When is testing for Antithrombin (AT) deficiency recommended?

Testing for Antithrombin Deficiency

Testing for antithrombin (AT) deficiency is recommended in patients with venous thromboembolism (VTE) occurring at a young age (e.g., <50 years), in the absence of identifiable risk factors, especially when there is a strong family history of VTE. 1

Recommended Testing Scenarios

High-Priority Testing Scenarios

• Testing is recommended for patients with a first episode of VTE occurring in the absence of a major reversible risk factor, as AT deficiency is a major persistent pro-thrombotic condition that may warrant indefinite anticoagulation 1
• Testing should be considered in patients with recurrent VTE episodes, as AT deficiency significantly increases the risk of recurrence 1
• Testing is appropriate for first-degree relatives of individuals with confirmed AT deficiency, particularly if the index case had thrombotic events 1

Moderate-Priority Testing Scenarios

• Testing should be considered in patients with VTE at unusual body sites 1
• Testing may be appropriate for patients with thrombosis during pregnancy 1
• Testing should be considered in patients with heparin resistance (inability to achieve therapeutic anticoagulation despite adequate heparin dosing) 2

Low-Priority Testing Scenarios

• Testing may be considered in patients with liver disease of unknown etiology, as AT deficiency can be associated with liver pathology 1
• Testing may be considered in patients with the syndrome of Wegener's granulomatosis (antiproteinase-3 vasculitis) 1

Testing Methodology

Initial Testing

• The recommended initial test is an AT activity (functional) assay 3, 4
• Normal AT activity levels generally exclude AT deficiency 3
• For borderline normal AT plasma levels (12-35 μmol/L or 90-140 mg/dL), further qualitative testing is recommended 1

Follow-up Testing

• If AT activity is low, an antigen test should be performed to calculate an activity-to-antigen ratio, which helps differentiate between type I (quantitative) and type II (qualitative) deficiencies 3, 5
• Repeat testing on a separate sample is recommended to confirm the diagnosis 5
• Consider molecular testing when available, as it may help determine thrombosis risk (which varies among different mutations) and identify mutations that might be missed by traditional activity assays 3

Special Considerations

Pediatric Testing

• Use pediatric reference ranges for AT testing until the age of 6 months, as normal newborns and infants have physiologically lower AT levels (20-80% of adult values) 2, 3

Excluding Acquired Causes

• Before diagnosing hereditary AT deficiency, rule out acquired causes of low AT levels 3, 4:
  • Liver dysfunction
  • Proteinuria/nephrotic syndrome
  • Heparin therapy
  • Disseminated intravascular coagulation (DIC)
  • Acute thrombosis
  • Recent surgery
  • Pregnancy
  • Oral contraceptive use

Potential False Results

• Be aware of factors that can cause falsely normal or elevated AT activity results 3:
  • Direct thrombin inhibitors (argatroban, bivalirudin, dabigatran) in factor IIa-based assays
  • Direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) in factor Xa-based assays

Clinical Implications of Testing

• Confirmed AT deficiency has significant implications for anticoagulation management and duration 1
• Patients with AT deficiency and a history of VTE are often candidates for indefinite anticoagulant treatment 1
• AT deficiency may require special management during high-risk periods such as surgery, pregnancy, or prolonged immobilization 2, 6
• In pediatric patients with VTE who have failed to respond clinically to standard anticoagulation, AT level measurement may be indicated to guide potential AT replacement therapy 1

Common Pitfalls to Avoid

• Avoid testing during acute thrombotic events, as this may lead to falsely low AT levels 3, 4
• Do not rely solely on AT activity levels without considering clinical context and family history 5
• Remember that heterozygous AT deficiency typically presents with AT levels approximately 40-60% of normal, while homozygous deficiency is usually fatal in utero 5, 7
• Consider that different types of AT deficiency (type I vs. various type II subtypes) have different thrombotic risks 5