Factor XIII deficiency is a rare bleeding disorder. Researchers have identified an inherited form and a less severe form that is acquired during a person's lifetime.

Signs and symptoms of inherited factor XIII deficiency begin soon after birth, usually with abnormal bleeding from the umbilical cord stump. If the condition is not treated, affected individuals may have episodes of excessive and prolonged bleeding that can be life-threatening. Abnormal bleeding can occur after surgery or minor trauma. The condition can also cause spontaneous bleeding into the joints or muscles, leading to pain and disability. Women with inherited factor XIII deficiency tend to have heavy or prolonged menstrual bleeding (menorrhagia) and may experience recurrent pregnancy losses (miscarriages). Other signs and symptoms of inherited factor XIII deficiency include nosebleeds, bleeding of the gums, easy bruising, problems with wound healing, bleeding after surgery, and abnormal scar formation. Inherited factor XIII deficiency also increases the risk of spontaneous bleeding inside the skull (intracranial hemorrhage), which is the leading cause of death in people with this condition.

Acquired factor XIII deficiency becomes apparent later in life. People with the acquired form are less likely to have severe or life-threatening episodes of abnormal bleeding than those with the inherited form.

Inherited factor XIII deficiency affects 1 to 3 per million people worldwide. Researchers suspect that mild factor XIII deficiency, including the acquired form of the disorder, is underdiagnosed because many affected people never have a major episode of abnormal bleeding that would lead to a diagnosis.

Inherited factor XIII deficiency results from mutations in the F13A1 gene or, less commonly, the F13B gene. These genes provide instructions for making the two parts (subunits) of a protein called factor XIII. This protein plays a critical role in the coagulation cascade, which is a series of chemical reactions that forms blood clots in response to injury. After an injury, clots seal off blood vessels to stop bleeding and trigger blood vessel repair. Factor XIII acts at the end of the cascade to strengthen and stabilize newly formed clots, preventing further blood loss.

Mutations in the F13A1 or F13B gene significantly reduce the amount of functional factor XIII available to participate in blood clotting. In most people with the inherited form of the condition, factor XIII levels in the bloodstream are less than 5 percent of normal. A loss of this protein's activity weakens blood clots, preventing the clots from stopping blood loss effectively.

The acquired form of factor XIII deficiency results when the production of factor XIII is reduced or when the body uses factor XIII faster than cells can replace it. Acquired factor XIII deficiency is generally mild because levels of factor XIII in the bloodstream are 20 to 70 percent of normal; levels above 10 percent of normal are usually adequate to prevent spontaneous bleeding episodes.

Acquired factor XIII deficiency can be caused by disorders including an inflammatory disease of the liver called hepatitis, scarring of the liver (cirrhosis), inflammatory bowel disease, overwhelming bacterial infections (sepsis), and several types of cancer. Acquired factor XIII deficiency can also be caused by abnormal activation of the immune system, which produces specialized proteins called autoantibodies that attack and disable the factor XIII protein. The production of autoantibodies against factor XIII is sometimes associated with immune system diseases such as systemic lupus erythematosus and rheumatoid arthritis. In other cases, the trigger for autoantibody production is unknown.

Normal Function

The F13A1 gene provides instructions for making one part, the A subunit, of a protein called factor XIII. This protein is part of a group of related proteins called coagulation factors that are essential for normal blood clotting. They work together as part of the coagulation cascade, which is a series of chemical reactions that forms blood clots in response to injury. After an injury, clots seal off blood vessels to stop bleeding and trigger blood vessel repair. Factor XIII acts at the end of the cascade to strengthen and stabilize newly formed clots, preventing further blood loss.

Factor XIII in the bloodstream is made of two A subunits (produced from the F13A1 gene) and two B subunits (produced from the F13B gene). When a new blood clot forms, the A and B subunits separate from one another, and the A subunit is cut (cleaved) to produce the active form of factor XIII (factor XIIIa). The active protein links together molecules of fibrin, the material that forms the clot, which strengthens the clot and keeps other molecules from breaking it down.

Studies suggest that factor XIII has additional functions, although these are less well understood than its role in blood clotting. Specifically, factor XIII is likely involved in other aspects of wound healing, immune system function, maintaining pregnancy, bone formation, and the growth of new blood vessels (angiogenesis).

Health Conditions Related to Genetic Changes

Factor XIII deficiency

At least 140 mutations in the F13A1 gene have been found to cause inherited factor XIII deficiency, a rare bleeding disorder. Without treatment, affected individuals have a greatly increased risk of abnormal bleeding episodes, including life-threatening bleeding inside the skull (intracranial hemorrhage). F13A1 gene mutations severely reduce the amount or activity of the A subunit of factor XIII. In most people with these mutations, the level of functional factor XIII in the bloodstream is less than 5 percent of normal. This loss of factor XIII activity weakens new blood clots and prevents them from stopping blood loss effectively.

Other disorders

Several common variations (polymorphisms) in the F13A1 gene have been studied as possible risk factors for diseases involving abnormal blood clotting. The most common F13A1 gene polymorphism changes a single protein building block (amino acid) in a critical part of the A subunit, replacing the amino acid valine with the amino acid leucine at protein position 34 (written as Val34Leu or V34L). This genetic change speeds up the activation of factor XIII. The Val34Leu polymorphism has been studied in relation to heart disease, stroke, recurrent pregnancy loss, and several other conditions. However, the results of these studies have been conflicting, and it remains unclear whether the polymorphism represents a major risk factor for any of these conditions.

Other Names for This Gene

• bA525O21.1 (coagulation factor XIII, A1 polypeptide)
• coagulation factor XIII A chain precursor
• coagulation factor XIII, A polypeptide
• coagulation factor XIII, A1 polypeptide
• coagulation factor XIIIa
• F13A
• factor XIIIa
• fibrin stabilizing factor, A subunit
• fibrinoligase
• FSF, A subunit
• protein-glutamine gamma-glutamyltransferase A chain
• TGase
• transglutaminase A chain
• transglutaminase. plasma

Genomic Location

Normal Function

The F13B gene provides instructions for making one part, the B subunit, of a protein called factor XIII. This protein is part of a group of related proteins called coagulation factors that are essential for normal blood clotting. They work together as part of the coagulation cascade, which is a series of chemical reactions that forms blood clots in response to injury. After an injury, clots seal off blood vessels to stop bleeding and trigger blood vessel repair. Factor XIII acts at the end of the cascade to strengthen and stabilize newly formed clots, preventing further blood loss.

Factor XIII in the bloodstream is made of two A subunits (produced from the F13A1 gene) and two B subunits (produced from the F13B gene). The role of the B subunits is to carry and stabilize the A subunits, protecting them from being broken down. When a new blood clot forms, the A and B subunits separate from one another, and the A subunits are cut (cleaved) to produce the active form of factor XIII (factor XIIIa). The active protein links together molecules of fibrin, the material that forms the clot, which strengthens the clot and keeps other molecules from breaking it down.

Studies suggest that factor XIII has additional functions, although these are less well understood than its role in blood clotting. Specifically, factor XIII is likely involved in other aspects of wound healing, immune system function, maintaining pregnancy, bone formation, and the growth of new blood vessels (angiogenesis).

Health Conditions Related to Genetic Changes

Factor XIII deficiency

At least 17 mutations in the F13B gene have been found to cause inherited factor XIII deficiency, a rare bleeding disorder. Without treatment, affected individuals have a greatly increased risk of abnormal bleeding episodes, including life-threatening bleeding inside the skull (intracranial hemorrhage). F13B gene mutations severely reduce the amount or disrupt the function of the B subunit of factor XIII, preventing it from stabilizing and protecting the A subunit. The resulting loss of factor XIII activity weakens new blood clots and prevents them from stopping blood loss effectively.

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Other Names for This Gene

• coagulation factor XIII B chain precursor
• coagulation factor XIII, B polypeptide
• fibrin-stabilizing factor B subunit
• FXIIIB
• protein-glutamine gamma-glutamyltransferase B chain
• TGase
• transglutaminase B chain

Genomic Location

Inherited factor XIII deficiency is considered to have an autosomal recessive pattern of inheritance, which means that it results when both copies of either the F13A1 gene or the F13B gene in each cell have mutations.

Some people, including parents of individuals with factor XIII deficiency, carry a single mutated copy of the F13A1 or F13B gene in each cell. These mutation carriers have a reduced amount of factor XIII in their bloodstream (20 to 60 percent of normal), and they may experience abnormal bleeding after surgery, dental work, or major trauma. However, most people who carry one mutated copy of the F13A1 or F13B gene do not have abnormal bleeding episodes under normal circumstances, and so they never come to medical attention.

The acquired form of factor XIII deficiency is not inherited and does not run in families.

Factor XIII replacement is used to treat bleeding, to prevent bleeding during surgical procedures, or to prevent recurrent bleeding (such as central nervous system or joint hemorrhages).