Antithrombin Activity, Plasma
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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 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: DVT and pulmonary embolism: PE) 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%-75%) may be more frequent (approximately 1:350-650). 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) or with 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 disseminated intravascular coagulation/ intravascular coagulation and fibrinolysis (DIC/IFC) is being evaluated.(4) Assay of antithrombin activity may be of diagnostic or prognostic value in some acquired deficiency states.
Diagnosis of antithrombin deficiency, acquired or congenital
Monitoring treatment of antithrombin deficiency disorders, including infusion of antithrombin therapeutic concentrate
Antithrombin deficiencies due to inherited causes are much less common than those due to acquired causes (see Clinical Information). Diagnosis or hereditary deficiency requires clinical correlation, with the prospect of repeat testing (including antithrombin antigen assay) and family studies (with appropriate counseling). DNA-based diagnostic testing may be helpful, but is not readily available.
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)
Antithrombin deficiency, acquired or congenital, may contribute to the phenomenon of "heparin therapy resistance" (requirement of larger heparin doses than expected for achievement of therapeutic anticoagulation responses). However, it may more often have other pathophysiology, such as "acute-phase" elevation of coagulation factor VIII or plasma heparin-binding proteins.
Increased antithrombin activity is of unknown hemostatic significance. Direct factor Xa inhibitors, rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) may falsely elevate the antithrombin activity and mask a diagnosis of antithrombin deficiency.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Antithrombin functional result is affected by:
-Heparin (unfractionated or low-molecular-weight) >4 U/mL
-Alpha(1)-antitrypsin >4 mg/mL
-Alpha(2)-macroglobulin >10 mg/mL
-Heparin cofactor II >4 U/mL
-Hemoglobin >500 mg/dL
-Bilirubin >40 mg/dL
-Triglycerides >2,300 mg/dL
Heparin therapy may temporarily decrease plasma antithrombin activity into the abnormal range.
Antithrombin activity in serum specimens may be significantly lower than in plasma.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
> or =6 months-adults: 80-130%
Normal, full-term newborn infants may have decreased levels (> or =35-40%), which reach adult levels by 90 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.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Lane DA, Olds RJ, Thein SL: Antithrombin and its deficiency. In Haemostasis and Thrombosis. Third edition. Edited by AL Bloom, CD Forbes, DP Thomas, et al: London, England, Churchill Livingstone, 1994, pp 655-670
2. Lane DA, Bayston T, Olds RJ, et al: Antithrombin mutation database: For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haesmostasis. Thromb Haemost 1997;77:197-211
3. Young G, Dricsoll MC: Coagulation abnormalities in the carbohydrate-deficient glycoprotein syndrome: case report and review of the literature. Am J Hematol 1999;60:66-69
4. Mammen EF: Antithrombin: its physiological importance and role in DIC. Semin Thromb Haemost 1998;24:19-25