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Congenital afibrinogenaemia
Affected individuals experience easy bruising and prolonged bleeding due to issues with blood clotting. It is present from birth and affects both males and females equally, with symptoms varying in severity.
Overview
Congenital afibrinogenaemia is a very rare genetic condition where the body cannot produce fibrinogen, a vital protein for blood clotting [PMID:33671239]. Fibrinogen (also known as Factor I) is essential for forming a stable blood clot, which helps stop bleeding after an injury. Without fibrinogen, even minor injuries can lead to significant bleeding, and spontaneous bleeding episodes can occur.
This condition is present from birth, and its severity can vary significantly among individuals, even within the same family. It is estimated to affect around 1 in 1,000,000 people worldwide [PMID:33671239]. Because it is a rare condition, diagnosis can sometimes be delayed.
Symptoms & clinical features
The main symptom of congenital afibrinogenaemia is a tendency to bleed easily and for bleeding to last longer than normal. This can manifest in various ways, often starting from infancy or early childhood. Common signs include nosebleeds, easy bruising, and prolonged bleeding from cuts or after dental procedures. Bleeding into joints (haemarthrosis) or muscles can also occur, causing pain and swelling.
More serious bleeding episodes can include gastrointestinal haemorrhage (bleeding in the digestive tract), intracranial haemorrhage (bleeding within the skull), and excessive bleeding after surgery or trauma. In women, heavy menstrual bleeding and complications during pregnancy, such as miscarriage or excessive bleeding after childbirth, are significant concerns. Umbilical cord bleeding shortly after birth is often an early indicator of the condition [PMID:24818451].
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Affected organs
Congenital afibrinogenaemia primarily affects the blood and the vascular system, which is the network of blood vessels throughout the body. While it doesn't directly damage specific organs, the bleeding complications can impact various body systems.
For example, bleeding into joints can lead to long-term joint damage. Bleeding into internal organs, like the brain or gastrointestinal tract, can cause significant complications and organ dysfunction if not managed promptly. The reproductive system in women is also particularly affected due to excessive menstrual bleeding and pregnancy-related risks.
Risks & severity
The severity of congenital afibrinogenaemia can range from mild to life-threatening. Some individuals may experience frequent and severe bleeding episodes, while others might have milder symptoms. Life-threatening bleeding, such as intracranial haemorrhage, is a serious risk. Pregnant women are at increased risk of miscarriage, placental abruption, and significant postpartum bleeding [PMID:33671239].
While the condition is present from birth, the frequency and type of bleeding episodes can change over an individual's lifetime. Early diagnosis and consistent management are crucial for reducing the risk of complications and improving quality of life.
Genetic causes
Congenital afibrinogenaemia is caused by pathogenic variants in one of three genes: FGA, FGB, or FGG. These genes contain the instructions for making the alpha, beta, and gamma chains of the fibrinogen protein, respectively. Fibrinogen is a complex protein made of six chains (two of each type) that come together to form the complete molecule.
Normally, after an injury, fibrinogen is converted into fibrin by an enzyme called thrombin, forming a mesh that helps to seal the wound and stop bleeding. When there are pathogenic variants in FGA, FGB, or FGG, the body cannot produce any functional fibrinogen, leading to its complete absence in the blood. This inability to form stable clots results in the bleeding symptoms seen in affected individuals.
- FGA fibrinogen alpha chain
- FGB fibrinogen beta chain
- FGG fibrinogen gamma chain
Inheritance pattern
Congenital afibrinogenaemia is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic variant - one from each parent - to develop the condition. If a person inherits only one pathogenic variant and one normal copy of the gene, they are considered a 'carrier'. Carriers typically do not have symptoms of the condition themselves.
When two carriers have children, there is a 25% chance with each pregnancy that their child will inherit two pathogenic variants and therefore have congenital afibrinogenaemia. There is a 50% chance the child will be a carrier, and a 25% chance the child will inherit two normal copies of the gene and not be a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of congenital afibrinogenaemia is typically suspected based on a history of prolonged or unusual bleeding, especially in infancy. It is confirmed through laboratory tests that measure the level and function of fibrinogen in the blood. These tests usually show undetectable levels of fibrinogen and severely impaired clotting times.
Genetic testing, which looks for pathogenic variants in the FGA, FGB, and FGG genes, can confirm the diagnosis and identify the specific genetic cause. Genetic testing for congenital afibrinogenaemia is available through the NHS Genomic Medicine Service (GMS) and is typically requested by a haematologist or clinical genetics specialist. The relevant R-code for testing would be determined by the Genomics England test directory.
Management & lifestyle
Management of congenital afibrinogenaemia primarily focuses on preventing and treating bleeding episodes. This often involves regular infusions of fibrinogen concentrate to replace the missing protein. The frequency and dosage of these infusions depend on the individual's bleeding history, activity level, and whether they are undergoing surgery or experiencing an acute bleed.
Patients are typically managed by a specialist haematology team at an NHS Haemophilia Centre. It is important for individuals with congenital afibrinogenaemia to avoid activities that carry a high risk of injury. Close monitoring during pregnancy and childbirth is essential for affected women. Genetic counselling is also an important part of managing the condition, providing information on inheritance patterns and family planning.
UK care pathway
In the UK, individuals suspected of having or diagnosed with congenital afibrinogenaemia would typically be referred to an NHS Haemophilia Centre, which specialises in inherited bleeding disorders. These centres provide comprehensive care, including diagnosis, treatment, and ongoing management by a multidisciplinary team. Genetic testing to confirm the diagnosis and identify the specific genetic cause is available through the NHS Genomic Medicine Service (GMS).
Referral to clinical genetics services and access to a genetic counsellor are integral parts of the care pathway. Genetic counsellors can provide detailed information about the condition's inheritance, discuss implications for family members, and offer support with family planning decisions.
Frequently asked questions
What is fibrinogen and why is it important?
Fibrinogen is a protein in the blood that is essential for clotting. When you get a cut, fibrinogen helps to form a strong mesh, called a fibrin clot, which stops the bleeding. Without enough functional fibrinogen, blood cannot clot properly, leading to prolonged bleeding.
Can congenital afibrinogenaemia be cured?
Currently, there is no cure for congenital afibrinogenaemia. However, the condition can be effectively managed with replacement therapy using fibrinogen concentrate. This treatment helps to prevent and control bleeding episodes, allowing individuals to live fulfilling lives.
How does congenital afibrinogenaemia affect pregnancy?
Women with congenital afibrinogenaemia face higher risks during pregnancy, including miscarriage, placental abruption, and severe bleeding after childbirth. Close monitoring and fibrinogen replacement therapy are typically required throughout pregnancy and delivery to manage these risks.
Will my children inherit congenital afibrinogenaemia?
Congenital afibrinogenaemia is an autosomal recessive condition. If you have the condition, your children will inherit one copy of the pathogenic gene variant from you. If your partner is not a carrier, your children will be carriers but typically won't have the condition. If your partner is also a carrier, there is a risk their children could inherit the condition. Genetic counselling can provide personalised information and guidance.
What should I do if I suspect I have a bleeding disorder?
If you experience unusual or prolonged bleeding, you should consult your GP. They may refer you to a haematologist, a doctor specialising in blood disorders, for further evaluation and diagnosis. Early diagnosis is important for effective management.
References
- Nagler M, Kremer Hovinga JA, Alberio L. Thromboembolism in patients with congenital afibrinogenaemia. Long-term observational data and systematic review. Thrombosis and haemostasis. 2016. PMID: 27384135
- Abdelwahab M, de Moerloose P, Casini A. High incidence of intracranial haemorrhage in Egyptian children with congenital afibrinogenaemia. Haemophilia : the official journal of the World Federation of Hemophilia. 2023. PMID: 36585888
- Mensah PK, Oppenheimer C, Watson C. Congenital afibrinogenaemia in pregnancy. Haemophilia : the official journal of the World Federation of Hemophilia. 2011. PMID: 20695910
- Djambas Khayat C, Lohade SD, Zekavat OR. Analysis of fibrinogen concentrate pharmacokinetics and dosing for bleeds and surgery in adults, adolescents, and children with congenital afibrinogenaemia and hypofibrinogenaemia. Haemophilia : the official journal of the World Federation of Hemophilia. 2022. PMID: 35925493
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- Neerman-Arbez M. The molecular basis of inherited afibrinogenaemia. Thrombosis and haemostasis. 2001. PMID: 11487003
- Mehta S, Mehta SR, Malhotra H. Congenital afibrinogenaemia. The Journal of the Association of Physicians of India. 1989. PMID: 2490152