Haemophilia A

What is haemophilia A?¹

• This is a 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.²

• Severity of disease depends upon levels of remaining factor activity, with normal range expressed as 50-200% (refer to local laboratory for reference range).

Severity of factor VIII deficiency

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

Causes of haemophilia A (aetiology)

• 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 phenotypical 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.

• Females born to affected fathers can (rarely) 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

How common is haemophilia A? (Epidemiology)

• It affects 1:4,000 to 1:5,000 live male births worldwide.³

• It is five times as common as haemophilia B (factor IX deficiency).⁵

• Acquired haemophilia has an incidence of 1-4 cases per million population per year, so is significantly rarer.⁶

Symptoms of haemophilia A (presentation)

Severe disease

• Neonatal bleeding may follow circumcision or other operative procedures. Neonatal intracranial haemorrhage can be a presenting feature of severe cases as can haematoma and prolonged bleeding from the cord or umbilical area.⁷ Intracranial haemorrhage 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 pathognomonic.

• 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 joints.⁸

• 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.

Differential diagnosis

• 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.

Diagnosing haemophilia A (investigations)

• 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 in inherited haemophilia, although the APTT may remain prolonged in acquired haemophilia.

• Factor VIII:C - is reduced, and percentage activity represents severity of disease (see above).

• Factor inhibitor assays can be used to identify factor VIII inhibitors, if acquired haemophilia is suspected.⁹

In acute situations imaging may be required - eg, CT scan of the head and body may be used to detect haemorrhage. Joint X-rays may show little in the acute situation but there can be signs of degenerative joint disease due to previous damage. MRI and Doppler ultrasound may be better modalities for the detection of arthropathy.¹⁰

Management of haemophilia A

Prophylactic factor VIII (FVIII) has dramatically improved haemophilia A treatment, preventing joint bleeding and halting the deterioration of joint status.¹¹

One of the most challenging issues facing us in the treatment of haemophilia is the development of alloantibodies against infused factor VIII, which render factor replacement therapy ineffective. Bypassing agents (activated prothrombin complex concentrate and recombinant activated factor VII) are used to treat or prevent bleeding in haemophilia patients with inhibitors. Other agents act by enhancing coagulation (emicizumab) or inhibiting anticoagulant pathways (fitusiran and concizumab).¹²

Guidelines divide the management into prophylaxis and treatment of acute bleeding.¹³ The following information is based on these.

Prophylaxis¹³

• The aim of prophylactic infusions of factor VIII is prevent haemarthroses and other bleeding episodes.

• Early initiation of prophylaxis (before joint disease occurs) provides the best long-term outcomes.

• Prophlyaxis should therefore be initiated prior to the onset of joint disease and ideally before age 3.

• Prophylaxis should be started before, or immediately after, the first joint bleed in children with factor VIII levels below 3 iU per dL.¹⁴

• It should also be started and continued long-term following initial treatment of a spontaneous intracranial haemorrhage.¹⁴

• Prophylaxis should be continued life-long in people with severe haemophilia.¹³

• Prophylaxis should be given on a regular basis; 'on-demand' (episodic) factor replacement therapy is no longer considered a suitable long-term treatment option.¹³

Acute bleeding episodes¹⁵

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

• 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 (central nervous, gastrointestinal and genitourinary systems, 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 bleeds 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.

• The prophylaxis regimen should be reviewed after resolution of the acute episode.

• Specific agents may be used as well for certain bleeding sides; for example, topical antifibrinolytics applied to gauze can be useful in treating epistaxis.¹³

Scheduled surgical procedures¹³

• Clotting factor concentrates should be given pre- and post-operatively to achieve the desired peak plasma factor levels; these differ from centre to centre and by the type of surgery, but suggested ranges are given in the World Federation of Haemophilia guidelines.

• Desmopressin can be used for people with mild haemophilia undergoing surgery, if preoperative testing demonstrates a good response (increase in plasma factor VIII activity levels).

• The safety of neuraxial anaesthesia in people with haemophilia has not been clearly established; some centres avoid it entirely, whereas others consider it acceptable once haemostasis has been restored.

Pregnancy¹⁶

• Women who may be haemophilia carriers should be offered genetic counselling.

• Carriers of severe haemophilia should be offered preimplantation genetic diagnosis.

• The management of a pregnant women known to be a haemophilia carrier should be undertaken by an obstetric team experienced in managing this condition, in conjunction with a haemophilia centre.

• Fetal sexing should be undertaken by free fetal DNA analysis, from 9 weeks of gestation onwards.

• Where the fetus is male, chorionic villus sampling at 11-14 weeks of gestation should be offered, for prenatal diagnosis of haemophilia.

• If no diagnostic investigations have previously been performed, all carriers of haemophilia with male fetuses should be offered third trimester amniocentesis to determine haemophilia status, as this informs options for delivery.

• Maternal factor VIII levels should be checked at booking, before antenatal procedures and in the third trimester.

• Desmopressin and recombinant factor VIII may be used if serum factor VIII levels are low.

• Mode of delivery should be informed by both obstetric and haemostatic factors.

  • A planned caesarean section should be offered for the delivery of affected male babies, as some evidence suggests that this has the lowest risk of neonatal intracranial haemorrhage compared to emergency caesarean sections and instrumental deliveries.

  • Some women may opt for a vaginal delivery.

• Invasive monitoring procedures such as placement of intrapartum scalp electrodes and fetal scalp blood sampling should be avoided in babies expected to have moderate or severe haemophilia.

• The diagnosis of haemophilia should be established using uncontaminated cord blood as soon as possible following delivery.

Gene therapy

Gene therapy is curative for haemophilia A. One treatment, valoctogene roxaparvovec (Roctavian) has been licensed for clinical use by the Food and Drug Administration in the USA¹⁷ and the European Medicines Association,¹⁸ but not, at the time of writing, by the UK's Medicines and Healthcare products Regulatory Agency.

Monitoring¹³

• During the prophylaxis phases clinical and laboratory markers should be used for monitoring.

• Adherence should regularly be determined and noted.

• Factor VIII levels should be routinely measured.

• Inhibitor screening should be performed 6-12 months after initiating factor VIII replacement therapy, and annually thereafter.

  • It should be performed more frequently if there are recurrent bleeds despite standard factor replacement.

Complications of haemophilia A

• Degenerative joint disease due to recurrent haemarthrosis.

• Antibody inhibitor formation affects about 25-30%, reducing efficacy of therapy.¹⁹

• Life-threatening haemorrhage.

• The use of plasma-derived factor VIII, before the availability of recombinant products, led to infection with HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) in many people with haemophilia.²⁰²¹ One case of likely transmission of variant Creutzfeldt-Jakob disease (vCJD) by UK factor VIII concentrates has been reported in an elderly person with haemophilia in the UK. The recent report of a blood test that may be used to detect vCJD has raised the possibility of a new way to identify infected individuals, perhaps even before the onset of clinical symptoms.²²

• Immune toleration induction (ITI) is recommended for patients with severe haemophilia A and a persistent inhibitor that interferes with prophylaxis or treatment of bleeds at standard doses of factor VIII inhibitor. ITI involves giving small amounts of factor concentrate irregularly over a period of time until inhibitor antibodies are no longer produced.¹⁰

• Bleeds due to a failure to respond to factor VIII should be treated using either prothrombin complex concentrates or recombinant factor VIIa. In mild-to-moderate haemophilia, a trial of immunosuppression should be given.¹⁰

Prognosis

This is much improved with modern recombinant factor VIII and approaches near-normal life expectancy. Gene therapy offers a cure for haemophilia, and is likely to become more widely available in the near future.

Patients should avoid competitive contact sports which will increase the risk of haemarthroses and head injuries. However, they should be encouraged to take part in other sports - eg, racquet sports, athletics or swimming.¹⁵

Preventing haemophilia A

• Genetic screening for carrier mothers and affected families.

• Patient education helps to prevent morbidity and mortality associated with acute bleeds.

• Medical emergency identification bracelets or similar can help to identify sufferers rapidly in case of haemorrhage/trauma, etc.