavy menstrual bleeding. Severity is classified by residual factor activity: severe below 1%, moderate 1-5%, mild 5-40%. Approximately 400,000 people worldwide have haemophilia. Since the 1990s, recombinant factor concentrates have eliminated the historical transmission risk of HIV and hepatitis that devastated the haemophilia community.

Haemophilia A is caused by mutations in the F8 gene on the X chromosome — the most common mutation in severe haemophilia A is an inversion of intron 22 (present in approximately 40-50% of severe cases). Haemophilia B is caused by mutations in the F9 gene. Both conditions follow X-linked recessive inheritance: affected males pass the mutation to all daughters (who become obligate carriers) but not to sons; carrier females have a 50% chance of an affected son and 50% chance of a carrier daughter. Approximately one-third of haemophilia cases arise from de novo mutations with no family history. Risk factors are therefore primarily genetic — a family history of haemophilia or known carrier status. Acquired haemophilia — a rare but serious condition — occurs when autoantibodies develop against FVIII in previously unaffected individuals, typically in older adults or postpartum women, causing sudden severe bleeding.

Severe haemophilia (factor activity below 1%) causes spontaneous bleeding into joints, muscles, and organs without identifiable trauma. Haemarthroses (joint bleeding) are the hallmark — knees, ankles, and elbows are most commonly affected; bleeding into a joint causes acute pain, swelling, warmth, and restricted movement. Repeated haemarthroses cause haemophilic arthropathy — progressive joint destruction, deformity, and chronic pain resembling severe osteoarthritis — the most disabling long-term complication. Muscle haematomas (intramuscular bleeds) — particularly in the iliopsoas, calf, and forearm — can be life-threatening from compartment syndrome. Intracranial haemorrhage (ICH) carries the highest mortality — any head trauma in a haemophilia patient requires urgent factor treatment and CT imaging regardless of severity. Easy bruising, prolonged bleeding from minor cuts and wounds, and bleeding after procedures (dental extractions, surgery). Moderate haemophilia: rarely bleeds spontaneously; usually bleeds after minor trauma. Mild haemophilia: bleeds after significant trauma or surgery only.

Coagulation screen: activated partial thromboplastin time (aPTT) is prolonged in haemophilia A and B (isolated prolongation — PT/INR is normal because haemophilia affects the intrinsic pathway only). Factor assays: FVIII activity level (haemophilia A) and FIX activity level (haemophilia B) confirm the diagnosis and establish severity. Von Willebrand factor antigen and activity (vWF:Ag, vWF:Act) are measured to exclude Type 3 von Willebrand disease (which also reduces FVIII). Mixing study: adding normal plasma to the patient's plasma — aPTT corrects in haemophilia (factor deficiency) but not in acquired haemophilia or lupus anticoagulant. Inhibitor assay (Bethesda assay): essential to detect factor inhibitors (IgG autoantibodies against FVIII or FIX) — present in 30% of severe haemophilia A patients after treatment — measured in Bethesda Units (BU); above 5 BU is a 'high-titre inhibitor' requiring bypassing agents. Genetic testing: identifies the specific F8 or F9 mutation for family counselling, carrier testing, and prenatal diagnosis.

Primary prophylaxis (regular preventive factor replacement) is the standard of care for severe haemophilia — preventing joint bleeding and preserving joint function. Haemophilia A: recombinant FVIII concentrates (octocog alfa, moroctocog alfa, turoctocog alfa) — standard half-life (SHL) administered 3x/week; extended half-life (EHL) products (efmoroctocog alfa — 2x/week; damoctocog alfa pegol — once weekly) reduce injection frequency. Emicizumab (Hemlibra): a bispecific antibody mimicking FVIII function (bridging FIXa and FX) — given subcutaneously once weekly, fortnightly, or monthly; equally effective in patients with and without inhibitors (Game-changer for inhibitor patients); dramatically reduces bleeding frequency (HAVEN trials). Fitusiran (antithrombin-lowering siRNA): once-monthly SC injection; effective in both haemophilia A and B regardless of inhibitors. Haemophilia B: recombinant FIX concentrates (nonacog alfa, eftrenonacog alfa — EHL, once weekly). Gene therapy: valoctocogene roxaparvovec (AAV5-FVIII-SQ) for severe haemophilia A — provides sustained FVIII expression from a single infusion, achieving normal or near-normal FVIII levels in the majority of patients for at least 5 years; etranacogene dezaparvovec (AAV5-FIX-Padua) for haemophilia B. Treatment of acute bleeds: 'RICE' (Rest, Ice, Compression, Elevation) plus immediate factor infusion (raise level to 50-100% for severe bleeds). Inhibitor management: bypassing agents (recombinant FVIIa — eptacog alfa; aPCC — FEIBA) for breakthrough bleeds; emicizumab prophylaxis.

Haemophilic arthropathy is the most disabling long-term complication — repeated haemarthroses cause progressive synovial inflammation, cartilage destruction, bone erosion, joint deformity, and chronic pain resembling end-stage osteoarthritis, predominantly affecting knees, ankles, and elbows. Primary prophylaxis from early childhood is specifically designed to prevent this irreversible complication. Inhibitor development occurs in approximately 30% of patients with severe haemophilia A and 3–5% with haemophilia B within the first 50 exposure days — inhibitors (IgG antibodies against infused factor) neutralise the concentrate and render standard treatment ineffective, requiring bypassing agents and immune tolerance induction (ITI) over months to years, dramatically increasing treatment complexity and cost. Intracranial haemorrhage (ICH) carries the highest mortality — occurring in 3–8% of people with severe haemophilia during their lifetime; any head injury requires immediate factor treatment and urgent CT imaging. Compartment syndrome from muscle haematoma (iliopsoas, forearm, calf) requires emergency fasciotomy and carries risk of permanent nerve damage and limb ischaemia. Pseudo-tumours (encapsulated haematomas) develop in bones or soft tissues when bleeds are not treated adequately — can erode bone and require surgical excision or embolisation. Chronic hepatitis C infection from contaminated plasma products (primarily 1970s–1980s) affects a significant proportion of older patients with haemophilia and carries long-term risk of cirrhosis, hepatocellular carcinoma, and liver failure. HIV was similarly transmitted via contaminated factor concentrates historically. Modern recombinant products have eliminated transmission risk. Target joint degeneration requiring total joint arthroplasty is a late complication of undertreated haemophilic arthropathy.

Prophylaxis is prevention — regular factor infusions or emicizumab prevent the haemarthroses that cause haemophilic arthropathy. Primary prophylaxis should begin before the second joint bleed and no later than age 2 in severe haemophilia A. Physical activity and physiotherapy: exercise is strongly encouraged — swimming, cycling, and walking strengthen the muscles that protect joints; contact sports (rugby, boxing, martial arts) are avoided; physiotherapy after joint bleeds maintains range of motion and prevents muscle atrophy. Medical alert identification: all haemophilia patients should carry a card/bracelet specifying diagnosis, factor type, inhibitor status, treatment product, and haemophilia centre contact. Avoid NSAIDs and aspirin which impair platelet function; use paracetamol for pain. Inform all healthcare providers (dentists, surgeons, anaesthetists) before any procedure. Vaccinate against hepatitis A and B. Genetic counselling and carrier testing for family members; prenatal diagnosis (chorionic villus sampling at 11-13 weeks) is available.

Seek emergency care immediately for: any head injury (even minor) — intracranial haemorrhage requires urgent CT imaging and immediate factor infusion before results; neck pain or swelling (possible pharyngeal/cervical haematoma causing airway compromise); signs of compartment syndrome in limbs (increasing pain, numbness, pallor, tightness) from muscle haematoma; severe abdominal pain (iliopsoas bleed — can cause femoral nerve palsy); or any bleed that does not stop after 2-3 doses of factor concentrate at home. Contact your haemophilia comprehensive care centre for: painful swollen joint (haemarthrosis) not responding to home treatment; suspected psoas bleed; inhibitor development (factor replacement not controlling bleeds as expected); and for all planned surgical procedures, dental extractions, or invasive procedures.