Factor XI Deficiency

Factor XI Deficiency

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Factor XI Deficiency is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • haemophilia C
  • hemophilia C
  • plasma thromboplastin antecedent deficiency
  • PTA deficiency
  • Rosenthal syndrome

Disorder Subdivisions

  • None

General Discussion

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 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.



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.

Symptoms

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.

Causes

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.)

Affected Populations

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.

Standard Therapies

Diagnosis

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.



Treatment

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.



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 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).

Investigational Therapies

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.

100 College Road West

Princeton, NJ 08540



NovoSeven® RT Coagulation Factor VIIa (Recombinant)

1-877-668-6777

http://www.novosevenrt.com/



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



For information about clinical trials sponsored by private sources, in the main, contact:

www.centerwatch.com

References

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

Santoro R, Prejano S, Iannaccaro P. Factor XI deficiency: a description of 34 cases and literature review. Blood Coagul Fibrinolysis. 2011;22:431-435. http://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. http://www.ncbi.nlm.nih.gov/pubmed/20008187



Seligsohn U. Factor XI deficiency in humans. J Thromb Haemost. 2009;7:84-87. http://www.ncbi.nlm.nih.gov/pubmed/19630775



Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia. 2008;14:1183-1189. http://www.ncbi.nlm.nih.gov/pubmed/18312365



Bolton-Maggs PH. Factor XI deficiency and its management. Haemophilia. 2000;6:100-109. http://www.ncbi.nlm.nih.gov/pubmed/10982275



O'Connell NM. Factor XI deficiency. Semin Hematol. 2004;41:76-81. http://www.ncbi.nlm.nih.gov/pubmed/14872426



INTERNET

Siegel JE. Factor XI Deficiency. Emedicine Journal, Jan 10 2012. Available at: http://emedicine.medscape.com/article/209984-overview Accessed on: May 30, 2012.



Bolton-Maggs PHB, Mathew P. Hemophilia C. Emedicine Journal, Sept 15 2011. Available at: http://emedicine.medscape.com/article/955690-overview Accessed on: May 30, 2012.



Goudemand J. Congenital factor XI deficiency. Orphanet encyclopedia, October 2009. Available at: http://www.orpha.net/ Accessed on: May 30, 2012.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:612416; Last Update:03/17/2004. Available at: http://omim.org/entry/612416 Accessed on: May 30, 2012.



Amesse C, Aubin N, Baillargeon L, et al. Canadian Hemophilia Society. Factor XI Deficiency. Available at: http://www.hemophilia.ca/en/bleeding-disorders/other-factor-deficiencies/factor-xi-deficiency--hemophilia-c/ Accessed On: May 30, 2012.

Resources

National Hemophilia Foundation

116 West 32nd Street, 11th Floor

New York, NY 10001

USA

Tel: (212)328-3700

Fax: (212)328-3777

Tel: (800)424-2634

Email: handi@hemophilia.org

Internet: http://www.hemophilia.org



Canadian Hemophilia Society

400-1255 University Street

Montreal

Quebec, H3B 3B6

Canada

Tel: 5148480503

Fax: 5148489661

Tel: 8006682686

Email: chs@hemophilia.ca

Internet: http://www.hemophilia.ca



NIH/National Heart, Lung and Blood Institute

P.O. Box 30105

Bethesda, MD 20892-0105

Tel: (301)592-8573

Fax: (301)251-1223

Email: nhlbiinfo@rover.nhlbi.nih.gov

Internet: http://www.nhlbi.nih.gov/



World Federation of Hemophilia

1425 René Lévesque Blvd. W. Suite 1010

Montreal

Quebec, H3G 1T7

Canada

Tel: 5148757944

Fax: 5148758916

Email: wfh@wfh.org

Internet: http://www.wfh.org/index.asp?lang=EN



Hemophilia Federation of America

210 7th St. SE

Suite 200B

Washington, DC 20003

USA

Tel: (202)675-6984

Fax: (202)675-6983

Tel: (800)230-9797

Email: info@hemophiliafed.org

Internet: http://www.hemophiliafed.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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