Haemophilia
Definition
Haemophilia is a inherited bleeding disorder, characterised by a deficiency or dysfunction of clotting factor VIII or IX.
Clotting factors VIII and IX are both involved in secondary haemostasis (intrinsic pathway).
Aetiology and Types
Inheritance pattern: X-linked recessive [Ref]
There are 2 main types of haemophilia:
- Mutation in factor VIII → haemophilia A (classic haemophilia) (~80% cases)
- Mutation in factor IX → haemophilia B (Christmas disease) (~20% cases)
Rarely haemophilia can be acquired, due to autoantibodies against factor VIII. [Ref]
Clinical Features
Mainly affects males (due to its X-linked recessive inheritance pattern)
Haemophilia characteristically causes musculoskeletal bleeding [Ref1][Ref2]
- Spontaneous haemarthroses (bleeding into joints) – classic
- Most commonly affects the knees, ankles and elbows
- Deep muscle haematomas
- Most commonly affects the thighs, calf muscles, iliopsoas
- Can result in compartment syndrome
- Excessive bleeding after trauma / surgery / dental procedures
- Bleeding into internal organs (including intracranial haemorrhage, GI bleeding, retroperitoneal haemorrhage)
Mucocutaneous bleeding (e.g. epistaxis, petechiae, menorrhagia) is characteristically absent in haemophilia A. While musculoskeletal bleeding is characteristically seen in haemophilia, but not VWD.
This feature is helpful in differentiating between haemophilia and VWD in exams.
Complications
The most frequent and characteristic complication is haemophilic arthropathy [Ref]
- Chronic haemarthrosis → progressive joint damage → loss of joint function, pain and disability
Muscle bleeds can cause compartment syndrome and permanent muscle atrophy.
Another important complication is the development of inhibitors in haemophilia A [Ref]
- Occurs in ~20-35% of patients with severe haemophilia A
- These ‘inhibitors’ are autoantibodies against infused factor VIII
- This makes standard replacement therapy ineffective and significantly increasing morbidity and mortality
Investigation and Diagnosis
Key laboratory findings in haemophilia: [Ref]
- Prolonged APTT (due to affected intrinsic clotting pathway)
- Reduced factor VIII or IX activity
- Haemophilia A = factor VIII affected
- Haemophilia B = factor IX affected
Importantly, the following parameters are normal in haemophilia:
- Platelet count
- PT (extrinsic clotting pathway is NOT affected, factors VIII and IX are involved in the intrinsic clotting pathway – measured by APTT)
- Bleeding time (haemophilia only affects secondary haemostasis, but not primary haemostasis – i.e. platelet function) (a prolonged bleeding time would point towards VWD)
If APTT is prolonged, mixing studies are performed to differentiate between a clotting factor deficiency and the presence of an inhibitor (autoantibodies against factor VIII)
Mixing studies involves mixing the patient’s plasma with normal plasma:
- Correction of APTT → factor deficiency (normal plasma supplies the missing factor)
- Failure to correct APTT → inhibitor present
Rationale: If an inhibitor is present, it neutralises the clotting factors in the normal plasma, preventing correction of the APTT
Management
Haemophilia A
Mild haemophilia A can be managed with desmopressin if there is adequate response [Ref1][Ref2]
- MoA: desmopressin increases endogenous VWF and factor VIII levels
Moderate and severe haemophili A requires factor VIII replacement therapy for acute bleeds and routine prophylaxis [Ref1][Ref2]
Haemophilia B
All severities of haemophilia B requires factor IX replacement therapy for acute bleeds and routine prophylaxis [Ref1][Ref2]