Haemophilia A (Factor VIII Deficiency)

• Bleeding disorder caused by deficiency of clotting Factor VIII.
• The vast majority of cases are inherited, but acquired forms do exist, largely in older patients, due to autoantibodies directed against Factor VIII or haematological malignancy.¹
• Severity of disease depends upon levels of remaining factor activity, with normal range expressed as 50–200% (0.1 μg/ml - but refer to local laboratory for reference range):

The totals in the various categories do not equal 100% as there is inter-population variability due to the heterogeneity of Factor VIII gene mutations, and inter-laboratory variation in Factor VIII activity measurement.²

• Haemophilia A results from heterogeneous mutations in the Factor VIII gene that map to Xq28.
• Carrier detection and prenatal diagnosis can be carried out by testing against the range of known mutations or indirectly by linkage analysis.³
• There is marked phenotypic variability leading to a spectrum of severity as outlined above.
• Inheritance is usually X-linked recessive, affecting males born to carrier mothers.
• There is usually a clear family history but sporadic cases do occur due to novel mutations or effects of mosaicism.
• Rarely females born to affected fathers can have the disease due to homozygosity for the gene, where there is marriage to close relatives.
• There is a reported case of a son inheriting the gene from his father due to uniparental disomy for the X chromosome.⁴

• Affects 1 in 5,000 to 1 in 10,000 male live births
• Five times as common as haemophilia B (Factor IX deficiency)
• Acquired haemophilia has an incidence of 1.34 cases per million population per year, so is significantly rarer⁵

Severe disease

• Neonatal bleeding in around a third to a half of cases. This may follow circumcision or other operative procedures. Neonatal intracranial haemorrhage can be a presenting feature of severe cases in about 1–2%, as can haematoma and prolonged bleeding from the cord or umbilical area.⁶
• Intracranial haemorrhage occurs in approximately 5% of all untreated, severe cases and requires immediate intervention.
• History of spontaneous bleeding into joints, especially the knees, ankles and elbows, without a history of significant trauma. Spontaneous haemarthroses are virtually pathognomic.⁷
• Intramuscular haemorrhage may also occur.
• Gastrointestinal and mucosal haemorrhage do occur but are more often associated with haemophilia B/Von Willebrand's disease.
• Haematuria may be a feature, which can vary from self-limiting minor episodes to gross haematuria.

Untreated cases of severe disease

This group of patients may develop the following:

• Arthropathy and joint deformity - may require replacement of affected joints⁸
• Soft tissue haemorrhages - common; may cause complications, including compartment syndrome and neurological damage
• Extensive retroperitoneal bleeds - with haemodynamic compromise
• Haematoma formation - spontaneously or following trauma and may require fasciotomy

Moderate disease

• Often presents with bleeding following venepuncture

Mild disease

• Only bleed after major trauma or surgery, with moderate disease after minor trauma or surgery

• Haemophilia B (Factor IX deficiency)
• Von Willebrand's disease
• Vitamin K deficiency/antagonism with anticoagulants
• Haemophilia C (Factor XI deficiency)
• Disorders of fibrinogen or fibrinolytic production
• Platelet disorders
• Blood vessel disorders

• FBC - low haematocrit and reduced Hb if recent bleeding.
• Prothrombin time, bleeding time, fibrinogen levels and Von Willebrand factor - are normal.
• Activated partial thromboplastin time (APTT) - usually prolonged but can be normal in mild disease. Mixing patient's plasma 1:1 with donor plasma should normalise APTT.
• Factor VIII:C - is reduced, and percentage activity represents severity of disease (see above).

In acute situations imaging may be required e.g. CT of head and body may be used to detect haemorrhage. Joint x-rays may show little in acute situation but there can be signs of degenerative joint disease due to previous damage.

Non-drug

For acute bleeding episodes haemostasis should be aided by physical methods and transfer to hospital arranged.

Medical

Acute bleeding episodes

• Patients who are able should administer their normal Factor VIII, as advised by their haemophilia service until they attend hospital.
• Fresh frozen plasma containing Factor VIII, monoclonal-antibody purified Factor VIII and recombinant Factor VIII are the available sources of Factor VIII used to treat acute haemorrhage, with recombinant Factor VIII preferred. Fresh Frozen Plasma and cryoprecipitate should only be used in an emergency when the concentrates are not available because they may cause the development of antibodies to the deficient protein (an inhibitor) which greatly complicates future therapy.
• The aim is to correct Factor VIII activity to 100% for severe haemorrhage (CNS, GI, GU, retroperitoneal, trauma and severe epistaxis) and to 30–50% for minor haemorrhage (haemarthrosis, oral mucosal and muscular).
• Enhanced Factor VIII levels are maintained for 7–10 days for severe and for 1–3 days for minor bleeds.
• Desmopressin (DDAVP) and antifibrinolytic agents (aminocaproic acid) may be used to boost Factor VIII activity and reduce Factor VIII administration requirements.

Scheduled surgical procedures

• Aim for 50–100% factor activity for 2–7 days after surgery.
• In brain or prostate surgery nearer 100% is required.
• Desmopressin may help increase factor levels.
• Prophylaxis is usually given for those with severe disease as intermittent recombinant Factor VII injections or continuous infusion.⁹
• Infants may receive prophylaxis from the age of 1–2 years.¹⁰
• Some studies reported a significant reduction in bleeding episodes in those with severe disease receiving prophylactic compared to on-demand therapy.¹¹ However, a review in 2006 failed to report similar findings, thus further controlled trials are needed.¹²

• Degenerative joint disease due to recurrent haemarthrosis.
• Antibody inhibitor formation affects about to 25–30%, reducing efficacy of therapy.¹³
• Life-threatening haemorrhage
• The use of plasma-derived Factor VIII, before the availability of recombinant products, led to infection with HIV, HBV and HCV in many haemophiliacs;^14,15 risk with regard to CJD exposure uncertain.
• Inhibitor formation occurs in severely affected patients. With high levels of inhibitor, need to bypass this using either prothrombin complex concentrates, porcine Factor VIII or recombinant factor VIIa. The efficacy of Factor VIIa compared to plasma-derived products is yet to be established.¹⁶

Much improved with modern recombinant Factor VIII and approaches near-normal life expectancy. Gene therapy offers hope of further improving outlook and prognosis in future.¹⁷ Those infected with HIV or other blood-borne viruses carry a worse prognosis due to the effects of those diseases.

• Genetic screening for carrier mothers and affected families.
• Patient education helps to prevent morbidity and mortality associated with acute bleeds.
• Medic-alert® bracelets or similar can help to rapidly identify sufferers in case of haemorrhage/trauma etc.