Haemophilia
Description
- A - factor VIII deficiency (~80-85%)
- B - factor IX deficiency, "Christmas disease" (~15-20%)
- Both X-linked recessive - the two commonest congenital coagulation factor deficiencies
- Clinically indistinguishable - only the factor assay separates them
- C - factor XI deficiency: autosomal, Ashkenazi Jewish, mild
- Bleeding poorly correlates with factor level; usually stops with pressure; mucosal/post-surgical rather than joint bleeding
Severity by factor activity
| Level | Bleeding | |
|---|---|---|
| Severe | <1% | Spontaneous joint and muscle bleeds |
| Moderate | 1-5% | Bleeding after minor trauma; occasional spontaneous |
| Mild | 5-40% | Only after surgery or major trauma; delayed post-operative bleeding |
- The pattern is delayed re-bleeding, not immediate - the platelet plug forms normally
Epidemiology
- Haemophilia A ~1 in 5,000 male births; B ~1 in 30,000
- ~2,900 people with haemophilia in Australia (Australian Bleeding Disorders Registry)
- ~30% arise from de novo mutation - no family history does not exclude it
- Carrier females: usually 40-60% factor levels, but can be symptomatic with extreme lyonisation, Turner syndrome or a second affected allele
Aetiopathogenesis
- Mutations in F8 (Xq28) or F9 (Xq27)
- Severe haemophilia A: ~45% from intron 22 inversion
- Null mutations (large deletions, nonsense, inversions) -> no endogenous protein -> highest inhibitor risk
Mechanism
- Primary haemostasis intact: platelet plug forms normally
- Intrinsic tenase (FVIIIa/FIXa) fails -> no thrombin burst on the platelet surface
- -> dec fibrin cross-linking, dec activation of TAFI
- -> soft, friable, fibrinolysis-susceptible clot
- -> delayed and persistent rebleeding
- Joint bleeding -> haemosiderin -> synovitis -> neoangiogenesis -> target joint -> cartilage loss and arthropathy
- Self-perpetuating: an inflamed synovium bleeds more easily
Inheritance
- Affected male x normal female: all daughters carriers, no sons affected
- Carrier female: 50% of sons affected, 50% of daughters carriers
- Factors VIII and IX do not cross the placenta - the fetus and neonate bleed according to their own genotype
Diagnosis
Screening coagulation
- inc APTT (2-3x normal in severe disease), normal PT/INR, normal platelets, normal fibrinogen
- Mixing study corrects -> factor deficiency; fails to correct -> inhibitor
- APTT can be normal in mild haemophilia - a normal APTT does not exclude it. Assay the factor if the history fits
Confirmation
- Factor VIII and IX activity assays - both, always
- If FVIII low: measure VWF antigen + activity to exclude type 2N or type 3 von Willebrand disease (commonest misdiagnosis)
- Genotype: predicts inhibitor risk, enables carrier testing and prenatal diagnosis
Presentation by age
- Neonate: cephalohaematoma, circumcision or heel-prick bleeding, intracranial haemorrhage (uncommon but devastating)
- Toddler: bruising as mobility starts, oral bleeding, intramuscular haematoma
- Child onwards: haemarthrosis - the classic finding
- Adults: iliopsoas bleed (hip flexion, femoral nerve palsy, falling Hb - imaging, not "appendicitis"), compartment syndrome, haematuria
Bleed distribution
- Haemarthrosis 70-80% - hinge joints: ankle, knee, elbow
- Muscle 10-20%
- Other major 5-10%
- CNS <5% - but the leading haemorrhagic cause of death; treat first, image second
Inhibitor testing
- Bethesda assay - quantifies the neutralising alloantibody in Bethesda units
- Test if bleeding fails to respond to adequate factor, at regular intervals in the first 50 exposure days, and before surgery
- Low titre <5 BU vs high titre >=5 BU determines strategy
Management
Care is delivered through a Haemophilia Treatment Centre. Two separate problems: keeping the patient bleed-free, and stopping a bleed now.
A. Routine prophylaxis - the goal is zero bleeds and zero arthropathy
- Haemophilia A: emicizumab is now standard prophylaxis
- Bispecific antibody bridging activated FIX and FX - mimics FVIIIa cofactor function
- Subcutaneous, weekly to monthly; effective with and without inhibitors
- Makes the APTT uninterpretable and one-stage FVIII assays falsely normal - use bovine chromogenic assays**
- Extended half-life factor concentrates - Fc-fusion, PEGylated, albumin-fusion
- Efanesoctocog alfa (FVIII with VWF D'D3 domain) breaks the VWF half-life ceiling -> near-normal levels on weekly dosing
- Rebalancing (non-factor) agents - work in both A and B
- Fitusiran (siRNA -> dec antithrombin), concizumab (anti-TFPI), marstacimab (anti-TFPI)
- Thrombotic risk - strict protocols when combining with factor for breakthrough bleeds
- Gene therapy (AAV, single infusion)
- Valoctocogene roxaparvovec (haemophilia A), etranacogene dezaparvovec (haemophilia B)
- Transaminitis needing corticosteroid; durability of expression falls over years in A; pre-existing AAV antibodies exclude
B. Treating an acute bleed
- *Treat on clinical suspicion. Do not wait for imaging or a factor level*
- Target levels and duration by site
| Bleed | Target factor | Duration |
|---|---|---|
| Joint, simple muscle | 30-50% | 1-3 days |
| Iliopsoas, deep muscle, GI | 50-80% | 5-7 days |
| CNS, airway, major trauma | 80-100% | 10-14 days |
- Major surgery: 80-100% from 24 h pre-op, maintained 5-7 days; minor surgery 3-5 days
- RICE, analgesia, early physiotherapy
- *No aspirin, no NSAIDs, no IM injections*; tranexamic acid for mucosal and dental bleeding
- Avoid tranexamic acid with aPCC (thrombosis) and in haematuria (clot colic)
C. Mild haemophilia A only
- DDAVP 0.3 microgram/kg - raises FVIII and VWF 3-5 fold
- Trial the response first - not everyone responds
- Tachyphylaxis after 2-3 doses; hyponatraemia - fluid restrict, avoid under 2 years of age
- No role in haemophilia B
D. Inhibitors
- Alloantibody to infused factor - ~30% of severe haemophilia A, ~5-10% of B
- Risk: null mutation, intensive early exposure, family history, non-Caucasian ancestry
- Immune tolerance induction - frequent high-dose factor over months to years; ~60-80% success in A, poorer in B
- Haemophilia B ITI complicated by anaphylaxis and nephrotic syndrome (particularly with gene deletions)
- Emicizumab prophylaxis regardless of inhibitor status - has largely replaced bypassing agents for prevention
- Breakthrough bleeds -> bypassing agents
- Recombinant activated factor VII - thrombin generation on activated platelets; controls bleeding in ~15 min; short half-life; expensive. Preferred if on emicizumab
- aPCC (FEIBA) - *thrombotic microangiopathy and thrombosis when combined with emicizumab - avoid or cap the dose*
E. Long-term care
- Vaccinate against hepatitis A and B; subcutaneous route where possible
- Screen historical plasma-product recipients for HCV and HIV; cure HCV with DAAs
- Physiotherapy, joint surveillance, radiosynovectomy or arthroplasty for established arthropathy
- Genetic counselling and carrier testing for female relatives
Associations
- Haemophilic arthropathy - the dominant long-term morbidity
- Inhibitor development
- Transfusion-transmitted HCV/HIV (pre-1985 plasma products) -> cirrhosis, HCC
- Chronic pain and opioid dependence
- Pseudotumour - encapsulated expanding haematoma eroding bone
- Von Willebrand disease type 2N and type 3 - mimic haemophilia A
- Acquired haemophilia A - autoantibody, elderly or post-partum, malignancy or autoimmune disease (not the same disease - different management)
Natural history & complications
- Untreated severe haemophilia: recurrent haemarthrosis from infancy -> crippling arthropathy by early adulthood
- With modern prophylaxis: near-normal life expectancy and joint function
- The therapeutic goal has shifted from preventing death, to zero bleeds, to normal joint health
Complications
- Target joint (>=3 bleeds into the same joint in 6 months) -> chronic synovitis -> arthropathy
- Inhibitors - the single greatest complication of therapy; loss of response, higher morbidity and cost
- Intracranial haemorrhage - leading haemorrhagic cause of death
- Iliopsoas bleed -> femoral neuropathy, contracture
- Compartment syndrome, pseudotumour
- Historical viral infection sequelae
- Age-related comorbidity now emerging (CVD, cancer) - anticoagulation and antiplatelet decisions in a bleeding disorder are unsolved
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