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. About 40 percent of people with antithrombin deficiency develop a thrombus that pulls away from the wall of a vein in the legs or pelvis (deep vein thrombosis or DVT) and travels through the blood stream to the lungs (pulmonary embolism or PE). Pulmonary emboli are dangerous and hence DVT and PE must be treated quickly. Thrombi also occur the superficial veins in the legs (superficial thrombophlebitis). Thrombi may also occur in the veins in the abdomen (mesenteric, portal, hepatic or splenic veins) or around the brain (sinus veins). 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.
The most common symptoms of a DVT are swelling, pain, redness, and warmth of the affected leg; pulmonary emboli typically present as chest discomfort on breathing (so-called pleuritic chest pain, shortness of breath, and anxiety; in more severe cases, patients can become dizzy, pass out (syncope), or go into shock.
There are several reports in the medical literature of newborn children with antithrombin deficiency who develop blood clots. This occurs rarely however, and may be due to the protective effect 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 a severe infection of the blood stream, severe trauma, severe burns or the presence of acute blood clots.
Hereditary antithrombin deficiency is caused by changes (mutations) in the SERPINC1 gene and many different mutations in this gene are responsible for individual cases of antithrombin deficiency.
Hereditary antithrombin deficiency is inherited as an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of an altered gene is necessary for the appearance of the disease. Heterozygote is the term used to describe such a person. However, not every person who has the altered gene will develop a blood clot. Geneticists call this variable clinical penetrance. Thus, antithrombin deficiency is an autosomal dominant disorder with variable clinical penetrance. The altered gene can be inherited from either parent, or very rarely can be the result of a new mutation in the affected individual. The risk of passing the altered gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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 though there are rare cases with so-called type IIB mutations.
Antithrombin deficiency is a rare disorder that affects males and females in equal numbers. Type I antithrombin deficiency is the most common subtype and 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 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 an adequate amount of 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. Reports of the incidence of blot clots during pregnancy in women with antithrombin deficiency range 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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