Antithrombin (Antithrombin III)

Function of Antithrombin
Antithrombin (previously known as Antithrombin III) is an important natural anticoagulant. Its function is to inhibit the activities of various serine proteinase enzymes produced during the clotting process. This includes not only thrombin as its name suggests, but also FXa, FIXa, IXa and probably FVIIa.

Antithrombin acts as a relatively inefficient coagulation inhibitor on its own. Its inhibitory activity is greatly (about 5,000-fold) accelerated by heparin. In fact, heparin's anticoagulant activity is almost entirely mediated via Antithrombin, and patients with Antithrombin deficiency are relatively resistant to heparin anticoagulation.

Antithrombin Deficiency
Antithrombin deficiency was initially described in 1965 and was the first inherited form of thrombophilia to be recognized. Congenital deficiency of Antithrombin leads to a severe hypercoagulable state. Such patients are generally heterozygotes as the homozygous state appears to be incompatible with life. It is an uncommon cause of venous thromboembolism, occuring in less than 0.5% of such patients. Acquired deficiency may follow surgery, treatment with L-Asparaginase, liver disease, and DIC and can complicate the nephrotic syndrome. Patients on continuous heparin therapy may also show modest falls in plasma Antithrombin activity. Full tern infants usually have AT levels between 40 and 70%.

Congenital Antithrombin deficiency is classified into Type I and Type II. Type I deficiency is a quantitative defect, characterized by reduced amounts of functionally normal antithrombin. Thus, the amount of Antithrombin present is not sufficient to inhibit the activated clotting factors. Type II Antithrombin deficiency is a qualitative defect, characterized by the presence of a functionally abnormal Antithrombin protein. Many different functional defects of Antithrombin have been described, including an abnormal ability to bind to heparin. Further information on the many Antithrombin defects can be obtained from the Antithrombin Mutation Database.

Laboratory Diagnosis of Antithrombin Deficiency
Laboratory diagnosis initially depends on measurement of Antithrombin activity in the patient's plasma. The Hemostasis and Thrombosis Laboratory uses a chromogenic assay for Antithrombin in which a fixed excess amount of purified thrombin is added to the test sample. After incubation in the presence of heparin, residual (non-inactivated) thrombin is measured with a specific chromogenic substrate. The normal range is 83 - 115%.

Low Antithrombin levels should be confirmed by repeat functional assay, preferably when the patient is not receiving heparin therapy, since this can reduced plasma Antithrombin levels. Direct thrombin inhibitors (DTI; lepirudin, argatroban, bivalirudin) may cause falsely elevated AT levels. Oral anticoagulants do not affect Antithrombin levels.

Determination of Antithrombin antigen will be necessary to classify the congenital deficiency into Type or Type II. The Hemostasis and Thrombosis Laboratory uses a Latex Immunassay to determine Antithrombin antigen. The normal range is 80 - 140%.

Treatment of Antithrombin Deficiency
Treatment of the patient with Antithrombin deficiency depends upon the individual patient's overall thrombotic risk. Initial treatment of a venous thrombosis will comprise heparin, followe by an oral anticoagulant for 3-6 months. Patients that have had multiple thromboembolic episodes or are at high risk of further episodes (e.g. those with multiple thrombotic risk factors) may be candidates for longer-term anticoagulation. Patients with Antithrombin deficiency in whom oral anticoagulants are contra-indicated (e.g. pregnancy or surgery) may require treatment with Antithrombin concentrate.