Haemophilia A and B are two diseases characterised by slow and inefficient formation of blood clots leading to prolonged bleeding from minor wounds and spontaneous internal haemorrhage. The diseases are caused by mutations in two closely linked genes on the X chromosome.
Haemophilia A and B are single gene disorders caused by malfunctioning genes on the X chromosome. They are both recessive diseases, and therefore occur much more commonly in males than females. This is because two defective chromosomes must be present for the disease to occur in females, whereas only one is required in males. Haemophilia A is the commoner of the two diseases, affecting one in 5000 males, whereas haemophilia B affects approximately one in 40 000 males.
Haemophilia A is one of the better-known inherited disorders because Queen Victoria was a carrier and transmitted the disease to several European royal families.
The disease genes, known as F8 and F9 are found close together on the long arm of the X chromosome. They encode proteins known respectively as factor VIII and factor IX, which play key roles in the blood coagulation cascade. In response to trauma or injury, these proteins are needed to activate another component of the cascade, factor X. It is factor X that converts the inert circulating protein prothrombin into active thrombin, which in turn converts fibrinogen into fibrin, the protein that forms the substance of blood clots.
Haemophilia A and B have very similar symptoms, and both can range from mild to severe depending on how little of each protein is produced. Mild forms of the diseases, in which there is only a moderate reduction in factor VIII or factor IX, result in longer than normal healing times for minor wounds caused by trauma or surgery.
In the most severe cases, where factor VIII or IX are reduced to below 1 per cent of their normal levels, there is a significant delay in clotting resulting in protracted bleeding, and there may be spontaneous haemorrhaging into joints in muscles, resulting in swelling and pain and eventual deformation of joints.
The severe forms of the disease are diagnosed by the easily recognisable symptoms – bleeding, haemorrhaging and bruising. The two different forms of the disease can be distinguished by a process of elimination (seeing whether the administration of factor VIII or factor IX helps alleviate the symptoms) and by direct testing of DNA for the presence of mutations in the F8 and F9 genes.
For many years, haemophilia has been treated successfully by the regular injection of purified factor VIII or factor IX into the blood. To avoid risks of contamination with viruses and prions, recombinant factor VIII produced in bacteria can be used instead. In each case, the injected protein lasts only a few hours, so the doses must be maintained especially under circumstances where bleeding is likely (e.g. surgery).
Haemophilia gene therapy is also being investigated because only small amounts of each factor are required in the blood to alleviate the disease symptoms.