About fibrin stabilizing factor deficiency

What is fibrin stabilizing factor deficiency?

Factor XIII deficiency is a rare, genetic bleeding disorder characterized by a 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.


What are the symptoms for fibrin stabilizing factor deficiency?

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 patients are diagnosed 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).

What are the causes for fibrin stabilizing factor deficiency?

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 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.

Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

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.

What are the treatments for fibrin stabilizing factor deficiency?

Treatment

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:

CSL Behring Website: http://www.corifact.com/

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).

In 2014, Tretten, a recombinant factor XIII replacement product, was approved for the prevention of bleeding in adults and children who have the rare clotting disorder congenital factor XIII A-subunit deficiency. Tretten is distributed by Novo Nordisk, Inc. USA. For more information, contact:

Novo Nordisk, Inc. Website: http://www.tretten-us.com/

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.

What are the risk factors for fibrin stabilizing factor deficiency?

Fibrin stabilizing factor deficiency is a rare condition that can be caused by a number of different factors. The most common one is genetic, but environmental factors like smoking can also contribute to the development of the condition.

There are some risk factors for developing fibrin stabilizing factor deficiency, including:

  • Genetic factors: If you have a family history of FSF deficiency and/or a close relative with it, there's an increased chance you will develop it too. Parents who are close relatives have a higher chance than unrelated parents to both carry the same abnormal gene. This can increase the risk of having children with a recessive genetic disorder.
  • Age: People over the age of 50 are more likely to develop fibrin stabilizing factor deficiency than younger people.
  • Gender: Women seem to be more prone to developing fibrin stabilizing factor deficiency than men.
  • Smoking: Smoking increases the likelihood that you'll develop fibrin-stabilizing factor deficiency.
  • Ethnicity: People with African, Asian, and Native American ancestry are at higher risk for developing this condition.
Symtpoms
Bleeding that lasts more than a few minutes after an injury, even if you're using pressure to stop it,Blood in your urine or stool,Bleeding under the skin that appears as bruising around joints and muscles (called purpura),Uncontrolled nosebleeds, bleeding from gums when brushing your teeth, or bleeding from the vagina during menstrual periods

Conditions
Hepatitis B,Hepatitis C (acute),Alcohol abuse,Autoimmune hepatitis,Malnutrition,Pregnancy

Drugs
Therapy

Is there a cure/medications for fibrin stabilizing factor deficiency?

There are no known medications or treatments for Fibrin stabilizing factor deficiency, but there are some things you can do to manage your symptoms.

  • The most important thing is to avoid any medications that can increase your risk of bleeding, including aspirin and ibuprofen. You should also avoid eating foods like beef liver, which contain high levels of vitamin K. If you have hemophilia, it's important to talk to your doctor about whether or not it's safe for you to receive vaccines or have dental work done.
  • If you have FSF deficiency, you may experience excessive bleeding after injuries or surgery. In these cases, doctors may prescribe blood transfusions to replace the missing protein in your blood—but this isn't always enough to stop the bleeding completely and may cause complications later on down the line due to iron overload.
  • While there is no cure for FSFD at this time, there are two medications that can help stabilize fibrinogen levels in some patients: idursulfase and aranesp. These medications work by splitting off excess fibrinogen and other plasma proteins into an inactive form that can be excreted by the kidneys rather than being deposited in tissues.
  • In addition to these two medications, there are other treatments that can help improve your quality of life with FSFD. These include things like diet changes (such as eating less protein), exercise routines, and quitting smoking.
Symtpoms
Bleeding that lasts more than a few minutes after an injury, even if you're using pressure to stop it,Blood in your urine or stool,Bleeding under the skin that appears as bruising around joints and muscles (called purpura),Uncontrolled nosebleeds, bleeding from gums when brushing your teeth, or bleeding from the vagina during menstrual periods

Conditions
Hepatitis B,Hepatitis C (acute),Alcohol abuse,Autoimmune hepatitis,Malnutrition,Pregnancy

Drugs
Therapy

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