1. Epidemiology and aetiology
Classical haemophilia is in fact two conditions; haemophilia A being factor VIII deficiency and haemophilia B being a deficiency of factor IX.
Inherited bleeding disorders are rare. Haemophilia A has a prevalence of one in 5,000–10,000 males. Haemophilia B has a prevalence of one in 35,000–50,000 males. In the UK there are approximately 6,000 patients with haemophilia A and just over 1,000 patients with haemophilia B.
Haemophilia is classified as mild, moderate or severe (see box). Severe forms are characterised by spontaneous bleeding into joints and major muscle groups. The main load-bearing joints are most commonly affected.
Characteristics of haemophilia
Haemophilia A and B are clinically indistinguishable and characterised by frequent spontaneous haemarthroses and bleeding following surgical intervention or minimal trauma.
Intramuscular haemorrhage is also a common occurrence in severe haemophilia. Mild bleeding into muscles usually resolves without major problems but severe complications can occur when bleeding occurs inside closed fascial compartments and causes compression of vital structures.
Acute intra-articular bleeds present with pain and swelling. Some patients often describe a prickling sensation in the joint as the bleed starts. Intramuscular bleeds usually present with pain and tenderness over the site of bleeding with decreased movement in the affected limb.
Recurrent intra-articular joint bleeds can cause irreversible damage. Associated with this joint destruction is the resulting loss of muscle due to immobility of the limb.
The activated partial thromboplastin time (APTT) is usually prolonged in factor VIII or IX deficiency. However, a mildly decreased factor VIII or IX level to 0.4iu/ml (40 per cent) may show a normal APTT because of test insensitivity.
Diagnosis of haemophilia
The diagnosis of haemophilia A or B is based on circulating levels of factor VIII or factor IX respectively. Diagnosis of severe haemophilia is usually made in the first year of life if there is a family history.
However, approximately 30 per cent of haemophilia occurs in families with no previous history, so diagnosis may occur some weeks or months later. Levels of factor VIII range from 0.22 to 1.78iu/dl at birth.
Levels of factor IX range from 0.15 to 0.91iu/dl at birth. The diagnosis of mild haemophilia B is affected by the fact that vitamin K-dependent factors are reduced in the neonatal period and usually rise to adult levels at about six months of age.
As part of the assessment for potential bleeding disorders a detailed family history should be taken. History should include any previous bleeding episodes, whether spontaneous or related to trauma or surgery.
Details of particular sites of bleeding such as joint, muscle or mucocutaneous should be recorded. Information should be sought from other family members who may be affected and a detailed family tree should be drawn. This may give clues to people in a family group who may be affected and would require testing.
Joint bleeding in the first year of life is unusual but can occur following traumatic injury. Intramuscular bleeding can be caused by IM injection of vitamin K following delivery or routine childhood immunisations.
Bleeding can also be slow to stop following the heel prick or Guthrie test. Subcutaneous bruising in the first year of life can often be mistaken for non-accidental injury.
Bleeding in the toddler age group can often be caused by cuts to the lip, tongue or frenulum.
Children with severe haemophilia often have multiple subcutaneous bruises caused by crawling or falling when learning to walk.
The management of haemophilia in the UK is organised through a system
of 22 regional comprehensive care centres.
Ideally all children suspected of having or with a diagnosis of haemophilia should be assessed at a comprehensive care centre and a management plan put into place. Haemophilia care is provided by a specialised multidisciplinary team on a 24-hour basis.
3. Treatment and prevention
The main principle of treatment is to treat spontaneous bleeds early.
Prophylaxis, which is predominantly given for severe and some moderate haemophilia, is the regular administration of factor concentrate two to three times a week.
Demand treatment is the administration of factor concentrate when a bleed has occurred or is suspected and it is given for mild haemophilia.
Most patients with haemophilia receive treatment at home, minimising hospital attendance and reducing absence from school or work. For younger children, treatment is provided by parents and older patients can self-administer treatment.
Clotting factor concentrates are given intravenously into a small peripheral vein in the antecubital fossa or the dorsum of the hand using a butterfly needle. For babies and those with poor venous access, a subcutaneous ‘port system’ may be used to aid the administration of factor VIII or factor IX. Port systems allow for several thousand accesses and may be in situ for some years; however, they pose a significant infection risk and scrupulous aseptic technique must be adhered to.
Treatment for mild, moderate and severe haemophilia is required for surgical intervention. Surgical episodes other than minor interventions should be carried out in a specialist centre with adequate nursing, medical and laboratory services.
Haemophilia patients in the UK now predominantly use recombinant factor VIII and factor IX, which no longer carry a viral exposure risk to hepatitis or HIV.
Mild and moderate haemophilia can often be treated with desmopressin acetate. The effect is rapid and levels are usually sustained for some hours.
Complications of therapy
The most serious side-effect of treatment is the development of inhibitors that neutralise the activity of a clotting factor. These can occur in patients who have been exposed to clotting factor concentrates. Inhibitors occur in approximately 20 to 30 per cent of patients with haemophilia A and 3 per cent of patients with haemophilia B. They make the management of bleeding episodes difficult, with the potential for uncontrollable bleeding and long-term disability.
Patients with low-titre antibodies may be treated with higher doses of clotting factor. For high-titre inhibitors bleeding episodes are usually treated with recombinant factor VIIa or FEIBA (factor eight bypassing activity). Eradication of inhibitors is usually attempted using an immune tolerance regimen, but this is expensive, complex and challenging.
Haemophilia would seem to be an ideal candidate for gene therapy as it involves the loss of a single protein. The long-term elevation of factor VIII or factor IX by 2 per cent could convert severe into moderate haemophilia, with a resulting decrease in morbidity.
Progress has been made with the development of longer-acting recombinant factor VIII using PEGylation technology. Human factor VIII has a half-life of 8–12 hours and treatment requires a dose every two to three days to maintain a level greater than 1 per cent.
A pegylated recombinant factor VIII will give reduced clearance and increased half-life, thus requiring less frequent dosing.
These products may be available in the next few years.