NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Marguerite Neerman-Arbez, PhD, Professor, Department of Genetic Medicine and Development, University Medical Centre, Geneva, Switzerland, for assistance in the preparation of this report
Congenital afibrinogenemia is a rare bleeding disorder characterized by absence of fibrinogen (also known as coagulation factor I) in the blood, a protein that is essential in the blood clotting (coagulation) process. Affected individuals may be susceptible to severe bleeding (hemorrhaging) episodes, particularly during infancy and childhood. Bleeding can occur anywhere in the body, including the skin, nose, oral cavity, gastrointestinal tract, liver, genital and urinary (genitourinary) tract, joints, muscles and central nervous system. Bleeding can also happen in the skull (intracranial hemorrhage) and is a leading cause of death and disability in individuals with congenital afibrinogenemia.
Women are at increased risk for vaginal bleeding and increased blood loss during menstruation (menometrorrhagia) and tend to have recurrent miscarriages. Other manifestations of the disease include risk of spontaneous spleen rupture, formation of painful bone cysts, poor wound healing, and increased risk of formation of unstable clots that can lodge in blood vessels and occlude them (thromboembolic complications).
Symptoms usually begin to show at birth with umbilical cord bleeding, but can manifest later in life. Individuals with this disease can be treated with fibrinogen replacement therapy, which might require frequent injections and monitoring of blood fibrinogen levels. Treatment can be preventive (prophylaxis) or can be administered when the individual has episodes of bleeding (symptomatic treatment). Congenital afibrinogenemia affects approximately 1/ 1 000 000 people worldwide and is transmitted in an autosomal recessive pattern.
Congenital afibrinogenemia is a hereditary fibrinogen abnormality, a rare category of bleeding disorder that can affect the quantity or quality of fibrinogen, a blood coagulation factor. Afibrinogenemia and hypofibrinogenemia respectively refer to the absence and reduced levels of fibrinogen in the blood. Dysfibrinogenemia and hypodysfibrinogenemia are fibrinogen abnormalities where the blood levels of fibrinogen are normal (in dysfibrinogenemia) or reduced (in hypodysfibrinogenemia), but the coagulation factor is modified in a way that makes it unable to function normally or optimally. When symptomatic, hereditary fibrinogen abnormalities have similar symptoms. Congenital afibrinogenemia patients are more likely to have symptoms and to experience severe bleeding episodes . Diagnosis can often be made at birth because most affected infants have severe umbilical cord bleeding. Early diagnosis of congenital afibrinogenemia can allow treatment initiation and prevent individuals from having severe bleeding episodes, particularly bleeding inside the skull (intracranial hemorrhage), which can lead to disability and death .
The absence of fibrinogen in the circulating blood of individuals with congenital afibrinogenemia makes them unable to effectively coagulate their blood, leading to prolonged bleeding. Bleeding episodes can be spontaneous or due to minor trauma and can happen anywhere in the body, including the skin, nose, oral cavity, gastrointestinal tract, liver, genital and urinary (genitourinary) tract and central nervous system [1, 3-6]. Symptoms begin to show at birth with umbilical cord bleeding in around 85% of individuals . Bleeding might also be noticed in the stools or vomit of newborns.
Intracranial hemorrhage is a leading cause of death and disability in affected individuals. Signs of intracranial hemorrhage include vomiting, dizziness, headache, confusion and seizures. Patients can suffer from long term sequelae such as psychomotor impairment after an episode of bleeding inside the skull .
Joint bleeding (hemarthrosis) might cause pain and limit movement. Most severe cases of joint bleeding might require total joint replacement (arthroplasty) . Pain and movement limitation can also happen from accumulation of blood (hematoma) in muscles. Some patients also experience bleeding in the bones (interosseous hemorrhage) after minimal trauma. Formation of bone cysts containing blood can happen, particularly in long bones, and cause bone pain.
Women are at increased risk for vaginal bleeding and increased blood loss during menstruation (menometrorrhagia) and tend to have recurrent miscarriages. Women who receive treatment might be able to give birth but might suffer from prolonged bleeding after delivering (postpartum hemorrhage) .
Other symptoms related to congenital afibrinogenemia include an increased risk of spontaneous rupture of the spleen, poor wound healing, and formation of unstable clots that can lodge in blood vessels and occlude them (embolus). Indeed, even without fibrinogen in their blood, affected individuals are able to form clots via the action of other coagulation factors, namely von Willebrand factor and thrombin. However, these clots are loose and have a tendency to disseminate in the body. They can then occlude the blood vessels in the lungs (pulmonary embolism), in the brain (ischemic stroke) or in the heart (coronary embolism) and cause severe consequences, including death. [3, 10]
Absence of fibrinogen in the blood is a result of mutations in one of three genes, known as the fibrinogen alpha-chain (FGA), beta-chain (FGB), and gamma-chain (FGG) genes [11-14].
Mutations in FGA, FGB and FGG can affect blood levels of fibrinogen in multiple ways. Some mutations impair fibrinogen synthesis by preventing the DNA from being read properly. Other mutations affect the fibrinogen protein itself, either by impairing its synthesis, its secretion, or the fusion of the different subunits of the protein. In all cases, the final result is the same: fibrinogen is absent from the blood. As the conversion of fibrinogen to fibrin is one of the crucial steps of blood coagulation (coagulation cascade), its absence severely impairs clot formation and can lead to episodes of prolonged bleeding. Clot formation is still possible via other coagulation factors known as von Willebrand factor and thrombin, but these clots are loose and ineffective. They tend to detach and can lodge in blood vessel and occlude them (embolus), which can lead to major consequences (thromboembolic complications).
Congenital afibrinogenemia follows an autosomal recessive inheritance pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Congenital afibrinogenemia is a very rare disorder that affects approximately one in a million people. Males and females are equally affected. There doesn’t seem to be any ethnic predisposition to this disease [6, 15]. However, as it is an autosomal recessive disorder, children whose parents are blood relatives (consanguineous) are more at risk. Indeed, individuals from the same family are more likely to have the same rare mutation and can have an affected child if he or she inherits the mutation from both parents. Therefore, the disease is more common in areas with high rates of consanguineous marriage, such as the Middle East and Southern India .
Diagnosis of congenital afibrinogenemia is made with a combination of blood coagulation tests, tests that measure blood levels of fibrinogen, and genetic testing. The presence of this disorder can be suspected in newborns with severe umbilical cord bleeding and in infants and children with severe and persistent bleeding episodes.
In a patient with congenital afibrinogenemia, all the coagulation tests that rely on fibrin (the product of the conversion of fibrinogen) will be infinitely prolonged. These tests include thrombin time (TT), prothrombin time (PTT), activated partial thromboplastin time (aPTT) and reptilase time. Tests to measure levels of fibrinogen, including the Clauss method and ELISA, will not detect any fibrinogen in the circulating blood [11, 15, 17]. Genetic testing of the parents and affected individual (proband) is used to detect disease-causing (pathogenic) mutations in the FGA, FGB, and FGY genes .
Individuals with congenital afibrinogenemia need to be treated with fibrinogen replacement therapy. Fresh frozen plasma and blood product made from plasma (cryoprecipitate) may be injected to replace fibrinogen. However, fibrinogen concentrates are the best option, as they have a faster onset, a greater dosing flexibility, are easier to administrate and are safer, as they are less likely to be contaminated with viruses than fresh frozen plasma and cryoprecipitate [1, 15, 18]. The goal of the treatment is to restore and maintain normal fibrinogen levels.
Depending on the patient’s needs, treatment can be given weekly or bi-weekly in prevention of bleeding (primary prophylaxis), after bleeding episodes to prevent recurrence (secondary prophylaxis) or as soon as bleeding starts (on demand). Primary prophylaxis is essential for pregnant women to avoid miscarriage [15, 19-21].
In some patients, fibrinogen replacement therapy might provoke the formation of unstable clots that will detach and disseminate throughout the body, potentially occluding blood vessels (thromboembolic complications). These patients should be administered an anticoagulant with their treatment, preferably low-molecular-weight heparin [18, 22].
For less severe bleeding episodes, patients can be given amino acids that prevent clot dissolution (antifibrinolytic amino acids), namely epsilon-aminocaproic acid and tranexamic acid. The major advantage of this treatment is that it is non-injectable .
Genetic counseling is recommended for patients and their families. Other treatment is symptomatic and supportive and include joint replacement surgery (arthroplasty) after joint damage due to excessive bleeding (hemarthrosis) and neurosurgical interventions to control severe bleeding inside the skull (intracranial hemorrhage).
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