Clinical Information

Antithrombin is a member of the serine protease inhibitor (serpin) superfamily. It is the principal plasma anticoagulant serpin mediating inactivation of serine protease procoagulant enzymes, chiefly thrombin and coagulation factors Xa and IXa.(1) Heparin and certain other naturally occurring glycosaminoglycans markedly enhance the anticoagulant activity of antithrombins (approximately 1000-fold) by providing a template to catalyze formation of covalently bonded, inactive complexes of serine protease and antithrombin that are subsequently cleared from circulation. Antithrombin is the mediator of anticoagulant activity of heparin.

The antithrombin gene on chromosome 1 encodes a glycoprotein with a molecular weight of approximately 58,000 D, which is synthesized in the liver and is present in a relatively high plasma concentration (approximately 2.3 mcmol/L). The biological half-life of antithrombin is 2 to 3 days.

Hereditary antithrombin deficiency, a relatively rare autosomal dominant disorder, produces a thrombotic diathesis (thrombophilia). Individuals with hereditary antithrombin deficiency are usually heterozygous with plasma antithrombin activity results of approximately 40% to 70%. These patients primarily manifest with venous thromboembolism (deep vein thrombosis and pulmonary embolism) with the potential of development as early as adolescence or younger adulthood. More than 100 different alterations have been identified throughout the gene producing either the more common type I defects (low antithrombin activity and antigen) or the rarer type II defects (dysfunctional protein with low activity and normal antigen).(2) Homozygous antithrombin deficiency appears to be incompatible with life.

The incidence of hereditary antithrombin deficiency is approximately 1:2000 to 1:3000 in general populations, although minor deficiency (antithrombin activity =70%-75%) may be more frequent (approximately 1:350-650). In populations with venous thrombophilia, approximately 1% to 2% of individuals have antithrombin deficiency. Among the recognized hereditary thrombophilic disorders (including deficiencies of proteins C and S, as well as activated protein C-resistance [factor V Leiden variant]), antithrombin deficiency may have the highest phenotypic penetrance (greater risk of venous thromboembolism). Arterial thrombosis (eg, stroke, myocardial infarction) has occasionally been reported in association with hereditary antithrombin deficiency.

Hereditary deficiency of antithrombin activity can also occur because of defective glycosylation of this protein in individuals with carbohydrate-deficient glycoprotein syndromes (CDGS).(3) Antithrombin activity assessment may be useful as an adjunct in the diagnosis and management of CDGS.

Acquired deficiency of antithrombin is much more common than hereditary deficiency. Acquired deficiency can occur due to:

-Heparin therapy (catalysis of antithrombin consumption)

-Intravascular coagulation and fibrinolysis (ICF) or disseminated intravascular coagulation (DIC), and other consumptive coagulopathies

-Liver disease (decreased synthesis and/or increased consumption) or with nephritic syndrome (urinary protein loss)

-L-asparaginase chemotherapy (decreased synthesis)

-Other conditions(1)

In general, the clinical implications (thrombotic risk) of antithrombin deficiency in these disorders are not well defined, although antithrombin replacement in severe disseminated intravascular coagulation/intravascular coagulation and fibrinolysis (DIC/ICF) is being evaluated.(4) Assay of antithrombin activity may be of diagnostic or prognostic value in some acquired deficiency states.