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Antithrombin Deficiency

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  • Protein C deficiency
  • Protein S deficiency

    Antithrombin deficiency also referred to as antithrombin III in older literature is a genetically acquired trait, although there are other diseases including some forms of liver and kidney disease can also result in antithrombin deficiency. It was first described in 1965 and was the first inherited trait associated with thrombophilia.

    Mechanism of Action of Antithrombin Deficiency:
    Antithrombin is a potent inhibitor of the reactions of the coagulation cascade. Although the name, antithrombin, implies that it works only on thrombin, it actually serves to inhibit virtually all of the coagulation enzymes to at least some extent. The primary enzymes it inhibits are factor Xa, factor IXa and thrombin (factor IIa). It also has inhibitory actions on factor XIIa, factor XIa and the complex of factor VIIa and tissue factor. Its ability to limit coagulation through multiple interactions makes it one of the primary natural anticoagulant proteins. Its numerous interactions are depicted on the above figure.

    Antithrombin acts as a relatively inefficient inhibitor on its own. However, when it is able to bind with heparin, the speed with which the reaction that causes inhibition occurs is greatly accelerated; this makes the antithrombin-heparin complex a vital component of coagulation. This interaction is also the basis for the use of heparin and low-molecular-weight heparins as medications to produce anticoagulation.

    There are two primary types of antithrombin deficiency: type I and type II. Type I antithrombin deficiency is characterized by an inadequate amount of normal antithrombin present. In this case, there is simply not enough antithrombin present to inactivate the coagulation factors. In type II antithrombin deficiency, the amount of antithrombin present is normal, but it does not function properly and is thus unable to carry out its normal functions. In many cases, the antithrombin in type I deficiencies has a problem binding to heparin, although there have been multiple other changes to the antithrombin molecule described.

    Epidemiology of Antithrombin Deficiency:
    Antithrombin deficiency is believed to be present in about 0.02% of the population, however some studies have seen rates as high as 1.1% of the population. It is seen in about 4% of patients who have had a venous thromboembolic event,

    Risks of Antithrombin Deficiency:
    The overall estimated incidence (annual occurrence) of deep venous thrombosis is 1 episode for every 1000 persons. This does not separate patients who had predisposing conditions from those who do not.

    In patients who are homozygous* (both copies of the antithrombin gene are abnormal) for type II antithrombin deficiency, severe venous thrombosis as well as arterial thrombotic disease has been reported.

    The condition of being homozygous for type I antithrombin deficiency is thought to be incompatible with life, leading to death of the fetus prior to birth.

    Although isolated reports exist of arterial disease in patients with heterozygous* (one copy of the antithrombin gene is abnormal, one copy of the antithrombin gene is normal) antithrombin deficiency, there is no clear evidence of increased arterial disease in antithrombin deficiency. Based on these data, for persons with the antithrombin deficiency mutation, the most important preventive steps for the purposes of arterial disease are controlling other risk factors including: smoking, hypertension (high blood pressure), hyperlipidemia (high cholesterol), obesity and a sedentary lifestyle (limited activity).

    The role of the antithrombin deficiency and venous thromboembolic events is discussed in the table below. Relative risk is a numerical representation of the effects of a condition or treatment on an individual. If a condition or treatment has a relative risk of 1, patients with the condition have no additional risk or benefit from those without the condition. In the studies used below, a relative risk greater than 1 shows an increased risk. For the table below, a relative risk of 4 means that individuals with that condition are 4 times as likely as similar individuals without the same condition, to develop a venous thrombotic event. Despite the increased risk, it is important to remember that the relative risk is a statistical tool to help guide clinicians and scientists and that individual persons can have increased or decreased risks. Even with a very high relative risk, there is no guarantee that a venous thrombotic event will occur.

    Treatment of Antithrombin Deficiency:
    Treatment of antithrombin deficiency depends upon the individual patient's risk of recurrent thromboembolic disease. When one has a venous clot, regardless of what thrombophilic state(s) one may have, that person will receive anticoagulation. This is accomplished by several different medications: 1) heparin, 2) warfarin and 3) low-molecular-weight heparins. These medications are generally used for 3-6 months.

    Patients that have had multiple thromboembolic episodes or are at high risk of further episodes (for example, multiple deficiencies) may be considered for long-term oral anticoagulation (warfarin). Because studies have demonstrated an increased risk of recurrent venous thromboembolic disease in patients with antithrombin deficiency, long-term oral anticoagulation is recommended.

    The use of long-term anticoagulation has risks associated with it (approximately a 3% chance per year of having a major hemorrhage, of which approximately 1/5 are fatal). Beginning long-term anticoagulation is influenced by the patient's overall risk of recurrent thrombosis balanced against the risks associated with long-term anticoagulation on an individual basis.

    In addition to anticoagulation, antithrombin concentrates are also available for the treatment of antithrombin deficiency. Use of the antithrombin concentrates is not done routinely unless certain conditions are present that prevent the use of oral anticoagulants (warfarin). The two most common situations would be prior to a major surgery, in which oral anticoagulation must be discontinued, and during pregnancy, in which oral anticoagulation with warfarin is contraindicated.

    Pregnancy and Antithrombin Deficiency:
    As discussed above, oral anticoagulation with warfarin is no recommended during preganancy and is discontinued. In patients with a history of thrombosis and antithrombin deficiency, alternative anticoagulation can be done with heparin or low-molecular-weight heparins. In most cases, use of antithrombin concentrate as discussed above is not necessary and patients can be managed with heparin or low-molecular-weight heparins.

    Further Information:
    For further information on the other thrombophilic states, please refer to their respective pages. Brief information on the various medications that are discussed above and are regularly used to treat clotting disorders is discussed on the medication pages. A selection of the references used to compile this information is listed on the references page.

    Thrombophilic Status
    Relative Risk of Venous Thrombosis
    Normal 1
    Oral contraceptive (OCP) use 4
    Factor V Leiden, heterozygous 5 to 7
    Factor V Leiden, heterozygous + OCP 30 to 35
    Factor V Leiden, homozygous 80
    Factor V Leiden, homozygous + OCP ??? >100
    Prothrombin Gene Mutation, heterozygous 3
    Prothrombin Gene Mutation, homozygous ??? Also possible risk of arterial thrombosis
    Prothrombin Gene Mutation, heterozygous + OCP 16
    Protein C deficiency, heterozygous 7
    Protein C deficiency, homozygous Severe thrombosis at birth
    Protein S deficiency, heterozygous 6
    Protein S deficiency, homozygous Severe thrombosis at birth
    Antithrombin deficiency, heterozygous 5
    Antithrombin deficiency, homozygous type I
    Thought to be lethal prior to birth
    Antithrombin deficiency, homozygous type II
    Both arterial and venous thrombotic disease. Often have severe complications.
    Hyperhomocysteinemia 2 to 4
    *The terms heterozygous (hetero-different) and homozygous (homo-same) are terms used in genetics. The human genome contains to copies of the information. If the copies are the same, they are homozygous; if the copies are different, they are heterozygous. For example, take a protein called A. The normal genome would code for the protein as AA. This is homozygous for the normal protein. If there is a variation of the protein called a, there are two possible ways to get the a. The genome could be Aa, which is called heterozygous or the genome could be aa, which is called homozygous.