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Last updated:
April 27, 2022
Years published: 2012, 2016, 2020
NORD gratefully acknowledges Paula H. B. Bolton-Maggs, BMBCh, DM, FRCP, FRCPath, UK, for assistance in the preparation of this report.
Summary
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 symptoms in factor XI deficiency can vary from one person to another and is not clearly related to the blood factor XI level. In most patients, 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 and can occur in males and females.
Introduction
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, even with very low factor levels, 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). Blood in the urine (hematuria) is rare. Bleeding in the gut (gastrointestinal hemorrhaging) has been reported usually in relation to an underlying disease rather than the factor deficiency itself.
Factor XI deficiency is caused by mutations in the F11 gene. 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.
Factor XI deficiency is usually inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working 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 working genes from both parents is 25%. The risk is the same for males and females.
Sometimes, factor XI deficiency is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Factor XI deficiency sometimes 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 Willebrand 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.
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). The sensitivity of this test varies with the reagents used; it can be 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. As this test does not predict for bleeding risk additional tests of whole blood clotting have been developed which may be more useful (thrombin generation tests) as they reflect the whole clotting process whereas the aPTT and factor XI levels only reflect the start of clotting. However, this test is not widely available. Other factors have been shown to be relevant.
Treatment
The treatment of factor XI deficiency is not always straightforward, the bleeding tendency is unpredictable and does not correlate with residual enzyme activity as detected by aPTT-based measurements, 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 in the treatment of individuals with hemophilia. Genetic counseling is recommended 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. Individuals with factor XI deficiency do not require therapy for daily activities. Usually, affected individuals only require preventive (prophylactic) therapy before undergoing some types of surgery or similar procedures. 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. Factor XI concentrates may be associated with thrombotic events (e.g. blood clots) in some individuals (1, 2). However, most of those affected had pre-existing risk factors for thrombotic events.
Many affected individuals are best 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.
Inhibitors
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 can 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 very small doses of 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, manufactured by Novo Nordisk, Inc., has been approved by the Food and Drug Administration for the treatment of inhibitors associated with hemophilia A and B.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
Seligsohn U, Bolton-Maggs P. Factor XI deficiency. In: Textbook of Hemophilia, 2nd ed. Lee C, Berntorp E, Hoots K editors. 2010 Wiley-Blackwell, Hoboken, NJ pp. 355-361.
Hilgartner MW. The Hemophilias. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:390-391.
JOURNAL ARTICLES
Gidley GN, et al. Abnormal plasma clot formation and fibrinolysis reveal bleeding tendency in patients with partial factor XI deficiency. Blood Adv. 2018; 2(10):1076-1088.
Puetz, J, Hugge C, Moser K. Normal aPTT in children with mild factor XI deficiency. Pediatr Blood Cancer 2018;65(4).
Salloum-Asfar, S, et al., Assessment of two contact activation reagents for the diagnosis of congenital factor XI deficiency. Thromb Res. 2018;163:64-70.
Pike GN, et al. Evaluation of the use of global haemostasis assays to monitor treatment in factor XI deficiency. Haemophilia 2017;23(2): 273-283.
Pike GN, Bolton-Maggs PH. Factor XI-related thrombosis and the role of concentrate treatment in factor XI deficiency. Haemophilia 2015;21(4):477-80. Epub 2015/04/10.
Bolton-Maggs P, Goudemand J, Hermans C, Makris M, de Moerloose P. FXI concentrate use and risk of thrombosis. Haemophilia 2014;20(4):e349-51. Epub 2014/05/03.
Santoro R, Prejano S, Iannaccaro P. Factor XI deficiency: a description of 34 cases and literature review. Blood Coagul Fibrinolysis. 2011;22:431-435.
https://www.ncbi.nlm.nih.gov/pubmed/21577094
Bolton-Maggs PH. Factor XI deficiency – resolving the enigma? Hematology Am Soc Hemtaol Educ Program. 2009:97-105. https://www.ncbi.nlm.nih.gov/pubmed/20008187
Seligsohn U. Factor XI deficiency in humans. J Thromb Haemost. 2009;7:84-87. https://www.ncbi.nlm.nih.gov/pubmed/19630775
Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia. 2008;14:1183-1189. https://www.ncbi.nlm.nih.gov/pubmed/18312365
Bolton-Maggs PH. Factor XI deficiency and its management. Haemophilia. 2000;6:100-109. https://www.ncbi.nlm.nih.gov/pubmed/10982275
O’Connell NM. Factor XI deficiency. Semin Hematol. 2004;41:76-81. https://www.ncbi.nlm.nih.gov/pubmed/14872426
INTERNET
Siegel JE. Factor XI Deficiency. Medscape. Last Update Updated: May 13, 2016. Available at: https://emedicine.medscape.com/article/209984-overview Accessed October 28, 2019.
Bolton-Maggs PHB, Mathew P. Hemophilia C. Medscape. Last Update Updated: Mar 01, 2019.Available at: https://emedicine.medscape.com/article/955690-overview Accessed October 28, 2019.
Goudemand J. Congenital factor XI deficiency. Orphanet encyclopedia. Last Update October 2009. Available at: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=4511&Disease_Disease_Search_diseaseGroup=Congenital-factor-XI-deficiency&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Congenital-factor-XI-deficiency&title=Congenital-factor-XI-deficiency&search=Disease_Search_Simple Accessed October 28, 2019.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:612416; Last Update: 10/21/2016. Available at: https://omim.org/entry/612416 Accessed October 28, 2019.
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