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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 antithrombin's anticoagulant activity (approximately 1,000-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 heparin's anticoagulant activity.
The antithrombin gene on chromosome 1 encodes a glycoprotein of approximately 58,000 molecular weight that is synthesized in the liver and is present in a relatively high plasma concentration (approximately 2.3 umol/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 mutations 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 1:2,000 to 1:3,000 in general populations, although minor deficiency (antithrombin activity =70% to 75%) may be more frequent (approximately 1:350 to 1:650). In populations with venous thrombophilia, approximately 1% to 2% have antithrombin deficiency. Among the recognized hereditary thrombophilic disorders (including deficiencies of proteins C and S, as well as activated protein C [APC]-resistance [factor V Leiden mutation]), 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)
-Nephritic syndrome (urinary protein loss)
-L-asparaginase chemotherapy (decreased synthesis)
In general, the clinical implications (thrombotic risk) of antithrombin deficiency in these disorders are not well defined, although antithrombin replacement in severe DIC/IFC is being evaluated.(4) Assay of antithrombin activity may be of diagnostic or prognostic value in some acquired deficiency states.
Assessing abnormal results of the antithrombin activity assay. (ATTF / Antithrombin Activity, Plasma), which is recommended as the primary (screening) antithrombin assay
Diagnosing antithrombin deficiency, acquired or congenital, in conjunction with measurement of antithrombin activity
As an adjunct in the diagnosis and management of carbohydrate-deficient glycoprotein syndromes
Hereditary antithrombin deficiency is much less common than acquired deficiency. Diagnosis of hereditary deficiency requires clinical correlation, testing of both antithrombin activity and antithrombin antigen, and may be aided by repeated testing and by family studies. DNA-based diagnostic testing may be helpful, but is generally not readily available.
Acquired antithrombin deficiency may occur in association with a number of conditions (see Clinical Information). The clinical significance (thrombotic risk) of acquired antithrombin deficiency is not well established, but accumulating information suggests possible benefit of antithrombin replacement therapy in carefully selected situations.(4)
Increased antithrombin activity has no definite clinical significance.
Antithrombin activity (ATTF / Antithrombin Activity, Plasma) is usually used for monitoring treatment of antithrombin deficiency disorders, including infusion of antithrombin therapeutic concentrate.
Antithrombin antigen results are potentially affected by:
-Heparin (unfractionated or low-molecular-weight) >4 U/mL
-Hemoglobin >7 g/L
-Bilirubin >500 mg/L
-Lipemia; may lead to an over-estimation of the antithrombin antigen level
-Rheumatoid factor (RF) >800 IU/mL; may lead to over-estimation of the antithrombin antigen level
-Antirabbit antibodies; in certain subjects leads to aberrant results
-Heparin therapy may temporarily decrease plasma antithrombin antigen into the abnormal range
Normal, full-term newborn infants may have decreased levels (> or =35-40%) which reach adult levels by 180 days postnatal.*
Healthy, premature infants (30-36 weeks gestation) may have decreased levels which reach adult levels by 180 days postnatal.*
*See Pediatric Hemostasis References in Coagulation Studies in Special Instructions.
1. Bock SC: Antithrombin III and heparin cofactor II. In Hemostasis and Thrombosis. Fourth edition. Edited by RW Colman, J Hirsh, VJ Marder, et al. Philadelphia, Lippencott Williams and Wilkins, 2001, pp 321-333
2. Viazzer H: Hereditary and acquired antithrombin deficiency. Semin Thromb Hemost 1999;25(3):257-263
3. Conrad J: Antithrombin activity and antigen. In Laboratory Techniques in Thrombosis-A Manual. Second edition. Boston, MA, Kluwer Academic Publishers, 1999, pp 121-128
4. Lane DA, Bayston T, Olds RJ, et al: Antithrombin mutation database: update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1997 January;77(1):197-211