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NORD is very grateful to Aida Inbal, MD, Professor in Hematology, Director Hematology Clinic and Thrombosis and Hemostasis Unit, Beilinson Hospital, Rabin Medical Center, Israel, for assistance in the preparation of this report.
Factor XIII deficiency is a rare, genetic bleeding disorder characterized by deficiency of clotting factor XIII. Clotting factors are specialized proteins that are essential for the blood to clot properly. Specifically, individuals with factor XIII deficiency form blood clots like normal, but these clots are unstable and often break down, resulting in prolonged, uncontrolled bleeding episodes. Factor XIII also affects other processes in the body and is known to play a role in proper wound healing and pregnancy. The severity of factor XIII deficiency bleeds can vary greatly from one person to another. Some individuals may have only mild symptoms; other individuals may have severe, life-threatening bleeds. With early diagnosis and prompt treatment, the more serious bleeds of factor XIII deficiency can be avoided. FXIII consists of two subunits: subunit A and subunit B. Most of the Factor XIII deficiency states are caused by mutations in subunit A; very few have a mutation in subunit B. Factor XIII deficiency is inherited as an autosomal recessive disorder.
This report deals with the genetic form of factor XIII deficiency, which is present at birth (congenital); the disorder can also be acquired during life. Although the genetic form is present at birth, symptoms may not become apparent until later during life. Congenital factor XIII deficiency was first described in the medical literature by Duckert, et al., in 1960.
The symptoms and severity of factor XIII 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 XIII 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 XIII deficiency may become apparent at any age, but most cases are identified during infancy. Symptoms commonly associated with factor XIII 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 XIII 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 XIII 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 XIII deficiency has also been associated with recurrent miscarriages (spontaneous abortion).
Mutations causing factor XIII deficiency are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal 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 for two carrier parents to both pass the defective 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the F13A1 gene is located on the short arm (p) of chromosome 6 (6p24.2-p23). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes (23 pairs). Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 6p24.2-p23" refers to bands 24.2-23 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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.
The F13B gene is located on the long arm (q) of chromosome 1 (1q31-q32.1). 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.
Factor XIII consists of two catalytic a subunits and two noncatalytic b subunits. The a subunits are regulated (encoded) by the F13A1 gene and produced (synthesized) in various cells including bone marrow cells that eventually become platelets (megakaryocytes) and certain white blood cells (monocytes and macrophages). The b subunits are encoded by the F13B gene and are synthesized in liver cells (hepatocytes).
Factor XIII plays a vital role in stabilizing blood clots. Clotting is the process by which blood specific (coagulation) proteins clump together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions to ultimately form a clot to plug a wound. This is referred to as the clotting (coagulation) cascade. The clotting cascade involves different substances in addition to clotting factors. Factor XIII is the last step of the clotting cascade, and it functions to stabilize the clot. Mutations of the F13A1 or the F13b gene result in deficient levels of functional factor XIII, which causes blood clots to be weak and unstable resulting in fast breakdown.
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.
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. The incidence of factor XIII deficiency has been estimated to be between 1 in 2,000,000-5,000,000 people in the general population. However, cases of factor XIII deficiency can go undiagnosed or misdiagnosed, making it difficult to determine the disorder's true frequency. Most researchers believe that the disorder is under-diagnosed. The incidence of factor XIII deficiency tends to be higher in countries where marriage to close relatives (consanguineous marriage) is more common.
Symptoms of the following disorders can be similar to those of factor XIII deficiency. Comparisons may be useful for a differential diagnosis.
Acquired factor XIII deficiency is a general term for individuals who develop factor XIII deficiency that is not inherited, but acquired at some point during life. Acquired factor XIII deficiency can result when the body produces autoantibodies (inhibitors) that attack factor XIII. Acquired factor XIII deficiency can be associated with an underlying condition such as severe liver disease, chronic kidney (renal) failure, inflammatory bowel disease, Henoch-Schonlein purpura, autoimmune disorders such as lupus or scleroderma, or certain cancers such as myeloid forms of leukemia. Acquired factor XIII deficiency has also been linked to the use of certain medications including isoniazid, penicillin, and phenytoin. The exact reason these autoantibodies develop is not always known. Acquired factor XIII deficiency occurs much less often than the genetic form and usually affects middle-aged or elderly individuals.
Hemophilia (Hemo = bleed; philia = tendency) is a general term for a group of rare bleeding disorders. Most forms of hemophilia are rare inherited blood clotting (coagulation) disorders caused by inactive or deficient blood coagulation proteins. There are three major forms of inherited hemophilia: hemophilia A (also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency); hemophilia B (Christmas disease or factor IX deficiency); and hemophilia C (factor XI deficiency). Hemophilia A and B are inherited as X-linked recessive genetic disorders, while hemophilia C is inherited as an autosomal recessive genetic disorder. Therefore, while hemophilia A and B are fully expressed in males only, hemophilia C affects males and females in equal numbers. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. Hemophilia may be classified as mild, moderate, or severe. The level of severity is determined by the percentage of active clotting factor in the blood (normal percentage ranges from 50 to 150 percent). People who have severe hemophilia have less than one percent of active clotting factor in their blood. Factor XIII deficiency belongs to a group of rare forms of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, and X. There are also combined deficiencies of more than one factor. The rare forms of bleeding disorders account for 3-5% of all bleeding disorders collectively. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of factor XIII 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 XIII 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 XIII 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 XIII, the clots will breakdown. Most untreated individuals with factor XIII 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 XIII 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 XIII 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 XIII deficiency were treated with fresh frozen plasma or cryoprecipitates. Fresh frozen plasma may be used if factor XIII 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 XIII deficiency undergo preventive (prophylactic) therapy with FXIII 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 XIII 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 (FXIII Concentrate) for the routine prophylactic treatment of congenital factor XIII 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. For more information, contact:
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In extremely rare cases, inhibitors have developed in individuals with factor XIII 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 XIII 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 XIII deficiency, additional therapy is required, specifically drugs that reduce the activity of the immune system (immunosuppressive agents).
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.
Researchers are studying the effectiveness of a genetically engineered (recombinant) form of factor XIII for the treatment of individuals with factor XIII deficiency. Initial studies have shown the drug to be effective in preventing bleeding episodes potentially associated with factor XIII deficiency. Because it is artificially created in a lab, recombinant factor XIII does not contain human blood or plasma and, consequently, there is no risk of blood-borne viruses or other such pathogens. The drug has not yet received approval from the FDA for the treatment of individuals with factor XIII deficiency.
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Report last updated: 2012/04/24 00:00:00 GMT+0