Factor XIII deficiency: a very rare clotting disorder

Blood clotting involves platelets clumping together at an injury and a chain of clotting proteins, called coagulation factors, being activated in order until a mesh of fibrin forms a clot. GOSH explains that each factor is numbered with Roman numerals, from I to XIII, and that if any is missing the process does not happen as it should, which can lead to blood loss that can be severe and life-threatening.

Factor XIII has a particular role. GOSH says that factor XIII deficiency is different from other clotting disorders in that a clot forms after injury, but it is unstable, so it breaks down and starts to bleed again. Factor XIII also seems to play a role in wound healing, pregnancy and the formation of new blood vessels, although GOSH says more research is needed to understand this.

Guy's and St Thomas' NHS Foundation Trust lists factor XIII deficiency among the rare bleeding disorders, which it describes as very rare, usually inherited, able to affect males and females, and ranging from mild to severe.

GOSH says factor XIII deficiency is caused by a mutation in the F13A1 or F13B gene, both inherited in an autosomal recessive manner, with the F13A1 mutation being the most common. Autosomal recessive means a person has to inherit the faulty gene from both parents to develop the disease. Each pregnancy of two carrier parents carries a 75 per cent chance of an unaffected child and a 25 per cent chance of an affected child.

People who carry one copy are called carriers. GOSH says most carriers are healthy but occasionally affected carriers may show mild symptoms because their factor XIII level can be half that of an unaffected person, which may or may not need treatment. The Haemophilia Society adds that as many as a third of bleeding disorder diagnoses have no known family history and can be the result of a random gene mutation.

GOSH says symptoms often appear soon after birth when the umbilical cord is still present: a clot may form for a day or two but then breaks down, causing repeated bleeding. This occurs in the majority of babies born with the condition. Bleeds inside the brain (intracranial haemorrhage) without trauma also occur in around one-third of people and can be severe enough to be life-threatening. Other bleeding can include nose and mouth bleeds and bleeding into muscle tissue.

Women with factor XIII deficiency often have heavy menstrual periods, and GOSH says pregnancy should be carefully planned because of an increased risk of early miscarriage or extended bleeding after childbirth. Men seem to have reduced fertility and a low sperm count, according to GOSH. Guy's and St Thomas' notes that affected women may have heavy periods or excessive bleeding with childbirth and that people may be diagnosed later in life, for example after unexpected heavy bleeding during surgery or dental extractions.

GOSH says the condition can be diagnosed before birth if there is a family history, by chorionic villus sampling early in pregnancy or amniocentesis around 15 to 20 weeks. After birth, it is diagnosed using a blood sample. The standard clotting-time test will show normal results, so a different test checks how stable a blood clot is after it has formed, which is abnormal in factor XIII deficiency. The level of factor XIII is measured and doctors will try to identify the gene mutation, which helps with planning for future siblings and testing other family members. Imaging scans such as MRI, CT or ultrasound may be used to find internal bleeds.

The Haemophilia Society notes that many people with a bleeding disorder are undiagnosed or diagnosed late because of a lack of understanding about these rare conditions, so it is worth asking for specialist testing if there is unexplained serious bleeding.

Unlike some rare bleeding disorders where treatment is needed only occasionally, GOSH says people with factor XIII deficiency need preventative (prophylaxis) treatment. It replaces the missing or reduced factor XIII with a substitute derived from human plasma, given regularly as an injection, sometimes into a central venous access device such as an implantable port. Injections can be given at home, which GOSH says is less disruptive to family life.

GOSH says that inhibitors, where the body fights off the injections, can be an extremely rare problem, and they are checked for regularly at review appointments. If they develop, additional injections will be needed. Guy's and St Thomas' says in all rare bleeding disorders tranexamic acid can be given as a tablet or into the veins to help minimise bleeding, and that plasma or cryoprecipitate is sometimes used when factor concentrates are not available.

GOSH also says immunisations should be given under the skin (subcutaneously) rather than into a muscle to reduce the risk of a painful bruised swelling (haematoma).

GOSH says most children and young people with factor XIII deficiency have a normal lifespan, and that the most common cause of death is a spontaneous intracranial haemorrhage. Some activities, such as contact sports with a high risk of head injury, may need to be avoided, but most day-to-day activities cause few problems. It advises wearing a medical identity necklace or bracelet, planning any surgery carefully in advance, and says women with severe deficiency should receive regular factor replacement throughout pregnancy to reduce the risk of early miscarriage.

Regular reviews at a specialist centre, usually with a physiotherapist and dentist, check response to treatment and side effects, and GOSH says lifelong monitoring and treatment are needed and that young people are prepared for the move to adult services. Genetic counselling is available before planning a family, for both affected individuals and carriers.

Rare bleeding disorders are managed in NHS haemophilia centres, which hold the specialised tests, factor products and expertise. Guy's and St Thomas' notes there is a national haemophilia database, and that the Haemophilia Society provides information and support. Private haematology can provide an initial assessment, but treatment of factor XIII deficiency in the UK depends on centre-based supplies and monitoring, so most people stay linked to a comprehensive care centre.