- 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.
- 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
Factor VIII activity level
Age of presentation
Percentage of sufferers
|1–5%||Before 2 years||15–26%|
|>5%||Older than 2 years||15–31%|
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.
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- 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.
- 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.
- 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 rarer
- 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.
- 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 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.
- 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.
- Often presents with bleeding following venepuncture.
- 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, 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.
Recent guidelines divide the management into prophylaxis and treatment of acute bleeding. The following information is based on these.
- Children with severe haemophilia should receive prophylactic infusions (once-weekly or more frequently, ideally three times a week if venous access allows) of factor VIII to prevent haemarthroses and other bleeding episodes.
- This should begin before the occurrence of a second joint bleed or significant soft tissue bleed (associated with possible reduced risk of development of haemarthrosis in later life).
- Doses should be tailored to the individual, eg just before physical education lessons.
- Prophylaxis should be encouraged to continue until physical maturity is achieved.
- If after stopping prophylaxis further spontaneous haemorrhage occurs then prophylaxis should be reinstated. This can then be reviewed again at a later date.
- Some patients will need to have long-term prophylaxis, eg intracranial haemorrhage with no other cause.
Acute bleeding episodes
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 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.
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 VIII injections or continuous infusion.
- Infants may receive prophylaxis from the age of 1–2 years.
- Some studies reported a significant reduction in bleeding episodes in those with severe disease and receiving prophylactic treatment compared with on-demand therapy. However, a review in 2006 failed to report similar findings, thus further controlled trials are needed.
- During the prophylaxis phases clinical and laboratory markers should be used for monitoring.
- The Haemophilia Joint Health Score should also be used in regular assessments.
- Adherence should regularly be determined and noted.
- Factor VIII levels should be routinely measured (trough level >1 IU/dL is used, but is not always necessary in stable patients).
- If levels remain low then check for inhibitors.
- Radiological surveillance of joints is not needed unless there is a specific indication.
- Degenerative joint disease due to recurrent haemarthrosis.
- Antibody inhibitor formation affects about 25–30%, reducing efficacy of therapy.
- 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 haemophiliacs; risk with regard to Creutzfeldt-Jakob disease (CJD) exposure is uncertain.
- Inhibitor formation occurs in severely affected patients. With high levels of inhibitor, there is a need to bypass this using either prothrombin complex concentrates, porcine factor VIII or recombinant factor VIIa. The efficacy of factor VIIa compared with plasma-derived products is yet to be established.
Much improved with modern recombinant factor VIII and approaches near-normal life expectancy. Gene therapy offers hope of further improving outlook and prognosis in the future. Those infected with HIV or other blood-borne viruses carry a worse prognosis due to the effects of those diseases.
Patients should avoid competitive contact sports, that will increase the risk of haemarthroses and head injuries. However, they should be encouraged to take part in other sports, eg racket sports, athletics or swimming.
- Genetic screening for carrier mothers and affected families.
- Patient education helps to prevent morbidity and mortality associated with acute bleeds.
- MedicAlert® bracelets or similar can help to identify sufferers rapidly in case of haemorrhage/trauma, etc.
Further reading & references
- Oyesiku JO, Turner CF; Reproductive choices for couples with haemophilia. Haemophilia. 2002 May;8(3):348-52.
- Franchini M, Gandini G, Di Paolantonio T, et al; Acquired hemophilia A: a concise review. Am J Hematol. 2005 Sep;80(1):55-63.
- Preston FE, Kitchen S, Jennings I, et al; SSC/ISTH classification of hemophilia A: can hemophilia center laboratories achieve the new criteria? J Thromb Haemost. 2004 Feb;2(2):271-4.
- Bolton-Maggs PH, Pasi KJ; Haemophilias A and B. Lancet. 2003 May 24;361(9371):1801-9.
- Hemophilia A, Online Mendelian Inheritance in Man (OMIM)
- Collins P, Macartney N, Davies R, et al; A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br J Haematol. 2004 Jan;124(1):86-90.
- Chalmers EA; Neonatal coagulation problems. Arch Dis Child Fetal Neonatal Ed. 2004 Nov;89(6):F475-8.
- Nolan B, Vidler V, Vora A, et al; Unsuspected haemophilia in children with a single swollen joint. BMJ. 2003 Jan 18;326(7381):151-2.
- Mannucci PM, Duga S, Peyvandi F; Recessively inherited coagulation disorders. Blood. 2004 Sep 1;104(5):1243-52. Epub 2004 May 11.
- Richards M, Williams M, Chalmers E, et al; A United Kingdom Haemophilia Centre Doctors' Organization guideline approved by Br J Haematol. 2010 Mar 11.
- Roberts HR, Monroe DM, White GC; The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood. 2004 Dec 15;104(13):3858-64. Epub 2004 Aug 24.
- Provan D, O'Shaughnessy DF; Provan D, O'Shaughnessy DF; Recent advances in haematology. BMJ. 1999 Apr 10;318(7189):991-4.
- Khoriaty R, Taher A, Inati A, et al; A comparison between prophylaxis and on demand treatment for severe haemophilia. Clin Lab Haematol. 2005 Oct;27(5):320-3.
- Stobart K, Iorio A, Wu JK; Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003429.
- Hilliard P, Funk S, Zourikian N, et al; Hemophilia joint health score reliability study. Haemophilia. 2006 Sep;12(5):518-25.
- Lavigne-Lissalde G, Schved JF, Granier C, et al; Anti-factor VIII antibodies: a 2005 update. Thromb Haemost. 2005 Oct;94(4):760-9.
- Pappenheim K; UK inquiry should establish why contaminated blood products were given to people with haemophilia. BMJ. 1999 Jul 3;319(7201):52-3.
- Wilde JT; HIV and HCV coinfection in haemophilia.; Haemophilia. 2004 Jan;10(1):1-8.
- Hind D, Lloyd-Jones M, Makris M, et al; Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with Haemophilia A and inhibitors. Cochrane Database Syst Rev. 2004;(2):CD004449.
- Ponder KP; Gene therapy for hemophilia. Curr Opin Hematol. 2006 Sep;13(5):301-7.
|Original Author: Dr Gurvinder Rull||Current Version: Dr Gurvinder Rull|
|Last Checked: 18/02/2011||Document ID: 2221 Version: 22||© EMIS|
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