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NORD is very grateful to Paula H. B. Bolton-Maggs, BMBCh, DM, FRCP, FRC Path, Department of Clinical Haematology, Manchester Royal Infirmary, United Kingdom, for assistance in the preparation of this report.
Factor XI deficiency is a rare genetic bleeding disorder caused by reduced levels and insufficient activity of a blood protein called factor XI. Factor XI is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood solidifies like glue to plug the site of a wound to stop bleeding. Individuals with factor XI deficiency do not bleed faster or more profusely than healthy individuals, but, because their blood clots poorly, they may have difficulty stopping the flow of blood from a deep or surgical wound. This may be referred to as prolonged bleeding or a prolonged bleeding episode. The severity of factor XI deficiency can vary from one person to another. In many cases, prolonged bleeding episodes only occur after surgery, dental procedures or trauma. Bleeding tendencies in factor XI deficiency are unpredictable and inconsistent, making the disorder difficult to manage in some cases. Factor XI deficiency is caused by disruptions or changes (mutations) to the F11 gene. Factor XI deficiency is inherited autosomally and can occur in people of either sex.
Factor XI deficiency was first described in the medical literature in 1953. It used to be also referred to as hemophilia C in order to distinguish it from the better known hemophilia types A and B. In rare cases, factor XI deficiency can be acquired during life (acquired factor XI deficiency). This report deals with the genetic form. Although the genetic form is present at birth, as it is a mild bleeding disorder symptoms do not usually occur until later in life.
In most cases, the bleeding tendency in individuals with factor XI deficiency is mild. Affected individuals may experience bleeding episodes following trauma or surgery including dental procedures, tonsillectomies or surgery involving the urinary or genital tracts. Bleeding may also occur after circumcision. Bleeding may begin at the time of injury and persist if untreated, or bleeding may develop several hours after the injury. Untreated individuals may develop large, solid swellings of congealed blood (hematomas) following a surgical procedure.
Affected individuals may be prone to bruising or nosebleeds. Women may experience prolonged, heavy bleeding during their menstrual periods (menorrhagia). Some affected women experience prolonged bleeding after childbirth.
Bleeding into the joints or spontaneous bleeding (both common with hemophilia types A and B) does not occur in individuals with factor XI deficiency (unless there is underlying joint disease). Specific injuries in individuals with factor XI deficiency can cause bleeding into the muscles and/or joints. Blood in the urine (hematuria) is rare. Bleeding in the gut (gastrointestinal hemorrhaging) has been reported.
Factor XI deficiency is caused by mutations in the F11 gene. 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.
Investigators have determined that the F11 gene is located on the long arm (q) of chromosome 4 (4q35). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. 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 4q35" refers to band 35 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The F11 gene encodes factor XI. Factor XI is one of the essential blood proteins and plays a role in aiding the blood to clot. Mutations of the F11 gene result in deficient levels of functional factor XI. The symptoms of factor XI deficiency occur, in part, due to this deficiency. Individuals with factor XI deficiency often have varying levels of residual factor XI. In many disorders, the amount of residual protein activity correlates with the severity of the disease (e.g. little to no residual protein activity results in severe disease). However, in factor XI deficiency the severity of the disorder does not always correlate with the residual activity of factor XI. For example, individuals with a severe deficiency of factor XI may have mild or no symptoms of the disorder and individuals with a partial deficiency of factor XI may have more significant symptoms. This suggests that additional genetic and environmental factors play a role in the severity of the disorder. This variability even exists among members of the same family.
In some cases, factor XI deficiency occurs in patients with Noonan syndrome, which is a disorder characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Noonan syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose "Noonan" as your search term in the Rare Disease Database.)
Factor XI deficiency affects males and females in equal numbers. The disorder can affect individuals of any age and any ethnic group. It is the second most common bleeding disorder to affect women (after von Willedbrand disease). The incidence of factor XI deficiency is higher in individuals of Ashkenazi Jewish descent where it is estimated to affect 8% of the population. The severe form of the disorder is estimated to affect approximately 1 in 1,000,000 people in the general population.
Symptoms of the following disorders can be similar to those of factor XI deficiency. Comparisons may be useful for a differential diagnosis.
Acquired factor XI deficiency is a general term for individuals who develop factor XI deficiency that is not inherited, but acquired at some point during life. Acquired factor XI deficiency can result when the body produces autoantibodies (inhibitors) that attack factor XI. Acquired factor XI deficiency can be associated with an underlying condition such as lupus or other immunological disorders.
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. Therefore, hemophilia A and B are fully expressed in males only. 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, but this classification does not apply to hemophilia C/factor XI deficiency.
Von Willebrand disease (VWD) is a genetic bleeding disorder resulting in prolonged bleeding and varies widely in its effects. Individuals with VWD have a defect in or deficiency of a clotting protein known as von Willebrand factor (VWF). Deficient or defective VWF results in improper functioning of platelets, which are specialized red blood cells that mass together to form clots to stop bleeding. In individuals with VWD, platelets do not stick to holes in blood vessels and bleeding is prolonged. Defective VWF can also cause reduced levels of another clotting protein in the blood (factor VIII). Most people have relatively mild symptoms and are not diagnosed until they are adults. A small percentage of individuals have problems during infancy or early childhood such as prolonged bleeding and an abnormally slow clotting time. Symptoms can include gastrointestinal bleeding, nosebleeds, bleeding from the gums, and easy bruising. Affected individuals may bleed easily after injury, childbirth, and/or surgery. There are three main forms of the disorder. Most cases are inherited as autosomal dominant disorders; some cases are inherited as autosomal recessive disorders. (For more information on this disorder, choose "Von Willebrand" as your search term in the Rare Disease Database.)
Fibrinogen disorders are a group of rare bleeding disorders characterized by deficiency or absence of a certain protein in the blood that is essential in the blood clotting (coagulation) process. This protein is known as fibrinogen or coagulation factor I. Three forms have been identified: congenital afibrinogenemia, hypofibrinogenemia and dysfibrinogenemia. Individuals with congenital afibrinogenemia may be susceptible to severe bleeding (hemorrhaging) episodes and prolonged bleeding from minor cuts. Individuals with hypofibrinogenemia or dysfibrinogenemia may not have symptoms (asymptomatic) or may develop mild bleeding episodes. (For more information on this disorder, choose "fibrinogenemia" as your search term in the Rare Disease Database.)
A diagnosis of factor XI deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, and a thorough clinical evaluation. Several different tests may be necessary to confirm a diagnosis.
Clinical Testing and Workup
Laboratories studies can include a complete blood count (CBC), coagulation tests and factor assay. Screening coagulation tests that measure how long it takes the blood to clot include activated partial thromboplastin time (aPTT) and prothrombin time (PT). In individuals with deficiency of factor XI, the aPTT test will be prolonged (it will take the sample longer to clot than normal). PT tests are normal in individuals with factor XI deficiency (but may be abnormal in individuals with other bleeding disorders).
Further tests known as assays are required to confirm a diagnosis. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor XI assay will demonstrate reduced activity of factor XI.
The treatment of factor XI deficiency is not always straightforward because the factor XI’s exact role in the coagulation pathway is not fully understood, the bleeding tendency is unpredictable and does not correlate with residual enzyme activity, and the various treatment options have side effects.
Individuals with factor XI deficiency will benefit from referral to federally-funded hemophilia treatment centers. These specialized centers can provide comprehensive care for individuals with hemophilia including the development of specific treatment plans, monitoring and follow up of affected individuals, and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapist, social worker and genetic counselor) experienced at treating individuals with hemophilia. Genetic counseling will be of benefit for affected individuals and their families.
Several different treatments are available for factor XI deficiency including fresh frozen plasma (preferably pathogen-inactivated), factor XI concentrates and antifibrinolytics. Most individuals with factor XI deficiency do not require therapy for daily activities. Usually, affected individuals only require preventive (prophylactic) therapy before undergoing surgery or similar procedures. Some individuals may not require replacement therapy when undergoing minor surgeries.
In the United States, fresh frozen plasma is the most widely used treatment and is effective in treating individuals with factor XI deficiency. Fresh frozen plasma is a blood derivative that is obtained from donors and is rich in coagulation factors including factor XI. Fresh frozen plasma carries a risk of infection as well as of an allergic reaction. The risk of infection is extremely low because donors are carefully selected and the products are screened to ensure they do not contain viruses. A large volume of fresh frozen plasma is often necessary because factor XI is not concentrated in fresh frozen plasma.
Fresh frozen plasma is used in the United States because factor XI concentrates are unavailable. Factor XI concentrates are blood products that contain a concentrated form of factor XI. Although not available in the United States, these products are available in certain European countries. Such products are created from the plasma of thousands of different blood donors. These products are fully treated to kill any viruses or similar pathogens that can potentially be present in the blood (viral inactivation). They have much shorter infusion times than fresh frozen plasma and are not associated with unnecessary elevation of other coagulation factor levels. When these factor XI concentrates were initially introduced, there were reports of thrombotic events (e.g. blood clots) in some individuals. However, most of those affected were elderly patients, most of whom had pre-existing risk factors for thrombotic events. The two products available in Europe are Hemoleven® from Laboratoire francais du Fractionnement et des Biotechnologies in France and factor XI concentrate from Bio Products Laboratories in the United Kingdom.
Some affected individuals may be treated with drugs known as antifibrinolytics, which slow the breakdown of clotting factors in the blood. Antifibrinolytics include aminocaproic acid and tranexamic acid. These drugs are especially beneficial in treating bleeding from the mucous membranes such as bleeding in the mouth and menstrual periods. Antifibrinolytics are often sufficient for dental procedures.
Excessive menstrual bleeding in women may be treated by hormonal contraceptives such as birth control pills or antifibrinolytics.
In some cases, inhibitors have developed in individuals with factor XI 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 XI deficiency they are also called inhibitors because they mistakenly attack replacement factor XI, inhibiting the effectiveness of the treatment. When inhibitors develop in individuals with factor XI deficiency, additional therapy is required (see investigational therapies below).
Some individuals who have developed inhibitors to factor XI have been treated for surgery or bleeding episodes with NovoSeven® RT. This drug is a genetically engineered (recombinant) version of factor VII. Because it is artificially created in a lab, it does not contain human blood or plasma and, consequently, there is no risk of blood-borne viruses or other such pathogens. NovoSeven has been approved by the Food and Drug Administration for the treatment of inhibitors associated with hemophilia A and B.
Novo Nordisk Inc.
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NovoSeven® RT Coagulation Factor VIIa (Recombinant)
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For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Report last updated: 2012/08/28 00:00:00 GMT+0