Factor 13 deficiency
Factor 13 deficiency also known as factor XIII deficiency, fibrin stabilizing factor deficiency or Laki-Lorand factor 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 13 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 13 deficiency tend to have heavy or prolonged menstrual bleeding (menorrhagia) and may experience recurrent pregnancy losses (miscarriages). Other signs and symptoms of inherited factor 13 deficiency include nosebleeds, bleeding of the gums, easy bruising, problems with wound healing, bleeding after surgery, and abnormal scar formation. Inherited factor 13 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 13 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 in 2 million to 1 in 5 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, making it difficult to determine the disorder’s true frequency. The incidence of factor XIII deficiency tends to be higher in countries where marriage to close relatives (consanguineous marriage) is more common.
Factor XIII deficiency affects males and females in equal numbers. Symptoms can become apparent at any age. Individuals of any race or ethnicity can be affected.
Factor 13 deficiency causes
Inherited factor 13 deficiency
Inherited factor XIII deficiency results from mutations in the F13A1 gene or, less commonly, the F13B gene. Investigators have determined that the F13A1 gene is located on the short arm (p) of chromosome 6 (6p24.2-p23). The F13B gene is located on the long arm (q) of chromosome 1 (1q31-q32.1). 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.
For years, it was believed that factor XIII only played a role in helping to stabilize the formation of blood clots. However, researchers have learned that factor XIII has multiple roles in the body and is involved in proper wound healing, carrying a pregnancy to full term, and in the development of new blood vessels (angiogenesis). More research is necessary to determine the exact functions that factor XIII plays in the body and the full spectrum of symptoms potentially associated with the disorder.
Cases of factor XIII deficiency due to mutations of the F13A1 gene are sometimes referred to as factor XIIIA deficiency or factor XIII deficiency type 2.
Factor XIII deficiency due to mutations of the F13B gene occurs very rarely and is generally less severe than when the disorder is caused by mutations of the F13A1 gene. Less than 5% of the report cases of factor XIII deficiency are due to mutations of the F13B gene. These cases are sometimes referred to as factor XIIIB deficiency or factor XIII deficiency type 1.
Acquired factor 13 deficiency
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.
Factor 13 deficiency inheritance pattern
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. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits 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 for two carrier parents to both pass the altered gene and 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.
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.
Figure 1. Factor 13 deficiency autosomal recessive inheritance pattern
People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.
Resources for locating a genetics professional in your community are available online:
- The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
- The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
- The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
- The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.
Factor 13 deficiency symptoms
The symptoms and severity of factor 13 deficiency can vary from one person to another. However, in most of the patients (80%) bleeding symptoms appear after birth with bleeding from the umbilical stump being most common. Some individuals may only have a mild expression of the disorder that will not become apparent until after a bleeding complication occurs following trauma or surgery. In more serious cases, bleeding can occur spontaneously or following activities that normally would not produce problems such as strenuous exercise. It is important to note the variability of factor 13 deficiency and to understand that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
The symptoms of factor 13 deficiency may become apparent at any age, but most patients are diagnosed during infancy. Symptoms commonly associated with factor 13 deficiency include chronic nosebleeds (epistaxis), bleeding from the gums, discoloration of the skin due to bleeding underneath the skin (ecchymoses), and solid swellings of congealed blood (hematomas). Affected individuals may bruise easily, extensively, and without cause (spontaneously). Bruising due to minor trauma may be delayed. Women with factor 13 deficiency may experience prolonged, heavy bleeding during the periods (menorrhagia). Bleeding into the soft tissues and around the joints (periarticular bleeding) can also occur. Bleeding into the joints (hemoarthrosis) is rare.
Thirty percent of the affected individuals may also experience spontaneous bleeding into the brain (intracranial hemorrhages), about 25% experience poor or delayed wound healing and others may have enhanced bleeding after trauma or surgery. The risk of intracranial hemorrhaging is greater in factor 13 deficiency than in other related bleeding disorders. Bleeding after trauma or surgery is initially normal, but abnormal, heavy bleeding often develops within 12-36 hours. In homozygous women, factor 13 deficiency has also been associated with recurrent miscarriages (spontaneous abortion).
Factor 13 deficiency diagnosis
A diagnosis of factor 13 deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Standard tests used to diagnose bleeding disorders such as activated partial thromboplastin time (aPTT) and prothrombin time (PT) are normal and therefore ineffective. A diagnosis of factor 13 may be suspected in infants that experience heavy or abnormal bleeding at birth.
Clinical testing and workup
A clot solubility test may be used to aid in a diagnosis factor 13 deficiency. However, this test is only effective when an affected individual has very low levels of factor XIII. During these tests, a clot is exposed to a solution of 1% monochloracetic acid or 5 m urea. In individuals with less than 1% factor 13, the clots will breakdown. Most untreated individuals with factor 13 deficiency will have close to 0% factor XIII activity in the blood.
To confirm a diagnosis, the quantity (amount) of factor XIII is tested in a blood sample through quantitative analysis of factor XIII (assay). A quantitative assay is a test that can measure the amount or activity of certain substances in the blood. In affected individuals this will demonstrate reduced amount and activity of factor XIII.
Factor 13 deficiency treatment
Factor 13 deficiency can be treated by factor XIII concentrates. Factor XIII levels only need to be elevated slightly to prevent or stop the bleeding symptoms associated with the disorder.
Factor XIII concentrate, which is a blood product that contains a concentrated form of factor XIII, is used to treat individuals with factor 13 deficiency. Such products are created from the plasma of thousands of different blood donors. These products undergo a viral inactivation process that kills any viruses or similar pathogens that can potentially be present in the blood.
In the past, individuals with factor 13 deficiency were treated with fresh frozen plasma or cryoprecipitates. Fresh frozen plasma may be used if factor 13 concentrates are unavailable. Cryoprecipitates are no longer recommended because of the risk (albeit small) of infection from a virus or similar pathogen. There is also a risk of an allergic reaction with fresh frozen plasma or cryoprecipitates.
It is recommended that individuals with factor 13 deficiency undergo preventive (prophylactic) therapy with factor XIII concentrate every 3-4 weeks in an attempt to prevent or minimize the symptoms of the disorder. Prophylactic therapy has been used to prevent mostly bleeding into the brain. The decision to undergo prophylactic therapy in factor 13 deficiency is made after careful consultation with a patient’s medical team.
In 2011, the U.S. Food and Drug and Administration (FDA) approved Corifact (factor XIII concentrate) for the routine prophylactic treatment of congenital factor 13 deficiency. Corifact is administered intravenously. In some cases, Corifact has been associated with adverse side effects such as blood clots (thromboses), and the benefits versus the risks of such therapy must be assessed on an individual basis.
In extremely rare cases, inhibitors have developed in individuals with factor 13 deficiency. Inhibitors are autoantibodies. Antibodies are specialized proteins produced by the body’s immune system that destroy foreign substances directly or coats them with a substance that marks them for destruction by white blood cells. When antibodies target healthy tissue they may be referred to as autoantibodies. In factor 13 deficiency they are also called inhibitors because they mistakenly attack replacement factor XIII, inhibiting the effectiveness of the treatment. When inhibitors develop in individuals with factor 13 deficiency, additional therapy is required, specifically drugs that reduce the activity of the immune system (immunosuppressive agents).
In 2014, Tretten, a recombinant factor 13 replacement product, was approved for the prevention of bleeding in adults and children who have the rare clotting disorder congenital factor 13 A-subunit deficiency.
Additional treatment for individuals with factor XIII deficiency is symptomatic and supportive. For example, excessive menstrual bleeding in women may be treated by hormonal contraceptives such as birth control pills or drugs known as antifibrinolytics, which prevent the breakdown of clots in the blood. Genetic counseling may be of benefit for affected individuals and their families.
