What are the other Names for this Condition? (Also known as/Synonyms)

• F I Deficiency
• Factor 1 Deficiency
• Fibrinogen Deficiency

What is Factor I Deficiency? (Definition/Background Information)

• Factor I Deficiency encompasses a group of extremely rare disorders arising from a deficiency of the protein fibrinogen in blood. Fibrinogen, or factor I, is a blood plasma protein generated by the liver
• Factor I (F I or factor 1) is one of the 12 clotting factors that are labeled factors I to XIII (factors V and VI actually denote the same clotting factor)
• Clotting factors are proteins that help form blood clots at the site of a blood vessel injury. A blood clot stops further blood loss and allows the blood vessel to continue functioning
• Factor I Deficiency can either be quantitative (due to reduced levels of fibrinogen) or qualitative (from a dysfunctional protein that is present in normal levels)
• It is classified into 3 major groups, as given below:
  • Afibrinogenemia, which indicates a complete absence of fibrinogen (quantitative type)
  • Hypofibrinogenemia, indicating reduced amounts of fibrinogen (quantitative type)
  • Dysfibrinogenemia, in which fibrinogen is present in normal levels, but are functionally defective (qualitative type)
• The symptoms may depend upon the type of Factor I Deficiency. The affected individuals may be symptomatic; or, they may have skin, mucous membrane, or gastrointestinal bleeding, as well as present abnormal bleeding during surgery or post-trauma
• Women may experience severe bleeding during menses, have additional complications during and after pregnancy. In such cases, there is also an increased risk of miscarriages
• Treatment for Factor I Deficiency involves fibrinogen supplementation. If complications, such as thrombosis develop, the prognosis may be guarded

Who gets Factor I Deficiency? (Age and Sex Distribution)

• Factor I Deficiency is extremely rare and about 200 cases have been reported in medical literature
• The following are the frequencies of occurrence of the various subtypes:
  • Afibrinogenemia - 1:2,000,000
  • Hypofibrinogenemia - less than 1:2,000,000 (more frequently seen than Afibrinogenemia)
  • Dysfibrinogenemia - is the more common type at 1:1,000,000
• Individuals of all ages may be affected by this disorder. Typically, Afibrinogenemia is diagnosed soon after birth
• Both males and females are affected by the disorder

What are the Risk Factors for Factor I Deficiency? (Predisposing Factors)

The following are some known risk factors for Factor I Deficiency:

• Having a family history of the deficiency disorder
• Children of parents who are close blood relatives (such as first cousins) may have an increased risk
• Liver disease

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Factor I Deficiency? (Etiology)

Congenital Factor I Deficiency is caused by mutation(s) in FGA, FGB, or FGG genes, which code for the alpha, beta, and gamma chains of fibrinogen protein, respectively.

• Factor I Deficiency can either be quantitative or qualitative. The disorder is classifies into three types, based on the amount of fibrinogen present and its function
  • Afibrinogenemia denotes a complete absence of fibrinogen protein in blood. This is termed as quantitative Factor I Deficiency
  • In Hypofibrinogenemia, the amount of fibrinogen is below the levels required for normal clotting. This type of disorder is also termed as quantitative Factor I Deficiency
  • Even though the amount of fibrinogen in Dysfibrinogenemia is normal, the function of these glycoproteins is compromised. It represents the qualitative subtype of Factor I Deficiency
• Afibrinogenemia is inherited in an autosomal recessive manner, whereas Hypofibrinogenemia and Dysfibrinogenemia are inherited in an autosomal dominant pattern
• Additionally, in rare instances, acquired Factor I Deficiency, particularly Dysfibrinogenemia, can be caused by liver disease or obstructive jaundice

Autosomal recessive inheritance: In this type of inheritance, an individual must possess both copies of a causative gene in the mutated form in every cell or his/her body, for the disorder to manifest itself. An affected individual inherits a defective copy of the gene from each parent. The parents themselves are typically unaffected and are known as the “carriers” of the disorder.

Autosomal dominant inheritance: In this type of inheritance, a single defective copy of the causative gene in every cell of an individual is sufficient to cause the disorder. An affected individual inherits the disorder from an affected parent.

The following is the sequence of events that lead to blood clotting:

• The clotting process starts with injury to a blood vessel, which causes it to constrict. Called the vascular phase, this is the first reaction of a blood vessel to damage. Constriction of a blood vessel reduces the flow of blood to the site of injury, which minimizes blood loss
• Next, the circulating platelets clump along the site of blood vessel injury. The platelets form a foundation for a blood clot and release chemicals that stimulate clotting
• The coagulation phase then causes a blood clot to form. Clotting occurs when an enzyme, called thrombin, converts a soluble protein fibrinogen, into its insoluble form, fibrin. Fibrin proteins make up the bulk of a blood clot
• Thrombin is activated by the merging of two pathways, called the intrinsic and extrinsic pathways, into the common pathway. These are initiated by different parts of the body after blood vessel damage:
  • The intrinsic pathway begins in blood with the activation of circulating proteins
  • The extrinsic pathway begins in the blood vessel with the release of protein factors by damaged cells lining the vessel
• The extrinsic pathway is the first to activate. The intrinsic pathway then reinforces the extrinsic pathway and provides longer-lasting clotting effects
• Coagulation factors, such as factor XII, are central to the action of these pathways. Each factor activates the next in a stepwise manner
• Factor I is situated in the common pathway of the clotting mechanism, and is crucial to the clotting process
• When the FGA, FGB, or FGG genes are mutated, the formation of the fibrinogen glycoprotein is compromised, leading to abnormal clotting and consequent bleeding disorders
• Any damage or dysfunction of the liver, which is the site of fibrinogen synthesis, can also lead to decreased fibrinogen polymerization, causing acquired Factor I Deficiency

What are the Signs and Symptoms of Factor I Deficiency?

The signs and symptoms of Factor I Deficiency may vary in type, severity, and duration between bleeding episodes. The signs and symptoms also depend on the type of Factor I Deficiency one has inherited. While some of those affected may be asymptomatic, others may present with severe bleeding signs and symptoms.

The signs and symptoms of Afibrinogenemia, occurring due to a complete lack of fibrinogen, may be apparent soon after birth. The manifestation of Hypofibrinogenemia and Dysfibrinogenemia are dependent on the amount of functional fibrinogen present in an individual.

The signs and symptoms of Factor I Deficiency may include:

• Bleeding from the umbilical cord soon after birth (characteristic of Afibrinogenemia)
• Severe bleeding following circumcision (characteristic of Afibrinogenemia)
• Nosebleeds
• Bleeding from the gums
• Easy bruising; spreading of the bruised area
• Redness and pain in the bruised region, which may increase over time
• Intracranial bleeding, or bleeding in the head, with symptoms such as:
  • Headaches
  • Nausea
  • Loss of balance
  • Fainting spells
• Bleeding in the neck region along with:
  • Pain
  • Swelling in throat
  • Swallowing and breathing difficulties
• Bleeding in the chest, with symptoms such as:
  • Chest pain
  • Cough
  • Bloody sputum
• Bleeding in the gastrointestinal tract, which may manifest as:
  • Abdominal pain
  • Nausea
  • Blood in stools
• Rupture of spleen causing symptoms that include:
  • Abdominal swelling
  • Left shoulder pain
  • DizzinessConfusion
• Bleeding in the urinary tract, causing blood in urine
• Bleeding in the joints, causing:
  • Swelling of joints
  • Pain, even while at rest
  • Pain with movement
  • Decreased range of motion
• Excessive bleeding after trauma
• Abnormal bleeding during (minor) surgery or dental procedures

The following additional symptoms are observed in women with Factor I Deficiency. The severity of signs and symptoms may depend on the type of Factor I Deficiency:

• Heavy bleeding during menstruation
• Vaginal bleeding during pregnancy
• Abdominal pain
• Premature labor
• Excessive bleeding during and after delivery

How is Factor I Deficiency Diagnosed?

The diagnosis of Factor I Deficiency is made on the basis of the following tools:

• A complete physical examination
• Assessment of signs and symptoms
• Evaluation of one’s personal and family medical history
• Blood tests that include:
  • Complete blood count (CBC)
  • Serum prothrombin or PT time test
  • Partial thromboplastin time (PTT) test
  • Testing abnormalities in fibrinogen with prolonged reptilase time
  • Checking for levels of fibrinogen using antibodies (immunological assay)
  • Checking for activity of fibrinogen using specific clotting assays
  • Liver function test
• Molecular genetic testing, if a family history of Factor I Deficiency exists

Relevant information:

• The normal level of fibrinogen in blood is in the range of 2-4 grams/liter
• Fibrinogen levels in individuals with various types of Factor I Deficiency are as follows:
  • Afibrinogenemia: Less than 0.2 grams/liter
  • Hypofibrinogenemia: Between 0.2-0.8 grams/liter
  • Dysfibrinogenemia: Normal, between 2-4 grams/liter

Note:

The normal values, called the reference range, may vary from lab to lab. Hence, most lab reports come with a reference range, which is used in that particular center. A physician interprets the results based on the reference values provided.

Certain medications that one is currently taking may influence the outcome of the lab tests. Hence, it is important to inform the healthcare provider of the complete list of medications (including any herbal supplements) one is taking. This will help the healthcare provider interpret the test results more accurately and avoid unnecessary chances of a misdiagnosis.

The laboratory test results are NOT to be interpreted as results of a “stand-alone” test. The test results have to be interpreted after correlating with suitable clinical findings and additional supplemental tests/information. The healthcare providers will explain the meaning of the test results, based on the overall clinical scenario.

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.

What are the possible Complications of Factor I Deficiency?

The potential complications of Factor I Deficiency may include:

• Pain in joints leading to reduced mobility
• Clumsiness; increased risk of falls 
• Convulsions
• Miscarriages in pregnant women
• Thrombosis or localized clotting of blood within the blood vessels

Complications due to treatment may include:

• Increased risk of allergies when treated with plasma or cryoprecipitate, which may contain substances other than fibrinogen
• Increased risk of pathogenic viral transmission from treatment with human blood products

How is Factor I Deficiency Treated?

• Factor I Deficiency is generally treated with fibrinogen concentrate. This concentrate is derived from human blood and contains the protein fibrinogen
• This treatment may be given in the following situations:
  • Following trauma
  • Before an invasive dental procedure
  • Before surgery
  • Before childbirth (in pregnant women)
  • To prevent bleeding in individuals who have no functional fibrinogen (Afibrinogenemia)
• In addition, blood plasma and cryoprecipitate (a blood product that is rich in blood clotting factor) may also be used for treatment of Factor I Deficiency
• If Factor I Deficiency is acquired due to a liver disorder or obstructive jaundice, treatments pertaining to the particular predisposing condition is necessary

How can Factor I Deficiency be Prevented?

• At the present time, there are no methods or guidelines for the prevention of Factor I Deficiency, since it is predominantly an inherited disorder
• The following steps may be considered to minimize bleeding in those with this blood disorder:
  • Avoiding aspirin, since it can increase the tendency for bleeding
  • Informing a healthcare professional about one’s coagulation status, before a dental procedure or surgery (even if it is a minor procedure)
  • Wearing a bracelet regarding one’s coagulation status, for alerting others
  • Wearing suitable protective gear, so as to minimize injuries
  • Proper prenatal care and prophylactic fibrinogen treatment for affected pregnant women, so as to prevent miscarriage
  • Treatment with fibrinogen during and after delivery in pregnant women
  • Being aware of symptoms, and seeking prompt medical attention for symptoms of bleeding in the head, neck, chest and abdominal regions
• Immediately seeking medical attention for treatment of liver conditions known to cause acquired Factor I Deficiency
• 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 genetic disorders such as Factor I Deficiency

Regular medical screening at periodic intervals with tests and physical examinations are strongly recommended in individuals who have been diagnosed with the condition.

What is the Prognosis of Factor I Deficiency? (Outcomes/Resolutions)

The prognosis of Factor I Deficiency is determined by the subtype of the condition, the severity of symptoms, overall health of the individual, and one’s response to treatment.

• If diagnosed early and treated promptly, the condition may be managed efficiently
• However, severe bleeding can cause thrombosis (localized clotting of blood in certain regions of the body), which may be life-threatening in some cases
• Delaying treatment during pregnancy may result in miscarriage

Additional and Relevant Useful Information for Factor I Deficiency:

Please visit our Blood Disorders Health Center for more physician-approved health information:

https://www.dovemed.com/diseases-conditions/blood-disorders/