Factor XII Deficiency

Disease Overview

Summary

Factor XII deficiency is a rare genetic blood disorder that causes prolonged clotting (coagulation) of blood in a test tube without the presence of prolonged clinical bleeding tendencies. It is caused by a deficiency of the factor XII (Hageman factor), a plasma protein (glycoprotein). Specifically, factor XII is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Although it is thought that factor XII is needed for proper blood clotting, when it is deficient, other blood clotting factors appear to compensate for its absence. Therefore, the disorder is thought to be benign and usually presents no symptoms (asymptomatic); it is usually only accidentally discovered through pre-operative blood tests that are required by hospitals.

Introduction

Factor XII deficiency was first described in the medical literature in 1955 by doctors Oscar Ratnoff and Jane Colopy in a patient named John Hageman. The disorder is sometimes known as Hageman factor deficiency or Hageman trait.

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Synonyms

• F12 deficiency
• HAF deficiency
• Hageman factor deficiency
• Hageman trait

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Signs & Symptoms

Factor XII deficiency is rarely associated with any symptoms (asymptomatic). However, when blood from a patient is subjected to a partial thromboplastin time test (PTT), a test measuring clotting time, it takes an abnormally long time for the blood to clot. Serum prothrombin (PT) time, another test of blood clotting, is also abnormally long. The blood level of factor XII tends to vary greatly.

According to some older medical reports, factor XII deficiency may predispose affected individuals to developing blood clots (thrombi) at an early age. For example, individuals may have a greater risk than the general population in developing deep vein thrombosis or acquired thrombotic disorders. However, such an association remains unproven.

Researchers are now studying drugs to block (inhibit) factor XII as a potential therapy for individuals who are prone to developing blood clots. More research is necessary to determine the exact role that factor XII plays in the development or prevention of blood clots and its overall functions in the body.

There are also reports in the medical literature that suggest an association between factor XII deficiency and repeated unexplained miscarriages in some affected women. However, such an association remains controversial and unproven.

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Causes

Factor XII deficiency is inherited as an autosomal recessive disorder. Genetic diseases are determined by two genes, one received from the father and one from 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 factor XII deficiency occurs due to mutations of the F12 gene located on the long arm of chromosome 5 (5q33-qter). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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 5q33” refers to band 33 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The F12 gene creates (encodes) factor XII, which is a clotting factor. Mutations of the F12 gene lead to low levels of functional factor XII in the blood (potentially less than 1%). The exact role that factor XII plays in the clotting process and any additional effects it has on the body are not fully understood. In addition to the clotting process, factor XII is believed to play a role tissue repair and the formation of blood vessels (angiogenesis).

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Affected populations

Factor XII deficiency affects persons of Asian descent more often than individuals of other ethnicities. Males and females are affected in equal numbers. Since no symptoms are usually associated with factor XII deficiency, many individuals remain undiagnosed. The exact incidence of the disorder in the general population is unknown, but estimated to be approximately 1 in 1 million individuals.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of factor XII deficiency. Comparisons may be useful for a differential diagnosis:

Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood 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 is classified as a rare form of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, X, and XIII. 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.)

Factor XIII deficiency is a rare, genetic bleeding disorder characterized by deficiency or reduced activity of clotting factor XIII. Clotting factors are specialized proteins that are essential for the blood to clot properly. Specifically, individuals with factor XIII 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 can vary greatly from one person to another. Some individuals may have no symptoms (asymptomatic) or only mild symptoms; other individuals may have severe, life-threatening complications. With early diagnosis and prompt treatment, the more serious complications of factor XIII deficiency can be avoided. Factor XIII deficiency is caused by mutations to one of two different genes. Factor XIII deficiency is inherited as an autosomal recessive disorder. (For more information on these disorders, choose factor XIII deficiency as your search term in the Rare Disease Database.)

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Diagnosis

Factor XII deficiency is often diagnosed accidentally during a routine blood clotting (coagulation) tests as in one done before surgery. In affected individuals, it will take longer for their blood to clot during these tests. Further tests can reveal low levels of factor XII in the blood.

Clinical Testing and Work-up

A diagnosis of factor XII deficiency may be suspected in individuals without clinical signs or a previous history of a bleeding disorder in whom specialized tests called screening coagulation tests known as activated partial thromboplastin time (aPTT) or prothrombin time PT) are abnormal. These tests measure how long it takes the blood to clot.

Individuals with abnormal results on these tests but no bleeding symptoms may then be screened for a condition known as antiphospholipid syndrome. A test will be run to detect a specific inhibitor called lupus anticoagulant, which is present in individuals with acquired antiphospholipid syndrome and can cause similar abnormal results on the aPTT or PT tests.

A diagnosis of factor XII deficiency can be confirmed by a test called an assay. An assay is a test that measures the activity of coagulation factors. It can demonstrate a deficiency of factor XII.

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Standard Therapies

Treatment

Treatment for this disorder is usually not necessary since bleeding abnormalities only mild or nonexistent.

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Clinical Trials and Studies

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:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

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

www.centerwatch.com

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References

TEXTBOOKS

Colman RW. Factor XII Deficiency. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:382-383.

Bick RL. Disorders of Thrombosis & Hemostasis. 3rd ed. Lippincott Williams & Wilkins. Philadelphia, PA; 2002:126.

Hoffman R, et al., eds. Hematology Basic Principles and Practice, 2nd ed. New York, NY: Churchill-Livingstone, Inc; 1995:1581-83, 1699.

JOURNAL ARTICLES

Pham M, Stoll G, Nieswandt B, Bendszus M, Kleinschnitz C. Blood coagulation factor XII – a neglected player in stroke pathophysiology. J Mol Med (Berl). 2012;90:119-126. https://www.ncbi.nlm.nih.gov/pubmed/21909687

Muller F, Gailani D, Renne T. Factor XI and XII as antithrombotic targets. Curr Opin Hematol. 2011;18:349-355. https://www.ncbi.nlm.nih.gov/pubmed/21730835

Stayrou E, Schmaier AH. Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis. Thromb Res. 2010;125;210-215. https://www.ncbi.nlm.nih.gov/pubmed/20022081

Schmaier AH, Larusch G. Factor XII: a new life for an old protein. Thromb Haemost. 2010;104;915-918. https://www.ncbi.nlm.nih.gov/pubmed/20806112

Schmaier AH. The elusive physiologic role of factor XII. J Clin Invest. 2008;118:3006-3009. https://www.ncbi.nlm.nih.gov/pubmed/18725991

Matsubayashi H, Sugi T, Suzuki T, et al. Decreased factor XII activity is associated with recurrent IVF-ET failure. Am J Reprod Immunol. 2008;59:316-322. https://www.ncbi.nlm.nih.gov/pubmed/18294355

Colman RW. Are hemostasis and thrombosis two sides of the same coin? J Exp Med. 2006;20:493-495. https://www.ncbi.nlm.nih.gov/pubmed/16533890

Girolami A, Randi ML, Gavasso S, Lombardi AM, Spiezia F. The occasional venous thromboses seen in patients with severe (homozygous) FXII deficiency are probably due to associated risk factors: a study of prevalence in 21 patients and review of the literature. J Thromb Thrombolysis. 2004;17:139-143. https://www.ncbi.nlm.nih.gov/pubmed/15306750

Renne T, Pozgajova M, Gruner S, et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med. 2005;202:271-281. https://www.ncbi.nlm.nih.gov/pubmed/16009717

Matsuura T, Kobayashi T, Asahina T, Kanayama N, Terao T. Is factor XII deficiency related to recurrent miscarriage. Semin Thromb Hemost. 2001;27:115-20. https://www.ncbi.nlm.nih.gov/pubmed/11372764

INTERNET

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:234000; Last Update:11/28/2006. Available at: https://omim.org/entry/234000 Accessed on: April 20, 2012.

Canadian Hemophilia Society. Factor XII Deficiency. 2004. Available at: https://www.hemophilia.ca/en/bleeding-disorders/other-factor-deficiencies/factor-xii-deficiency/ Accessed On: April 20, 2012.

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