• Disease Overview
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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Congenital Afibrinogenemia

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Last updated: 04/24/2023
Years published: 1993, 1999, 2007, 2018, 2023


Acknowledgment

NORD gratefully acknowledges Etienne Leveille, MD 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.


Disease Overview

Summary
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 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 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 is genetic disease that follows an autosomal recessive inheritance pattern.

Introduction
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 it does not 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 and early treatment can prevent severe bleeding episodes, particularly bleeding inside the skull (intracranial hemorrhage), which can lead to disability and death.

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Signs & Symptoms

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 tract and central nervous system. 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 problems such as psychomotor impairment after an episode of bleeding inside the skull.

Joint bleeding (hemarthrosis) might cause pain and limit movement. 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). Even without fibrinogen in their blood, affected individuals can form clots via the action of other coagulation factors, namely von Willebrand factor and thrombin. However, these clots are loose and tend to disseminate in the body. They can then occlude the blood vessels in the lungs (pulmonary embolism), brain (ischemic stroke) or heart (coronary embolism) and cause severe consequences, including death.

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Causes

Absence of fibrinogen in the blood is caused by changes (pathogenic variants or mutations) in one of three genes, known as the fibrinogen alpha-chain (FGA), beta-chain (FGB), and gamma-chain (FGG).

Variants in FGA, FGB and FGG can affect blood levels of fibrinogen in multiple ways. Some impair fibrinogen synthesis by preventing the DNA from being read properly. Others 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 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 vessels 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 altered 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 altered 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.

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Affected populations

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. 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 gene variant and can have an affected child if they inherit the pathogenic variant 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.

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Diagnosis

Diagnosis of congenital afibrinogenemia is made with a combination of blood coagulation tests, tests that measure blood levels of fibrinogen, and genetic testing. The 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. Genetic testing of the parents and affected individual is used to detect disease-causing pathogenic variants in the FGA, FGB, and FGG genes.

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Standard Therapies

Treatment
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, 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. 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.

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.

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 includes 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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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

Valiton V, Hugon-Rodin J, Fontana P, Neerman-Arbez M, Casini A. Obstetrical and postpartum complications in women with hereditary fibrinogen disorders: A systematic literature review. Haemophilia. 2019;25(5):747-754. doi:10.1111/hae.13825

Neerman-Arbez M and Casini A. Clinical Consequences and Molecular Bases of Low Fibrinogen Levels. Int J Mol Sci. 2018; 19(1).

Ross C, et al. Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency. J Thromb Haemost. 2018; 16(2): 253-261.

Tabibian S, et al. Prenatal diagnosis in rare bleeding disorders-An unresolved issue? Int J Lab Hematol. 2018; 40(3): 241-250.

Undas A. Determination of fibrinogen and thrombin Time (TT). Methods Mol Biol. 2017; 1646: 105-110.

Casini A, de Moerloose P and Congenital Fibrinogen Disorders Group. Management of congenital quantitative fibrinogen disorders: a Delphi consensus. Haemophilia. 2016; 22(6): 898-905.

Casini A, de Moerloose P, Neerman-Arbez M.Clinical Features and Management of Congenital Fibrinogen Deficiencies. Semin Thromb Hemost. 2016; 42(4): 366-74.

Malaquin S, et al. Congenital afibrinogenemia: a case report of a spontaneous hepatic hematoma. Medicine (Baltimore). 2016; 95(28): e4150.

Neerman-Arbez M, de Moerloose P and Casini A. Laboratory and genetic investigation of mutations accounting for congenital fibrinogen disorders. Semin Thromb Hemost. 2016; 42(4): 356-65.

Negrier C, et al. post-authorization safety study of Clottafact((R)), a triply secured fibrinogen concentrate in congenital afibrinogenemia. A prospective observational study. Vox Sang. 2016; 111(4): 383-390.

Chapin J. and DeSancho M. Pulmonary embolism in a patient with congenital afibrinogenemia. Haemophilia. 2013; 19(6): e380-2.

de Moerloose P, Casini A, and Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost. 2013; 39(6): 585-95.

Peyvandi F, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012; 10(4): 615-21.

Peyvandi F. Epidemiology and treatment of congenital fibrinogen deficiency. Thromb Res. 2012; 130 Suppl 2: S7-11.

Siboni SM, et al. Central nervous system bleeding in patients with rare bleeding disorders. Haemophilia. 2012; 18(1): 34-8.

Bornikova, L., et al., Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost. 2011; 9(9): 1687-704.

ReidyK, Brand B, and Jost B. Severe elbow arthropathy in a patient with congenital afibrinogenemia: a case report. J Bone Joint Surg Am. 2010; 92(2): 456-8.

de Moerloose P and Neerman-Arbez M. Treatment of congenital fibrinogen disorders. Expert Opin Biol Ther. 2008; 8(7): 979-92.

Peyvandi F and Spreafico M. National and international registries of rare bleeding disorders. Blood Transfus. 2008; 6 Suppl 2: s45-8.

Vu D and Neerman-Arbez M. Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins. J Thromb Haemost. 2007; 5 Suppl 1: 125-31.

Peyvandi F, et al. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost. 2006; 4(7): 1634-7.

Vu D, et al. Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion. Blood. 2003; 102(13): 4413-5.

Neerman-Arbez M, et al. Mutations in the fibrinogen Aalpha gene account for the majority of cases of congenital afibrinogenemia. Blood. 2000; 96(1): 149-52.

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