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Antithrombin Deficiency

NORD is very grateful to Kenneth A. Bauer, MD, Professor of Medicine, Harvard Medical School, for assistance in the preparation of this report.

Synonyms of Antithrombin Deficiency

  • AT 3
  • AT III deficiency
  • thrombophilia, hereditary, due to AT III

Disorder Subdivisions

  • antithrombin III deficiency, classical (type I)
  • AT III variant IA
  • AT III variant IB

General Discussion

Antithrombin deficiency is a blood disorder characterized by the tendency to form clots in the veins (thrombosis). An inherited tendency to thrombosis is known as thrombophilia. Antithrombin is a substance in the blood that limits the blood's ability to clot (coagulation). In people with congenital antithrombin deficiency, there is a reduced amount of this substance in the blood due to a genetic abnormality. Antithrombin deficiency may also be acquired; in such cases, the disorder may be reversible with treatment.

Symptoms

People with antithrombin deficiency are at risk of developing a blood clot (thrombus) within a vein (thrombosis). The first episode of thrombosis typically occurs before the age of 40 years. A thrombus is a clump of blood cells (i.e., platelets, clotting factors, fibrin, etc.) that may become attached (adhere) to the interior wall of a blood vessel, usually a deep vein in the leg. This may be brought on by surgery, pregnancy, childbirth, trauma, or use of oral contraceptives. Because pregnancy and estrogen use are significant risk factors, women with antithrombin deficiency tend to develop thrombosis at an earlier age than men.

About 40 percent of people with antithrombin deficiency develop a thrombus that pulls away from the wall of a vein and travels through the blood stream to the lungs (pulmonary embolism). Pulmonary emboli are dangerous and must be treated quickly. Thrombi are also common in the veins deep in the legs and pelvis (deep vein thrombosis or DVT), and the superficial smaller veins in the legs (superficial thrombophlebitis). They may also occur in the veins in the abdomen (mesenteric, portal, hepatic or splenic veins) or around the brain (sinus veins). A DVT of the leg often leads to an abnormal accumulation of body fluid (edema). Clots in the arteries of the heart may lead to heart attack (myocardial infarction) and clots in the arteries of the brain to stroke. However, arterial clots are rare in antithrombin deficiency.

There are several reports in the medical literature of newborn children with antithrombin deficiency that develop blood clots. This occurs rarely, but is probably due to the presence of a secondary plasma inhibitor of thrombin called alpha-2 macroglobulin.

Causes

Antithrombin deficiency may be inherited or acquired. Inherited AT deficiency increases the risk of blood clots; acquired AT deficiency often does not. Acquired AT deficiency is the consequence of some other disorder, usually of the liver, kidneys, or treatment of certain types of blood disorders, i.e. leukemias, with a drug called L-asparaginase. Low antithrombin levels may also be temporarily associated with some other disorders such as heparin therapy, disseminated intravascular coagulation usually due to severe infection of the blood stream, severe trauma, severe burns or acute blood clots.

Inherited antithrombin deficiency is transmitted as an autosomal dominant genetic trait. The altered (mutated) gene has been traced to gene map locus 1q23-q25.

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 1q23-q25" refers to a region on the long arm of chromosome 1 between bands 23 and 25. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

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.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. Heterozygote is the term used to describe such a person. Antithrombin deficiency is a dominant disease. However, not every person who has the abnormal gene will develop a blood clot. Geneticists call this variable clinical penetrance. Thus, antithrombin deficiency is a dominant disorder with variable clinical penetrance. The abnormal gene can be inherited from either parent, or very rarely can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. A person who inherits two altered genes, one from each of the parents is known among geneticists as a homozygote. Homozygous babies with antithrombin deficiency seldom survive.

Affected Populations

Antithrombin deficiency is a rare disorder that affects males and females in equal numbers. It is thought to occur in about one in every 3,000 to 5,000 people in the United States and is not limited to any particular ethnic group. It is estimated that approximately 1 percent of people who have venous thrombosis and embolism have congenital antithrombin deficiency. The acquired form of antithrombin deficiency is more prevalent than the congenital form of the disorder.

Related Disorders

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

Antiphospholipid syndrome (APLS) is a rare autoimmune disorder characterized by recurring blood clots in the veins or arteries. Clots in arteries may break away from the walls of the blood vessels and result in stroke. Women with this disorder can experience a high rate of miscarriages. Other symptoms may include inflammation and thickening of the valves of the heart, migraine headaches, and skin rashes. (For more information on this disorder, choose "Antiphospholipid" as your search term in the Rare Disease Database.)

Protein C deficiency is a rare inherited disorder characterized by the abnormal formation of blood clots and pulmonary emboli. Protein C is a vitamin K dependent coagulation factor. People with this deficiency have approximately 50 percent of the normal level of this factor in their blood. Symptoms may include blood clots in the deep veins of the legs, pulmonary emboli, and/or the brain.

Protein S deficiency is a rare inherited disorder characterized by the formation of recurrent blood clots and emboli. Occasionally protein S deficiency may be acquired as a result of kidney disease (i.e., nephrotic syndrome).

Standard Therapies

Diagnosis
A low blood level of antithrombin suggests that the patient may have antithrombin deficiency. However, it is important to keep in mind that many conditions can lower antithrombin level (acute clot, heparin therapy, liver or kidney disease, etc.) without the patient having an inherited antithrombin deficiency. Repeat testing should be done at a time when the patient is not ill, is not on heparin and does not have related medical problems.

Treatment
Due to a lack of clinical studies, hematologists differ over the treatment of antithrombin deficiency. Often, intravenous antithrombin concentrates are prescribed when surgery or infant delivery is close at hand. Antithrombin concentrates are also used to prevent venous clots when other blood thinners (such as heparin) are not advisable because they may lead to an increased risk of bleeding. This is especially true for neuro-surgery and in severe trauma or delivery.

For people with low antithrombin levels, heparin may not work well if administered alone. This is called heparin resistance. In order for heparin to work properly some antithrombin must be present in the blood. If heparin treatment is ineffective, then antithrombin concentrate may be prescribed.

Women with antithrombin deficiency are at particularly high risk for developing clots during pregnancy or after delivery. Little reliable information is available on the incidence of blot clots during pregnancy. Reports are widely spread and suggest that the incidence ranges anywhere from 3% to 50%. Many recommend the use of subcutaneous heparin injections during pregnancy for women with antithrombin deficiency.

Pregnant women with antithrombin deficiency are at slightly increased risk of losing the fetus without treatment. Pregnancy loss is likely due to blood clots forming in the placenta and cutting off the blood supply and oxygen to the fetus.

As noted above, patients with antithrombin deficiency who undergo surgery are at considerable risk of a thromboembolism event, unless accompanied by treatment. The duration of treatment with blood thinners or antithrombin concentrate depends on the type of surgery. In some cases treatment will last only a few days while in other instances treatment may last for several weeks.

A family in which one or more members have antithrombin deficiency should consult with a hematologist and genetic counselor who can help the family understand and cope with the disorder.

In 2009, the U.S. Food and Drug Administration approved ATryn for the prevention of blood clots in patients with hereditary antithrombin deficiency. This is the first approval for a biological product produced by genetically engineered (GE) animals.

ATryn is a therapeutic protein derived from the milk of goats that have been genetically engineered by introducing a segment of DNA into their genes (called a recombinant DNA or rDNA construct) with instructions for the goat to produce human antithrombin in its milk. Antithrombin is a protein that naturally occurs in healthy individual and helps to keep blood from clotting in the veins and arteries. ATryn is manufactured by GTC Biotherapeutics, Inc., Framingham, MA.

Investigational Therapies

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

Organizations related to Antithrombin Deficiency

References

TEXTBOOKS
Lichtman MA, Beutler E, Kipps TJ, Selisohn U, et al. Eds. Williams Hematology. 7th ed. New York, NY: McGraw-Hill Companies; 2006:1703-04, 1912-14, 1988-89.

Kasper, DL, Fauci AS, Longo DL, et al. Eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill Companies; 2005:685-86.

Manco-Johnson M. Congenital Antithrombin III deficiency. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:376-77.

Berkow R., ed. The Merck Manual-Home Edition. 2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:1000.

JOURNAL ARTICLES
Moll S. Thrombophilias -- practical implications and testing caveats. J Thromb Thrombolysis. 2006;21(1)7-15.

Wu O, Robertson L, Twaddle S, et al. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Health Technol Assess. 2006;10:1-110.

Franchine M, Veneri D. Inherited thrombophilia: an update. Clin Lab. 2005;51:357-65.

Pabinger I, Vormittag R. Thrombophilia and pregnancy outcomes. J Thromb Haemost. 2005;3:1603-10.

Janssen MC, den Heijer M, Cruysberg JR, Wollersheim H, Bredie SJ. Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost. 2005;93:1021-26.

Kyrle PA, Eichinger S. Deep vein thrombosis. Lancet. 2005;365:1163-74.

Feero WG. Genetic thrombophilia. Prim Care. 2004;31:685-709.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Serpin Peptidase Inhibitor, Clade C (Antithrombin), Member 1; SERPINC1. Entry No: 107300. Last Edited July 27, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed July 30, 2012.

Rajun A, Grethlein SJ, McKenna R. Antithrombin Deficiency Emedicine. http://emedicine.medscape.com/article/198573-overview. Updated January 10, 2012. Accessed July 30, 2012.

Harper JL. Antithrombin III Deficiency. Emedicine. http://emedicine.medscape.com/article/954688-overview. Updated August 1, 2011. Accessed July 30, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/08/02 00:00:00 GMT+0

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