Bleeding in haemophilia

The disease usually becomes apparent when the child begins to crawl. Severely affected patients not receiving prophylactic treatment experience 30–50 bleeding episodes each year. The most common problems are spontaneous bleeds into joints, often elbows or knees, although any joint can be involved. Patients may develop particular target joints which bleed frequently. They often have an innate feeling that a bleed has started prior to any objective signs. Recurrent or inadequately managed joint bleeds lead to chronic deformity of the joint with swelling and pain (Fig 36.1).

Bleeding may also afflict deep-seated muscles, often the flexor muscle groups. If ignored, the enlarging haematoma can compress adjacent nerves and vessels with serious consequences (Fig 36.2). Haematuria is not unusual and, until recently, intracranial bleeding was the most common cause of death in haemophilia.

Complications of treatment

In affluent countries, factor VIII replacement treatment as described below has been enormously beneficial in allowing early control of bleeding and the avoidance of chronic joint damage. Unfortunately, most haemophiliac patients treated before 1985 became infected with pathogenic viruses contaminating factor VIII concentrate, notably HIV and hepatitis C. There are now improving therapies for both HIV and hepatitis C infection and younger patients receiving only virus-free factor products have avoided these complications. Approximately 25% of patients with severe haemophilia will develop antibodies to factor VIII (‘inhibitors’). They tend to appear in childhood but may occur after years of treatment.

Treatment of bleeding

Most haemophiliac patients require replacement therapy with factor VIII concentrate and this is often self-administered at home when a bleed occurs (‘on demand’ treatment). The dose and duration of treatment depends on the patient’s size and the locality and magnitude of the bleed. One unit of factor VIII is the amount contained in 1 mL of normal plasma. For spontaneous haemarthroses it is sufficient to raise the factor VIII level to 30% of normal; in a 70 kg man this entails a dose of around 1000 units. More serious bleeding or surgery requires levels of 70–100% maintained until the risk subsides (Fig 36.3). Factor VIII products undergo processing to maximise quality, purity and viral safety. Plasma-derived factor VIII is being increasingly replaced by recombinant factor VIII. Third-generation recombinant factor VIII is free of any animal or human protein. Prophylactic (alternate day) recombinant factor VIII treatment in children eradicates bleeding and improves quality of life. Periods of ‘secondary prophylaxis’ may be considered in older patients with problematic joint bleeds.

Treatment of inhibitors is highly specialised. Acute bleeds can be treated with recombinant factor VII_a or a concentrate of activated vitamin K derived clotting factors (FEIBA). Eradication of the inhibitor may be achieved by immune tolerance regimens where factor VIII is given regularly in high doses with or without immunomodulatory agents.

In patients with mild disease, 1-amino-8-D-arginine vasopressin (DDAVP), given intravenously or by nasal spray, mobilises factor VIII from stores and may avoid the need for concentrate. The antifibrinolytic agent tranexamic acid can also be used to reduce bleeding – it should, however, be avoided in haematuria where it can induce clot colic. Likely advances in haemophilia drug therapy are pegylated recombinant factor VIII allowing less frequent administration and novel approaches including non-peptide haemostatic agents which reduce reliance on replacement coagulation factor.

Treatment of viral infection

Haemophiliac patients with HIV infection require state-of-the-art management of the physical and social problems which can arise. Hepatitis C infection carries a long-term risk of cirrhosis (20–30%) and hepatocellular cancer. The combination of pegylated interferon and ribavirin eradicates the virus in 50–80% of cases dependent on the viral genotype.

Gene therapy

Gene therapy is a potentially curative treatment for haemophilia and is discussed on page 103.

The carrier state and genetic counselling

Female carriers are generally asymptomatic but some will have low enough levels of factor VIII (10–30%) to cause excessive bleeding after trauma. In families with inversion of the factor VIII gene (see above), first-generation molecular biology methods have been used in carrier and prenatal diagnosis (Fig 36.4). The more recent development of polymerase chain reaction (PCR)-based screening and sequencing technology has allowed identification of the mutation in nearly all patients with haemophilia A. Large databases of the known mutations are freely available.