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]
Severity Classification
Severity classification of haemophilia A & B based on factor levels. [Ref]
| Severity | Factor VIII / IX level | % of normal | Typical bleeding pattern | Usual Diagnosis |
|---|---|---|---|---|
| Mild haemophilia | >0.05 – <0.40 IU/mL | >5% – <40% | Bleeding mainly after surgery, dental work, or major trauma | Later in life Unlike severe or moderate hemophilia, which are usually diagnosed in infancy or early childhood, mild hemophilia may remain undetected until adulthood unless there is a known family history or a hemostatic challenge occurs. |
| Moderate haemophilia | 0.01 – 0.05 IU/mL | 1% – 5% | Bleeding after minor trauma + occasional spontaneous bleeds | Early childhood (≤6 yrs) |
| Severe haemophilia | <0.01 IU/mL | <1% | Frequent spontaneous haemarthroses, muscle bleeds, life-threatening haemorrhage | Infancy |
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 VWDVon Willebrand disease.
This feature is helpful in differentiating between haemophilia and VWDVon Willebrand disease 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 APTTActivated partial thromboplastin time (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
- PTProthrombin time (extrinsic clotting pathway is NOT affected, factors VIII and IX are involved in the intrinsic clotting pathway – measured by APTTActivated partial thromboplastin time)
- Bleeding time (haemophilia only affects secondary haemostasis, but not primary haemostasis – i.e. platelet function) (a prolonged bleeding time would point towards VWDVon Willebrand disease)
If APTTActivated partial thromboplastin time 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 APTTActivated partial thromboplastin time → factor deficiency (normal plasma supplies the missing factor)
- Failure to correct APTTActivated partial thromboplastin time → inhibitor present
Rationale: If an inhibitor is present, it neutralises the clotting factors in the normal plasma, preventing correction of the APTTActivated partial thromboplastin time