What is the management for patients with antithrombin III (ATIII) deficiency?

Management of Antithrombin III (ATIII) Deficiency

For patients with antithrombin III deficiency, long-term anticoagulation with vitamin K antagonists (target INR 2.0-3.0) is recommended for those with a history of thrombosis, while AT III supplementation is indicated when heparin resistance is present. 1

Understanding AT III Deficiency

• AT III deficiency can be inherited (autosomal dominant with prevalence of 1 in 2000 to 1 in 20,000) or acquired, and is associated with increased risk of venous thromboembolism 1
• Congenital AT III deficiency typically presents with AT III levels <50% of normal, with patients often experiencing lower-extremity venous thrombosis and pulmonary embolism in teenage years or young adulthood 2, 1
• 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

Clinical Manifestations and Diagnosis

• AT III deficiency increases risk of thrombosis, particularly venous thromboembolism 1
• Testing for AT III deficiency is recommended in patients with:
  • Venous thromboembolism occurring at a young age 1
  • VTE occurring without major reversible risk factors 1
  • Recurrent VTE episodes 1
  • First-degree relatives of individuals with confirmed AT III deficiency 1
• Before diagnosing hereditary AT III deficiency, rule out acquired causes of low AT III levels, such as liver dysfunction, proteinuria/nephrotic syndrome, DIC, acute thrombosis, recent surgery, or oral contraceptive use 1

Management Approach

Anticoagulation Therapy

• For patients with history of thrombosis, long-term anticoagulation with vitamin K antagonists (target INR 2.0-3.0) is recommended 1
• For acute thrombotic events, initial treatment with heparin followed by transition to oral anticoagulants is recommended 1
• Patients with AT III deficiency and a history of VTE are often candidates for indefinite anticoagulant treatment 1

Management of Heparin Resistance

• Heparin resistance is defined as the inability to achieve an ACT >300 seconds after administration of >600 U/kg heparin 2
• AT III deficiency should be suspected when the ACT fails to prolong beyond 300 seconds despite high-dose heparin administration 2, 1
• Treatment options for heparin resistance include:
  • AT III concentrate - preferred option to improve heparin sensitivity 1
  • Fresh-frozen plasma - alternative when AT III concentrate is unavailable, though it has disadvantages including volume load and transfusion-related complications 2, 1

Special Situations

Pregnancy Management

• Postpartum antithrombotic prophylaxis is recommended for women with AT III deficiency and a family history of VTE 1
• Some cases have been successfully managed with heparin alone during pregnancy, maintaining APTT in therapeutic range 3
• Other cases have required both heparin and AT III supplementation, particularly when beta thromboglobulin levels remained elevated despite heparin therapy 4

Surgical Management

• For patients undergoing surgery, AT III supplementation is indicated to reduce thrombotic risk 5, 6
• AT III concentrate should be administered before surgery at a dose calculated to increase AT III activity to at least 120% 6
• Initial doses of 1 U/kg body weight are typically used to achieve a 1.5% rise in plasma AT III level 5
• Subcutaneous heparin and oral anticoagulants should be initiated post-surgery 6

Monitoring Recommendations

• Regular monitoring of coagulation parameters is essential, including:
  • 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
  • AT III activity levels - particularly when administering AT III concentrate 6

Potential Pitfalls

• Patients with hereditary AT III deficiency receiving concurrent AT III therapy may experience enhanced anticoagulant effects of heparin, requiring dose reduction to reduce bleeding risk 7
• The half-life of administered AT III concentrate varies (reported between 7-14 hours), necessitating repeated dosing 6
• Despite theoretical benefits, clinical evidence for AT III concentrates in acquired AT III deficiency is limited, with no proven reduction in morbidity or mortality 8
• Avoid abrupt discontinuation of anticoagulation therapy, which may result in a temporary hypercoagulable state 1