Haemophilia A (factor VIII, F8 gene): inheritance, carriers and testing

Blood clots depend on a series of proteins called clotting factors. In haemophilia A the one called factor VIII (factor 8) is reduced. The NHS says haemophilia affects the way the blood clots, so that people bleed more easily than others, and that it cannot usually be cured although treatment helps to control symptoms. People with haemophilia do not bleed faster than normal; they take longer for bleeding to stop, and may bleed into joints and muscles without an obvious injury, as The Haemophilia Society explains.

The NHS Genomics Education Programme sorts the condition by the amount of factor VIII activity. In severe haemophilia A the level is below 1%, with a risk of spontaneous bleeding into joints and muscles. In moderate haemophilia (1% to 5%) bleeding generally follows trauma, though spontaneous bleeds can occur. In mild haemophilia (above 5%) symptoms range from easy bruising to joint bleeds after injuries. The greater the severity, the earlier it tends to appear.

F8 sits on the X chromosome and holds the instructions for making factor VIII. The NHS Genomics Education Programme says inversions in this gene, which usually leave no detectable factor VIII, are found in about 45% of people with severe haemophilia A. In other people the change is a smaller deletion, insertion or single-letter alteration, and more than 100 different point mutations have been described.

Identifying the exact change is more than academic. Some changes are known to go with a particular severity, and some raise the chance of developing inhibitors, which are antibodies against factor VIII that make treatment less effective. The NHS notes that if inhibitors develop the haemophilia team works with the person to find a more suitable treatment.

Females have two X chromosomes and males have one X and one Y. A man with an altered F8 gene on his X chromosome has haemophilia. His sons receive his Y chromosome and so cannot inherit it from him, whereas all of his daughters receive his X and will be carriers, as The Haemophilia Society and the NHS Genomics Education Programme describe. A carrier woman passes either of her two X chromosomes at random, so each son has a 50% chance of haemophilia and each daughter a 50% chance of being a carrier.

The word carrier can mislead. The Haemophilia Society points out that some female carriers have significantly reduced factor levels and a mild form of haemophilia themselves, and the NHS says women with the altered gene can have symptoms, though less commonly and less severely than men. Rarely, a carrier is severely affected, for example when her working X chromosome is silenced, as in Turner syndrome or complete X-inactivation.

Because about one-third of cases arise from a new change, a boy can be the first in his family. Equally, no affected males may have been known in a family for generations. The Haemophilia Society lists both explanations when there is no apparent family history.

Haemophilia may be suspected from symptoms and a prolonged APTT clotting screen, with the diagnosis confirmed by a factor VIII activity assay, according to the NHS Genomics Education Programme. The NHS says if a GP suspects haemophilia a blood test measures the clotting factor, and anyone diagnosed is referred to a local haemophilia centre. A baby known to be at risk can be tested shortly after birth using cord blood.

Female siblings of affected boys, and any known or suspected carrier, should have factor VIII levels checked in childhood to establish a baseline. Predictive genetic testing for relatives without symptoms is considered once the person can consent for themselves, generally in the mid-teens.

If you are at risk of having a child with haemophilia, the NHS says a GP may refer you to a genetic counsellor. Options before, during and after pregnancy include a genetic test to see whether you carry the altered gene, a blood test in early pregnancy to determine the baby's sex (boys are at more risk), chorionic villus sampling or amniocentesis, and testing the baby after birth. The NHS Genomics Education Programme adds that non-invasive fetal sexing can be done from about 7 to 8 weeks, and that IVF with pre-implantation genetic testing is an option. It recommends carriers discuss options before conception where possible and have their carrier status and factor levels known so labour and delivery can be planned.

The NHS says haemophilia is usually treated with injections of clotting factor, and other medicines including emicizumab, desmopressin and tranexamic acid may also be used. People with severe haemophilia usually have injections up to three times a week to prevent bleeding, often self-administered at home, while those with mild or moderate haemophilia usually have treatment to stop bleeds after they start, and before surgery or dental work. Care is delivered through a haemophilia comprehensive care centre, with physiotherapy, education and bleed management, per the NHS Genomics Education Programme.

• Treat any bleed early, including joint and muscle bleeds, because the NHS says this reduces pain, recovery time and the risk of permanent damage.

• Contact the haemophilia team straight away for joint pain, swelling, tingling or numbness, blood in the urine, or any bleeding without treatment to hand; call 111 if the team is unavailable.

• Call 999 or go to A&E for a head injury, a serious cut, vomiting or coughing blood, black or red stools, or a sudden severe headache with confusion.

• If you had a blood transfusion before 1996 and have not been tested for hepatitis C, speak to your specialist (NHS advice).