How is antithrombin III (AT III) enzymatic activity measured and treated?

Antithrombin III Measurement and Treatment

Antithrombin III (AT III) deficiency should be treated with AT III concentrate as the primary intervention, especially in cases of heparin resistance, as it provides superior clinical outcomes compared to alternatives like fresh frozen plasma. 1

Measurement of AT III Activity

• AT III activity is primarily measured through functional assays that assess its enzymatic inhibitory action against serine proteases (thrombin and factor Xa) 2, 3

• Common laboratory tests for AT III include:

  • Functional assays measuring AT III activity in serum and plasma 3
  • Immunological assays measuring AT III antigen levels 3
  • Anti-Xa activity assays, which can indirectly reflect AT III function 2

• The most widely used method is the chromogenic substrate assay, which measures the inhibition of thrombin or factor Xa by AT III in the presence of heparin 3

Clinical Significance of AT III Deficiency

• AT III deficiency can be inherited (autosomal dominant with prevalence of 1 in 2000 to 1 in 20,000) or acquired 2
• Congenital AT III deficiency typically presents with AT III levels <50% of normal, with increased risk of venous thromboembolism 2
• Normal newborns and infants have physiologically lower AT III levels (20-80% of adult values) that approach adult values by 6 months of age 2
• Acquired AT III deficiency can occur in various clinical conditions including:
  • Protein-losing states (nephrotic syndrome) 4
  • Liver dysfunction 4
  • Disseminated intravascular coagulation 4
  • Major surgery 5

Diagnosis of Heparin Resistance Due to AT III Deficiency

• Heparin resistance should be suspected when the Activated Clotting Time (ACT) fails to prolong beyond 300 seconds despite administration of >600 U/kg heparin 2
• AT III deficiency is a major cause of heparin resistance as heparin's anticoagulant effect depends on AT III 2
• In patients with suspected heparin resistance, AT III levels should be measured before initiating treatment 2

Treatment of AT III Deficiency

AT III Concentrate

• AT III concentrate is the preferred treatment for AT III deficiency, particularly in cases of heparin resistance 1
• AT III concentrate is a stable, lyophilized product derived from pooled normal human plasma, purified, and heat-treated to eliminate viral transmission 2
• Advantages of AT III concentrate over fresh frozen plasma include:
  • Diminished volume load 2
  • Absence of transfusion-related complications 2
  • Rapid availability 2
  • More predictable increase in AT III levels 1

Fresh Frozen Plasma

• Fresh frozen plasma can be used as an alternative source of AT III when concentrate is unavailable 1
• Disadvantages of fresh frozen plasma include:
  • Higher volume load 2
  • Risk of transfusion-related complications 2
  • Less predictable increase in AT III levels 2
  • Limited evidence supporting its effectiveness for heparin resistance 2

Monitoring Treatment

• Regular monitoring of coagulation parameters is essential during treatment:
  • Activated Partial Thromboplastin Time (aPTT) - target 1.5-2.5 times control value 1
  • Anti-Factor Xa levels - target 0.3-0.7 U/mL for patients on extracorporeal support 1
  • ACT should be checked at least every 30 minutes during cardiopulmonary bypass 2

Special Clinical Scenarios

Cardiopulmonary Bypass

• For patients undergoing cardiopulmonary bypass with AT III deficiency:
  • Target ACT should be achieved before initiating cardiopulmonary bypass 2
  • Additional heparin should be given if ACT is below target value 2
  • In cases of heparin resistance, AT III supplementation is indicated 2

Pregnancy

• Postpartum antithrombotic prophylaxis is recommended for women with AT III deficiency and family history of venous thromboembolism 1

Common Pitfalls and Considerations

• Anti-Xa assays used to monitor heparin therapy can be affected by concurrent use of direct oral anticoagulants (DOACs), potentially leading to falsely elevated results 2
• Oral factor Xa inhibitors can interfere with UFH anti-Xa measurement even at clinically insignificant levels (<30 ng/mL) 2
• Physicians should inform the laboratory about recent (<1 week) oral FXa inhibitor treatment when requesting aPTT or anti-Xa for UFH monitoring 2
• Before diagnosing hereditary AT III deficiency, rule out acquired causes of low AT III levels such as liver dysfunction, proteinuria, DIC, acute thrombosis, recent surgery, or oral contraceptive use 1