Congenital Afibrinogenemia

Congenital afibrinogenemia is a rare, genetically inherited Blood fibrinogen disorder in which the blood does not clot normally due to the lack of fibrinogen, a blood protein necessary for coagulation. Congenital afibrinogenemia is a Bleeding disorder caused by 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 with this condition often experience prolonged bleeding from the umbilical cord stump after birth.

Nosebleeds (epistaxis) and bleeding from the gums or tongue are common and can occur after minor trauma or in the absence of injury (spontaneous bleeding). Some affected individuals experience bleeding into the spaces between joints (hemarthrosis) or the muscles (hematoma). Rarely, bleeding in the brain or other internal organs occurs, which can be fatal.

Women with congenital afibrinogenemia can have abnormally heavy menstrual bleeding (menorrhagia). Without proper treatment, women with this disorder may have difficulty carrying a pregnancy to term, resulting in repeated miscarriages.

In afibrinogenemia, with fibrinogen levels less than 0.1 g/L, bleeding abnormalities range from mild to severe. Bleeding from the umbilical cord just after birth frequently provides an early alert to the abnormality.

Other symptoms include the following:

• Nosebleeds that are difficult to stop
• Bleeding in the mucus membranes
• Bleeding in the joints
• Bruising easily
• Gastrointestinal bleeding
• Menorrhagia and postpartum hemorrhage
• Heavy bleeding after injury or surgery
• Spontaneous rupture of the spleen
• Bleeding inside the skull (intracranial hemorrhage) – very rare
• Miscarriage

Congenital Afibrinogenemia is a rare disorder characterized by absence of a certain substance (protein) in the blood that is essential in the blood clotting (coagulation) process. This protein is known as fibrinogen or coagulation factor I. Affected individuals may be susceptible to severe bleeding (hemorrhaging) episodes, particularly during infancy and childhood. Congenital Afibrinogenemia is thought to be transmitted as an autosomal recessive trait.

Congenital abnormalities of fibrinogen are divided into 2 types: type I, or quantitative abnormalities (afibrinogenemia and hypofibrinogenemia), and type II, or qualitative abnormalities (dysfibrinogenemia and hypodysfibrinogenemia).

Afibrinogenemia and hypofibrinogenemia are quantitative defects in fibrinogen (type I), which result from mutations that affect plasma fibrinogen concentration inherited on both chromosomal alleles and are frequently associated with a bleeding diathesis but occasionally a thrombotic event. Dysfibrinogenemia is a qualitative defect in fibrinogen (type II) marked by functional abnormalities of fibrinogen who carry one abnormal allele that may result in either bleeding or thrombosis.

Congenital Afibrinogenemia is a very rare, genetic disorder that causes abnormal excessive bleeding. It is inherited in an autosomal recessive manner.

Fibrinogen is a 340-kD glycoprotein that is synthesized in the liver and circulates in plasma at a concentration of 2-4 g/L, with a half-life of 4 days. The fibrinogen molecule is a hexamer, consisting of 3 paired polypeptide chains: A-α, B-β, and γ; A and B refer to specific polypeptides on 2 of the chains. Synthesis of the protein in hepatocytes is under the control of 3 genes (one for each chain), FGA, FGB, and FGG, located within 50 kilobases (kb) on chromosome 4.

Normally, the protein fibrinogen is one of the proteins that allows for blood to clot following an injury. The formed blood clot closes (seals) the damaged blood vessels and prevents further blood loss. Individuals with Congenital Afibrinogenemia lack this protein, leading to excessive blood loss.

Babies with this condition are most commonly present with abnormal umbilical cord bleeding at birth. Other signs and symptoms may also include bleeding into the skin, gums, tongue, joints, nosebleeds, gastrointestinal tract (blood in the stools and vomit), or central nervous system bleeding.

Treatment options are available, but they cannot bring about a cure; rather, they help replace the absent fibrinogen. The prognosis of Congenital Afibrinogenemia is usually favorable, if the bleeding episodes are treated promptly. These individuals may have a fatal bleed, if the condition is left untreated.

Comparison of the electrophoretic patterns of afibrinogenemic plasma and serum confirmed the fact that except for fibrinogen no other clotting factor is detectable by routine electrophoretic analysis. This is due to the extremely small concentration of these entities when compared with the value of total serum proteins.

On the basis of family studies the hereditary pattern of congenital afibrinogenemia is assumed to be recessive and not sex-linked.

Causes

This rare disease is due to an abnormal gene that causes a complete lack of fibrinogen. The gene must be passed down from both parents.

Congenital afibrinogenemia can occur in males or females.

Milder forms can occur in people who inherit only one abnormal gene from their parents.

This rare disease is caused by an abnormal gene that causes a severe lack of fiborgen. The gene must be passed down from both parents.

Milder forms can occur in people who inherit only one abnormal gene from their parents. Congenital afibrinogenemia can occur in males or females. The main risk factor is a family history of bleeding disorders.

A missense or nonsense mutation to the genes that code for the fibrinogen protein are affected. Usually the mutation leads to an early stop in the production of the protein.Due to the problem being genetically based, there is no way to prevent the disease.

Individuals can get genetic testing done to see if they are a carrier of the trait, and if so may choose to complete genetic counseling to better understand the disorder and help manage family planning. Parents can choose to do prenatal genetic testing for the disorder to determine if their child will have the disease.

Afibrinogenemia is caused by a severe lack of fibrinogen, a protein in the blood that is essential in the blood clotting (coagulation) process.This defect in fibrinogen synthesis can result from mutations in one or another of the fibrinogen genes alpha (FGA), beta (FGB) or gamma (FGG).Each of these three genes provides instructions for making one part (subunit) of the fibrinogen protein. When an injury occurs, fibrinogen is converted to fibrin, the main protein in blood clots.

Fibrin proteins attach to each other, forming a stable network that makes up the blood clot. If there is a mutation in the FGA, FGB or FGG gene, the respective subunit is not made and the fibrinogen protein cannot be assembled. This results in the absence of fibrin, so blood clots cannot form, leading to the excessive bleeding seen in people with afibrinogenemia.

Congenital Afibrinogenemia is thought to be transmitted as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms.

The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Absence or deficiency of fibrinogen is thought to result from abnormal changes (mutations) of one of three genes, known as the fibrinogen alpha-chain (FGA), beta-chain (FGB), or gamma-chain (FGG) genes. These genes have been mapped to the long arm (q) of chromosome 4 (4q28). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual.

Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered.

According to one team of researchers, genetic analysis of individuals with congenital afibrinogenemia within one extended family (i.e., including two siblings and two first cousins) revealed deletion of genetic material from the fibrinogen alpha-chain gene (FGA) on both chromosomes (homozygous deletion). Because previous studies have not detected this homozygous deletion, the study’s researchers indicate that other genetic abnormalities (mutations) may play some role in causing the disorder in some affected individuals.

Symptoms

Symptoms may include any of the following:

• Bruising easily
• Bleeding from the umbilical cord just after birth
• Bleeding in the mucus membranes
• Bleeding in the brain
• Bleeding in the joints
• Heavy bleeding after injury or surgery
• Nosebleeds that do not stop easily
• Bruising
• Bleeding from the umbilical cord just after birth
• Bleeding in joints
• Excessive bleeding after injury or surgery
• Nosebleeds that are difficult to stop
• Bleeding in the mucus membranes
• Bruising easily
• Gastrointestinal bleeding
• Menorrhagia and postpartum hemorrhage
• Heavy bleeding after injury or surgery
• Spontaneous rupture of the spleen
• Bleeding inside the skull (intracranial hemorrhage) – very rare
• Miscarriage

Treatment

There is no known prevention or cure for afibrinogenemia.To treat bleeding episodes or to prepare for surgery to treat other conditions, patients may receive:

• The liquid portion of the blood (plasma)
• Fibrinogen (RaiSTAP)
• A blood product containing concentrated fibrinogen (cryoprecipitate) through a vein (transfusion)

Prophylactic therapy should also be considered for patients with recurrent bleeding episodes, CNS hemorrhage, or during pregnancy for women with recurrent miscarriage.

Individuals with afibrinogenemia should consider the following as part of their management plan:

Consultation with a hematologist/hemostasis specialist, particularly for patients who require fibrinogen replacement therapy.

Genetic counseling and family studies, especially for individuals with extensive family history or those considering pregnancy.

Follow-up by a comprehensive bleeding disorder care team experienced in diagnosing and managing inherited bleeding disorders.

Vaccination with the hepatitis B vaccine because transfusion increases the risk of hepatitis.

Exams And Tests

If your health care provider suspects this problem, you will have lab tests to confirm the type and severity of the disorder.

This disorder usually shows up in children, often at birth.

Tests include:

• Bleeding time
• Fibrinogen levels
• Partial thromboplastin time (PTT)
• Prothrombin time (PT)
• Reptilase time
• Thrombin time

You will have abnormal results on all of these tests if you have the disorder.

Related Disorders

Symptoms of the following blood clotting disorders can be similar to those of Congenital Afibrinogenemia. Comparisons may be useful for a differential diagnosis:

Factor IX Deficiency is a severe genetic bleeding disorder that resembles classic Hemophilia A. Factor IX is a component of the blood clotting substance thromboplastin. It is deficient at birth in patients with this disorder. Factor IX Deficiency varies in severity between families and occurs most often among males. In rare instances, female carriers have been known to exhibit this deficiency in a mild form. Symptoms include prolonged bleeding episodes, and in very severe cases, joint pain and bone deformities.

Factor XIII Deficiency is a very rare inherited disorder that prevents the blood from clotting normally. The lack of clotting factor XIII can cause slow, oozing internal bleeding which may begin several days after even a mild trauma, such as a bump or bruise. The bleeding may persist so that large cysts form in the tissue spaces, destroying the surrounding bone and causing peripheral nerve damage. This typically occurs in the thigh and buttocks area

Hageman Factor Deficiency is a rare genetic blood disorder. It is caused by a lack in activity of the Hageman factor in blood plasma, a single-chain glycoprotein which is also called Factor XII. This factor is needed for blood clotting. However, when it is deficient, other blood clotting factors tend to compensate for Factor XII. This disorder usually presents no symptoms and is only accidentally discovered through pre-operative blood tests that are required by hospitals. (For more information on this disorder, choose “Hageman Factor Deficiency” as your search term in the Rare Disease Database.)

Hemophilia is a hereditary blood clotting disorder which affects males almost exclusively. Hemophilia is caused by the inactivity of one of the blood proteins necessary (usually Factor VIII) for clotting and can be classified by its level of severity, mild, moderate, and severe. Severity is determined by the percentage of active clotting factor in the blood

Von Willebrand Disease is a hereditary blood clotting disorder characterized by prolonged bleeding. Blood clotting is slow due to a deficiency of the Von Willebrand factor protein and factor VIII protein (the factor VIII complex). Also, platelets do not stick normally causing excessively slow clotting time. Increased risk of excessive bleeding following surgery, dental procedures or injury occurs in patients with this disorder. With proper treatment and appropriate precautions, few patients become seriously handicapped by Von Willebrand Disease. The tendency to prolonged bleeding usually decreases with age.

Standard Therapies

Patients with Congenital Afibrinogenemia may be treated with infusions of cryoprecipitate concentrates. This is prescribed to raise the fibrogen level in the blood permitting clots to form.

Fibrogen concentrates may be given but there is a risk of contracting an infectious disorder. Cryoprecipitate is the preferred treatment.

Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.

How is Congenital Afibrinogenemia Diagnosed?

The following procedures may be used to diagnose Congenital Afibrinogenemia:

Thorough evaluation of the individual’s medical (and family) history and a complete physical examination including of the skin, joint, muscle, etc.

During history-taking the physicians may want to know the following:

When the symptoms began and whether they are becoming worse

List of prescription and over-the-counter medications currently being taken

One’s personal and family history of bleeding disorders, associated illnesses, etc.

Hematologist consultation is often necessary, as they are the experts in dealing with bleeding disorders

Often, the healthcare provider will perform certain blood tests to help determine the severity of the condition. These tests include:

Fibrinogen levels are absent or very minimal in Congenital Afibrinogenemia

All of the following tests are prolonged in Congenital Afibrinogenemia:

• Prothrombin time (PT)
• Activated partial thromboplastin time (aPTT)
• Thrombin time
• Reptilase time
• Bleeding time

If the above tests are shown to be positive, then genotyping (examination for gene mutation) may also be performed to confirm the diagnosis

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

How can Congenital Afibrinogenemia be Prevented?

Currently, there are no specific methods or guidelines to prevent Congenital Afibrinogenemia, since it is a genetic condition

Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy

If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child

Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Congenital Afibrinogenemia?

Excessive bleeding is common in individuals with Congenital Afibrinogenemia. If bleeding episodes remain untreated, it may result in fatalities

Bleeding in the brain is the main cause of death in individuals diagnosed with Congenital Afibrinogenemia

With early detection and appropriate treatment of the condition, bleeding episodes can be controlled and fatal complications potentially avoided.

Calling your health care provider

Call your health care provider or seek emergency care if you have excessive bleeding.

Tell your surgeon before you have surgery if you know or suspect you have a bleeding disorder.

Prevention

There is no known prevention. Couples who are thinking about having children may find genetic counseling helpful if at least one partner has this condition.

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