NORD gratefully acknowledges Kenneth A. Bauer, MD, Professor of Medicine, Harvard Medical School, for assistance in the preparation of this report.
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 (in birth control pills) 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 who develop blood clots. This occurs rarely and may be due to the presence of higher levels of a secondary plasma inhibitor of thrombin called alpha-2 macroglobulin.
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 involving the liver, kidneys, or treatment of certain types of blood disorders, e.g.,. leukemias with a drug called L-asparaginase. Low antithrombin levels may also be temporarily associated with some other conditions such as heparin therapy, disseminated intravascular coagulation usually due to severe infection of the blood stream, severe trauma, severe burns or the presence of 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 as a homozygote. Homozygous babies with antithrombin deficiency seldom survive.
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.
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 levels (acute clots, heparin therapy, liver or kidney disease, etc.) without the patient having 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.
Due to a lack of clinical studies, hematologists differ in their opinions regarding 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 at the time of delivery.
For people with very 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 suggest that the incidence ranges anywhere from 3% to 50%. Many recommend the use of subcutaneous low molecular weight 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 increased risk of a thromboembolic event unless appropriate preventive measures are taken. 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.
Two different concentrates of antithrombin concentrate are available in the US. Antithrombin concentrate (Thrombate) is a highly purified and viral-safe product prepared from pooled normal human plasma. Its half-life in the circulation is approximately 2.8 to 4.8 days. A recombinant human antithrombin (Atryn), produced from the milk of transgenic goats, is also available. This product is only approved for use in high-risk situations (eg, surgery, childbirth) in patients with antithrombin deficiency.
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