Version July 2025
ALGORITHM —
INITIAL EVALUATION —
Antithrombin (AT; formerly called AT III) is a natural anticoagulant. AT activity level is measured in selected patients with venous thromboembolism (VTE) and features suggestive of an inherited thrombophilia, such as a strong family history of VTE, known familial AT deficiency, first VTE prior to age 50, VTE in an unusual site (eg, portal, mesenteric, or cerebral vein), or recurrent VTE. Individuals who have not had a VTE but have a known family history of AT deficiency are also candidates for testing. (See "Antithrombin deficiency".)
AT deficiency may be acquired or hereditary. Acquired conditions that can transiently reduce AT levels include heparin, disseminated intravascular coagulation (DIC), liver disease, major surgery, and others (table 1). Hereditary AT deficiency is rare. Patients with hereditary AT deficiency due to heterozygosity for a SERPINC1 mutation typically have AT activity in the range of 40 to 60 percent. The two major consequences of AT deficiency are increased thrombotic risk and possible resistance to heparin. Heparin resistance is more likely with AT activity <30 percent. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Heparin resistance/antithrombin deficiency'.)
A functional assay for plasma AT activity is the best first test for AT deficiency. It can detect type I (reduced AT levels) and type II (functionally defective AT) deficiencies. Assays for AT protein levels (rather than function), such as enzyme-linked immunosorbent assays (ELISAs), are also available; however, these are less useful for initial testing because they do not reflect AT function and will fail to identify individuals with a type II defect.
Most patients will require repeat measurement (using a functional assay) for evaluation of AT deficiency. Testing may be deferred if the results do not immediately impact management. Obtain hematology consultation to guide diagnostic decision-making:
●In an asymptomatic individual with a known family history of AT deficiency, a low AT in either a functional or immunoassay confirms the diagnosis of hereditary AT deficiency. Repeat testing is not necessary. Provide education about avoiding conditions that increase thrombotic risk (eg, estrogen-containing contraceptives, prolonged immobility) and about VTE prophylaxis. Inform other first-degree relatives about diagnosis and need for testing if not yet performed. (See "Antithrombin deficiency", section on 'VTE prophylaxis (hereditary deficiency)' and "Antithrombin deficiency", section on 'Testing of family members and genetic counseling'.)
●If the patient is anticoagulated during initial testing, obtain a repeat measurement using a functional assay to confirm AT deficiency. In an individual receiving an anticoagulant that can increase AT levels (eg, a direct oral factor Xa inhibitor such as apixaban, edoxaban, or rivaroxaban), low AT functional activity on repeat testing two or more days after the anticoagulant has been discontinued confirms AT deficiency. In an individual receiving unfractionated heparin, repeat testing should not be performed while the individual is receiving heparin; unfractionated heparin administered at therapeutic doses for several days can reduce AT levels.
●If the patient's presentation is most consistent with acquired AT deficiency (table 1), obtain AT activity after recovery using a functional assay. If this is not possible, it may be reasonable to base decisions on the result and its implication for management. In the majority of patients, normal AT activity on retesting implies an acquired transient deficiency and rules out hereditary AT deficiency.
REFERENCE RANGE —
Most laboratories report a normal AT functional activity of approximately 80 to 120 percent. The mean concentration of AT antigen in normal plasma is approximately 140 mcg/mL. Interpretation of a specific abnormal test result should be based upon the reference range reported by the laboratory.
CITATIONS —
The supporting references for this content are accessible in the linked topics.
