Introduction

Haemophilia A is one of several genetic inherited clotting disorders, the other most common ones being haemophilia B and von Willebrand’s disease.

It typically presents in neonates and young children, and can occasionally be fatal – usually from an acute intracranial bleed. Most patients have a normal life-expectancy with treatment. In severe cases, it is important to treat it effectively to prevent bony deformities and disability caused by large spontaneous bleeding into joints.

Haemophilia A is caused by deficiency of factor VIII, an important constituent of the clotting cascade.

  • von Willebrand’s disease (vWD) also affects factor VIII – although indirectly – von Willebrand factor (vWF) helps to prolong the life of factor VIII, and in vWD, there are defects of vWF
    • von Willebrand’s disease is the most common inherited clotting disorder
  • Haemophilia B affects factor IX
  • Occasionally haemophilia A can also be caused by an acquired defect – such as antibodies against factor VIII – which tends to occur in older patients

The severity of the disease is related to the levels of functioning factor VIII which remain:

  • Mild disease – >5% factor VIII activity – presents after age of 2
    • About 15-30% of cases
  • Moderate disease – 1-5% factor VIII activity – presents before age 2
    • About 15-30% of cases
  • Severe disease – <1% factor VIII activity – presents in infancy
    • About 40-70% of cases

Epidemiology and Aetiology

  • Range of possible mutations, 30% of cases due to sporadic mutation
  • When inherited – X-linked recessive condition
    • Xq28
    • Typically affects males born to maternal carriers
    • Usually an obvious family history
    • Females born to affected fathers rarely have the disease – only if their mother was also a carrier
  • Prevalence 1 in 5,000
    • 5x more common than haemophilia B
    • Acquired haemophilia affects about 1 per million per year (much rarer than inherited)
  • Marked variability of disease

Presentation

  • Top tip:
    • Platelet disorders tend to cause petechial haemorrhage and bruising
    • Clotting disorders tend to cause haematoma and haemarthrosis

Mild disease

  • Typically only causes bleeding after dental procedures, major surgery or trauma
  • Female carriers may also have a slight increased bleeding risk
    • They tend to have factor VIII levels of 10-30% of normal

Moderate disease

  • In addition to events seen in mild disease, also causes bleeding after mild trauma, e.g. venipuncture

Severe disease

  • Bleeding in the neonatal period occurs in up to half of cases
  • Spontaneous bleeding into joints
    • Haemarthrosis – can cause chronic deformity, swelling and pain
  • Intramuscular haemorrhage
  • GI and mucosal bleeding
    • More commonly associated with von Willebrand’s disease and haemophilia B
  • Haematuira
  • Haematoma formation
    • Occasionally may require surgical drainage

Pathology

Low factor VIII levels predispose to bleeding – risk proportional to factor VIII level

  • Mild disease –  (11-30 units/dl) risk after significant trauma/surgery
  • Moderate disease –  (2-10 units) – minor trauma
  • Severe disease –  (<2 units) – frequent, unprovoked bleeds into muscles and joints.  May be 30-50 bleeds a year

Investigations

  • FBC
    • May have low Hb and haematocrit if frequent or recent bleeding
  • Prolonged APTT
    • May be normal in mild disease
  • Normal:
    • PT
    • Bleeding time
    • Fibrinogen
    • von Willebrand Factor (vWF)
  • Diagnosis confirmed by factor VIII assay
    • factor VIII levels low
    • Severity of disease correlates to level of factor VIII

Imaging

  • May be appropriate in situations of acute bleed
    • CT brain if suspected intracranial haemorrhage
    • USS to assess for soft tittle haematoma
    • Joint x-rays may detect effusion from haemarthrosis, but often MRI or USS is required

Differential diagnosis

  • Haemophilia B
  • von Willebrand’s disease
  • Haemophilia C
  • Vitamin K deficiency
  • Platelet disorders
  • Disorders of fibrinogen

Management

Management can be divided into the prevention and treatment of acute bleeding.

Prevention

  • Prophylactic infusions of factor VIII
    • Typically weekly in severe cases
    • The need for prophylaxis is reviewed as the child ages
    • Some patients need life-long prophylaxis
    • Antibodies to factor VIII can develop – making treatment particularly difficult
  • By preventing bleeding in children – particularly haemarthrosis – long term joint deformity and disability can be prevented
  • Avoid NSAIDs
  • Avoid IM injections (usually can be given SC instead)
  • Advise patients to wear medical emergency bracelets stating they have haemophilia A, and their usual factor VIII levels
  • Avoid contact sports, and sports with a high risk of trauma
  • Avoid manual labour

Acute bleeding episodes

  • Administer dose of factor VIII
    • Typically self-administered when bleeding occurs until patient can attend hospital
  • If unsuccessful, then on arrival at hospital:
    • Recombinant factor VIII, OR
    • Fresh frozen plasma (FFP) containing factor VIII
    • Recbominatn factor preferred due to decreased risk of viral transmission
  • Aim to titrate to measurable factor VIII levels in the blood
    • Spontaneous haemarthroses: correct to 30% of normal factor VIII
    • More serious bleeds/surgery: correct to 70-100% of normal
    • Keep these levels for 7-10 days after a severe bleed, and 1-3 days after a minor bleed
  • Desmopressin (DDAVP) may also be used
    • Mobilises stored factor VIII
  • Antifibrinolytics – such as tranexamic acid – may also be used
  • Review the prophylactic regimen after each actor bleed and consider increased doses
  • Patients may develop inhibitors (antibodies which inhibit factor VIII) – managed with porcine factor VIII, activated factor IX, recombinant factor VIIIa and immune tolerance regimens.

Prognosis

  • Near normal life expectancy if treated
  • In past decades, use of FFP lead to contraction of hepatitis B and C as well as HIV
    • These patients may have reduced life-expectancy as a result of these diseases
    • Now this is rare due to use of recombinant factor VIII as well as screening for blood-borne viruses in FFP
  • Joint deformities can occur after episodes of haemarthrosis – especially if young when episode occurred

References

  • Haemophilia A - patient.info
  • Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
  • Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
  • Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

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