Introduction
The body has innate mechanisms to control bleeding from injury. Understanding these basic physiological processes is important to aid in the identification and diagnosis of bleeding disorders. A hemostatic system, aided by prostacyclin, antithrombin III, and nitric oxide within endothelial cells, is responsible for maintaining blood in a fluid state free of platelet aggregation and thrombus formation. Naturally occurring in the blood, these substances help prevent blood clots by converting plasminogen to plasmin, promoting fibrinolysis. Damage or injury to the endothelium triggers a series of events that control bleeding. Endothelial disruption initially causes local vasoconstriction (constriction of blood vessels), restricting blood flow to the area. Primary hemostasis is initiated by platelets with the release of Von Willebrand factor (vWF), a large plasma glycoprotein made and stored in endothelial cells and megakaryocytes. Platelets and vWF combine to form a plug at the injury site.
What Is Afibrinogenemia?
Congenital afibrinogenemia is a bleeding disorder that occurs due to impairment of the blood clotting process. Normally, blood clots protect the body after an injury by sealing off damaged blood vessels and preventing further blood loss. However, bleeding is uncontrolled in people with congenital afibrinogenemia.
Newborns having this condition experience prolonged bleeding from the umbilical cord stump after birth. Frequent nosebleeds and bleeding from the gums or tongue are common and can occur after minor trauma or no injury (spontaneous bleeding). Some patients bleed into the space between the joints (articular hemorrhage) or the muscle (hematoma). Rarely, bleeding inside the brain or other internal organs can lead to death. Women diagnosed with congenital afibrinogenemia may undergo abnormally heavy menstrual bleeding (menorrhagia). Without appropriate treatment, women with this disorder may have difficulty getting pregnant and have repeated miscarriages.
What Are the Causes of Afibrinogenemia?
Congenital afibrinogenemia is caused by mutations in one of three genes: FGA, FGB, or FGG. Each of these genes contains instructions for making a part (subunit) of a fibrinogen protein. This protein is important for clot formation (clotting), which is necessary to stop excessive bleeding after injury. In response to injury, fibrinogen is converted to fibrin, the major protein in blood clots. Fibrin proteins bind to each other to form a stable network that constitutes a thrombus.
Congenital afibrinogenemia occurs due to a complete deficiency of the fibrinogen protein. Most mutations in the FGA, FGB, and FGG genes lead to this condition providing premature stop signals to the instructions for making that particular protein. Even if a protein is made, it doesn't work. Without a subunit, the fibrinogen protein cannot assemble, and there is no fibrin. As a result, blood clots do not form in response to injury, leading to excessive bleeding seen in people diagnosed with congenital afibrinogenemia.
What Are the Risk Factors of Afibrinogenemia?
Men and women are equally affected. There does not appear to be an ethnic predisposition to this disease. However, because it is an autosomal recessive disorder, children whose parents are consanguineous are at increased risk. People from the same family are more likely to carry the same rare gene variant, and if they inherit the pathogenic variant from their parents, they may have an affected child. It is more common in areas with high inbreeding rates, such as South India and the Middle East.
What Are the Symptoms of Afibrinogenemia?
The symptoms of afibrinogenemia are listed below:
1. Bleeding episodes can be due to any minor trauma.
2. Umbilical cord bleeding at birth.
3. Intracranial hemorrhage might cause the following symptoms:
4. Vomiting.
5. Dizziness.
6. Headache.
7. Confusion.
8. Seizures.
9. Joint bleeding (hemarthrosis) might lead to pain and limited movement.
10. Women are at an elevated risk of vaginal bleeding and blood loss during menstruation (menstrual bleeding) and are more likely to have repeated miscarriages.
11. Poor wound healing.
12. Increased risk of spleen rupture.
13. Formation of unstable clots that can get lodged in the blood vessels.
How Is Afibrinogenemia Diagnosed?
Diagnosis of congenital afibrinogenemia is made using a combination of blood clotting tests, tests that measure the level of fibrinogen in the blood, and genetic tests. The disorder may be suspected in neonates with severe umbilical cord bleeding and infants and children with severe and prolonged bleeding episodes.
All coagulation tests that rely on fibrin (a conversion product of fibrinogen) are postponed indefinitely in patients with congenital afibrinogenemia. These tests are listed below:
-
Activated partial thromboplastin time (aPTT).
-
Reptilase time.
-
Thrombin time (TT).
-
Prothrombin time (PTT).
Tests that measure fibrinogen levels, such as the Claus method and ELISA (Enzyme-linked immunosorbent assay), do not detect fibrinogen in the blood. Genetic testing of parents and affected individuals is used to detect disease-causing pathogenic variants in the FGA, FGB, and FGG genes.
What Is the Treatment of Afibrinogenemia?
People with congenital afibrinogenemia are treated with fibrinogen replacement therapy. Fresh frozen plasma and blood products made from plasma (cryoprecipitate) can be injected instead of fibrinogen. However, fibrinogen concentrates are preferred because of their rapid onset of action, greater dosage flexibility, ease of administration, and less potential for viral contamination than fresh frozen plasma or cryoprecipitate. It is the best option because it is safe.
The goal of treatment is to restore and maintain normal fibrinogen levels. Depending on patient needs, it may be administered weekly or biweekly to prevent bleeding (primary prophylaxis), to prevent recurrence after a bleeding episode (secondary prophylaxis), or as soon as bleeding begins (as needed). Primary prevention is essential for pregnant women to avoid miscarriage.
In some patients, fibrinogen replacement therapy causes unstable blood clots to form that can break and spread throughout the body, blocking blood vessels (thromboembolic complications). Low-molecular-weight heparin should be given with treatment, if possible.
People may be given amino acids that prevent clots from breaking down (antifibrinolytic amino acids) for less severe bleeding episodes: ε-aminocaproic acid and tranexamic acid. A big advantage of this treatment is that there are no injections.
What Are the Complications of Afibrinogenemia?
Complications may include:
-
Blood clots with treatment.
-
Development of antibodies to fibrinogen with treatment.
-
Miscarriage or excessive intestinal bleeding.
-
Rupture of the spleen.
-
Slow healing of wounds.
Conclusion
Afibrinogenemia, also called congenital afibrinogenemia, is an inherited blood disorder in which the blood does not clot normally. It occurs when there is a deficiency of a protein called fibrinogen (or clotting factor I) that blood needs to clot. Affected individuals are prone to bleeding, especially during infancy and childhood. Afibrinogenemia is thought to be inherited in an autosomal recessive manner. Genetic counseling and treatment with clotting factors help manage and prevent this condition.
