Antithrombin (AT) Deficiency Profile

Antithrombin (AT), often referred to as antithrombin III, is a glycoprotein produced in the liver.^7-9 AT is a serine protease inhibitor, or SERPIN, that irreversibly inhibits several of the enzymes involved in hemostasis. In this way, AT serves an important role in controlling coagulation by limiting the extent of thrombus formation. AT inhibits several steps of the coagulation cascade by binding to the catalytic sites of thrombin (factor IIa) and factors IXa, Xa, XIa, and XIIa. The complexes of AT with these thrombogenic serine proteinases are then rapidly cleared from the plasma. The binding of AT to these coagulation factors is slow in the absence of heparin. Heparin sulfate from endothelial cells or exogenously administered heparin binds to a specific site on the AT molecule. This produces a conformational change in the structure of AT, enhancing its binding to the activated coagulation factors by 1000-fold.⁸ Congenital defects in both the heparin binding site and the proteinase binding site of AT can cause functional deficiencies in AT activity.

Congenital AT deficiency: Congenital AT deficiency has been estimated to occur in approximately 3 out of 1000 individuals.⁸ Heterozygous AT deficiency is responsible for approximately 4% of families with inherited thrombophilia.⁷ Approximately 1% of cases of initial episodes of venous thrombosis are associated with congenital AT deficiency.⁷ Approximately 85% of individuals with congenital AT deficiency will experience at least one thrombotic episode by age 55 and recurrent thrombotic events are common.^8,9 Initial thrombotic events frequently occur between 20 and 30 years of age.⁸ Thrombosis can sometimes occur at unusual sites such as the mesenteric and axillary veins. In the majority of cases, thrombosis can be linked to trauma, surgery, pregnancy, oral contraceptive use, or other risk factors; however, thrombosis occurs spontaneously with no precipitating events or other known risk factors in about 33% of cases.⁸

Congenital AT deficiency can be classified as either type I or type II.^7-9 Type I deficiency results from a quantitative reduction in AT production, leading to a simultaneous decrease of both the functional and antigenic levels of AT. In type II deficiency, AT antigen concentration is normal but its activity is diminished because a fraction of the AT is dysfunctional due to genetic defect. This is reflected by a diminished AT activity in the context of normal AT antigen levels. Type II deficiency is more common than type I.

Acquired AT deficiency: Acquired AT deficiency is more common than congenital deficiency.^7-9 AT levels can be diminished in women receiving oral contraception or estrogen replacement therapy.⁷ Levels can also be diminished during pregnancy. Oral anticoagulant therapy with warfarin will lower AT levels. AT levels are usually diminished in patients with disseminated intravascular coagulation (DIC) and sepsis. AT levels can be transiently diminished after a thrombotic event or surgery. AT deficiency can be found in patients with severe hepatic disorders (hepatitis, cirrhosis, etc) due to diminished synthesis and nephrotic syndrome due to urinary protein loss. Malignancy and inflammatory bowel disease can also produce diminished AT levels.⁹ Drug therapy with L-asparaginase or fluorouracil can also reduce AT levels.