How is antithrombin deficiency diagnosed and treated?

Diagnosis and Treatment of Antithrombin Deficiency

Antithrombin deficiency is diagnosed through functional activity assays followed by antigen testing, and treated with anticoagulation therapy and antithrombin concentrates when necessary. 1

Diagnostic Approach

Initial Testing

• A functional antithrombin activity assay should be the first test performed when antithrombin deficiency is suspected 2, 1
• Testing should be considered in patients with:
  • Unprovoked venous thromboembolism (VTE) 3
  • Family history of thrombosis 3
  • Thrombosis at unusual sites (e.g., portal vein, cerebral veins) 4
  • Thrombosis at a young age (<50 years) 3

Confirmation Testing

• If antithrombin activity is low, the following steps should be taken:
  • Repeat testing on a fresh specimen to confirm the result 5
  • Perform an antithrombin antigen assay to differentiate between type I (quantitative) and type II (qualitative) deficiencies 1
  • Calculate the activity-to-antigen ratio (values <0.7 suggest type II deficiency) 1

Classification of Antithrombin Deficiency

• Type I: Quantitative deficiency with reduced antithrombin activity and antigen levels 3
• Type II: Qualitative deficiency with normal antigen levels but reduced functional activity 3
  • Type IIa: Defect in the thrombin-binding site (more thrombogenic) 3
  • Type IIb: Defect in the heparin-binding region (less thrombogenic) 3
  • Type IIc: Pleiotropic defect affecting multiple functional sites 3

Excluding Acquired Causes

• Before confirming hereditary antithrombin deficiency, rule out acquired causes:
  • Liver disease 5, 1
  • Disseminated intravascular coagulation (DIC) 1
  • Nephrotic syndrome/proteinuria 1
  • Heparin therapy (can cause false low results) 1
  • Recent thrombosis or surgery 1
  • Direct thrombin inhibitors (can cause falsely normal results in factor IIa-based assays) 1
  • Direct factor Xa inhibitors (can affect Xa-based assays) 1

Treatment Approach

Acute Thrombosis Management

• For patients with antithrombin deficiency and acute thrombosis:
  • Initiate therapeutic anticoagulation with non-heparin anticoagulants if heparin resistance is suspected 4
  • Consider antithrombin concentrates in cases of severe thrombosis or heparin resistance 3

Long-term Management

• Patients with antithrombin deficiency and history of thrombosis require:
  • Long-term anticoagulation therapy 3
  • Consideration of indefinite anticoagulation due to high recurrence risk 3

Special Situations

• Pregnancy management:

  • Increased thrombosis risk during pregnancy and postpartum period 3
  • Consider prophylactic anticoagulation throughout pregnancy and 6 weeks postpartum 3
  • Antithrombin concentrates may be needed during delivery or surgery 3

• Surgery or invasive procedures:

  • Perioperative bridging anticoagulation 3
  • Consider antithrombin supplementation to maintain adequate levels 3

Clinical Pearls and Pitfalls

• Family studies can be helpful in establishing the diagnosis of hereditary antithrombin deficiency 5
• Molecular testing may help determine thrombosis risk, as this varies among different mutations 1
• Pediatric reference ranges should be used for children under 6 months of age 1
• Antithrombin deficiency is associated with a 5-50 fold increased risk of venous thrombosis compared to the general population 3
• Unlike protein C and protein S deficiencies, antithrombin deficiency has only a weak association with arterial thrombosis 3
• Avoid prophylactic doses of danaparoid in patients with heparin-induced thrombocytopenia and antithrombin deficiency; curative doses are more effective 4