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Haemophilia

Created: 13/4/2004
Updated: 6/2/2009
 

Background

Haemophilia A (HA), which comprises approximately 80% of cases, is considered the classic form of haemophilia, and haemophilia B (HB) is termed Christmas disease. Haemophilia A is caused by a congenital deficiency of factor VIII. Haemophilia B is caused by a congenital deficiency of factor IX. This deficiency results in insufficient generation of thrombin by Factor Xa and Factor VIIIa complex through the intrinsic pathway.
Patients with less than 1% normal factor (<0.01 IU/mL) are considered to have severe haemophilia. Patients with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately severe haemophilia. Patients with more than 5% but less than 40% normal factor (>0.05 to <0.40 IU/mL) are considered to have mild haemophilia.

Pathophysiology

The genes for both Factor VIII and Factor IX are located on the long arm of chromosome X. Approximately 40% of cases of severe Factor VIII deficiency arise from a large inversion that disrupts the Factor VIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of haemophilia A defects. Low Factor VIII levels may arise from defects outside the Factor VIII gene, as in type IIN von Willebrand disease, in which the molecular defect resides in the Factor VIII-binding domain of von Willebrand factor.
Point mutations and deletions in the Factor IX gene are the most common causes of haemophilia B.
The most common complication of haemophilia is haemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint, resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths. Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa (FXa) inhibition, which predisposes haemophilic joints to bleed. This effect may also account for the dramatic response of FVIIa infusions in patients with acute haemarthroses and FVIII inhibitors. Synovial hypertrophy, haemosiderin deposition, fibrosis, and damage to cartilage progress, with subchondral bone-cyst formation.

Acquired haemophilia is the development of Factor VIII inhibitors (autoantibodies) in patients without a history of Factor VIII deficiency. This condition can be idiopathic (occurring in people >50 y), it can be associated with collagen vascular disease or the peripartum period, or it may represent a drug reaction (eg, to penicillin). High titres of Factor VIII autoantibodies may be associated with lymphoproliferative malignancies.

Frequency

The annual incidence of haemophilia A in Europe and North America is approximately 1 case per 5000 male births. It is the most common X-linked genetic disease, and the second most common factor deficiency after von Willebrand disease (VWD). The incidence of haemophilia B is estimated to be approximately 1 case per 30,000 male births.

The worldwide incidence of haemophilia A is approximately 1 case per 5000 male individuals, with approximately one third of affected individuals not having a family history. Haemophilia B occurs in 1 case per 25,000 male individuals and represents one fourth to one fifth of all patients with haemophilia. The prevalence of haemophilia A varies with the reporting country, with a range of 5.4-14.5 cases per 100,000 male individuals. The prevalence of haemophilia B varies from 0.9-3.2 cases per 100,000 male individuals.

Morbidity

Before the widespread use of replacement therapy, patients with severe haemophilia had a shortened lifespan and diminished quality of life that was greatly affected by haemophilic arthropathy. Home therapy for haemarthroses became possible with factor concentrates. Prophylactic therapies with lyophilized concentrates that eliminate bleeding episodes help prevent joint deterioration, especially when instituted early in life (ie, at age 1-2 y). Life expectancy has increased from 11 years before the 1960s for patients who were severely affected to older than 50-60 years by the early 1980s.1

Overall, the mortality rate for patients with haemophilia is twice that of the healthy male population. For severe haemophilia, the rate is increased 4-6 times. If hepatitis and cirrhosis are excluded, the overall mortality rate of patients with severe haemophilia A is 1.2 times that of the healthy male population.

Viral complications

The most serious of these was HIV infection. The first deaths of people with haemophilia due to AIDS were observed in the early 1980s. Rates of seroconversion were more than 75% for severe disease, 46% for moderate disease, and 25% for mild disease. In severe haemophilia B, seroconversion was observed at a rate of 46%. More than 50% of patients with haemophilia were infected with HIV by 1983.

Life-threatening haemorrhage

Intracranial haemorrhage is a life-threatening haemorrhage with a lifetime risk of 2-8%, accounting for one third of deaths due to haemorrhage. Other life-threatening haemorrhages include soft-tissue haemorrhages that obstruct the airway or damage internal organs.

Demographics

Haemophilia A and haemophilia B are observed in all ethnic and racial groups. Both forms of haemophilia are sex-linked coagulopathies. They are inherited as X-linked traits, therefore, the disease primarily affects male individuals. Female individuals who carry the affected genes usually do not have bleeding manifestations. Lyonized females (ie, those with unequal inactivation of Factor VIII or Factor IX alleles and with hemizygosity of all or part of the X chromosome) may be symptomatic.

Medical Management

Various Factor VIII and Factor IX concentrates are now available to treat haemophilia A and haemophilia B. Reductions in infectious complications and improved purity are the main advantages of these concentrates. During production, a specific viral-inactivation stage, either solvent-detergent treatment or liquid-phase heat treatment, is implemented to inactivate viruses, such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a problem.

Recombinant Factor VIII and Factor IX are now commercially available. They have lowered the risk of viral contamination.

Analgesia

Pain medications are used for acute bleeding or chronic arthritis. Safe analgesics include paracetamol, oxycodone, and morphine (avoid all aspirin products).

The treatment of patients with inhibitors of FVIII is difficult.

Porcine Factor VIII, which has low cross-reactivity with human factor VIII antibody, has been used. Factor VIII inhibitor-bypassing agents (FEIBA), including Factor IX complex, activated prothrombin complex concentrate (aPCC), and activated Factor VII has also been used.

Plasmapheresis, IVIG, or immunosuppressive therapy with cyclophosphamide and prednisolone, have showed some success in achieving long-term control.
Rituximab with prednisone plus or minus the addition of mycophenolate mofetil may be used when standard therapy has failed.


Anaesthetic Management of Patients with Haemophilia

Intramuscular pre medication should be avoided. Vascular access does not cause excessive bleeding, but should be placed with care, central venous lines should ideally be placed used ultrasound. After induction of anaesthesia, extra care should be taken in manipulation or intubation of the airway as it can cause submucosal haemorrhages, which can become a life threatening condition. Nasal intubation should be avoided, as it can prove traumatic and bleeding from the site can lead to aspiration. Care should be taken during positioning of the extremities and pressure points should be padded to prevent intramuscular haematomas or haemarthrosis.

Post operatively, analgesics such as NSAIDs should not be given as it can predispose patients to gastrointestinal haemorrhage. Patient-controlled analgesia is a safe and effective alternative to intramuscular injections. All patients should be admitted, even for minor procedures and optimal management should be discussed with the local haematologists.


ArticleDate:20040413
SiteSection: Article
 
   
    
                                            
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