What is the recommended management for a patient with Antithrombin III (ATIII) deficiency to prevent thrombosis?

Management of Antithrombin III Deficiency

Primary Recommendation

For patients with confirmed Antithrombin III deficiency and a history of thrombosis, initiate long-term anticoagulation with warfarin targeting an INR of 2.0-3.0, and consider indefinite therapy for those with idiopathic thrombosis. 1, 2

---

Understanding AT III Deficiency

AT III deficiency significantly increases the risk of venous thromboembolism and can be either inherited (autosomal dominant, prevalence 1 in 2,000 to 1 in 20,000) or acquired. 1

Key diagnostic features:

• Congenital deficiency typically presents with AT III levels <50% of normal 1, 2
• Patients commonly experience lower-extremity deep vein thrombosis and pulmonary embolism during teenage years or young adulthood 1, 2
• Normal newborns have physiologically lower AT III levels (20-80% of adult values) that normalize by 6 months of age 1

---

Long-Term Anticoagulation Strategy

Warfarin is the cornerstone of management:

• Start with 2-5 mg daily, adjusting based on INR monitoring 2
• Target INR: 2.0-3.0 1, 2
• Duration: Indefinite therapy for patients with idiopathic thrombosis 1, 2

For acute thrombotic events:

• Initial treatment with heparin followed by transition to oral anticoagulants 1
• Bridge therapy is critical during the warfarin initiation period 1

---

Managing Heparin Resistance

AT III deficiency causes heparin resistance because heparin's anticoagulant effect depends entirely on AT III. 3

Diagnosis of heparin resistance:

• Suspect when ACT fails to prolong beyond 300 seconds despite administration of >600 U/kg heparin 1, 2, 3
• Measure AT III levels before initiating treatment in suspected cases 3

Treatment of heparin resistance:

• AT III concentrate is the primary treatment and is superior to fresh frozen plasma 1, 2, 3
• AT III concentrate advantages include: diminished volume load, absence of transfusion-related complications, rapid availability, and more predictable AT III level increases 3
• If AT III concentrate is unavailable, use fresh frozen plasma as an alternative 1

---

Monitoring Requirements

Essential laboratory monitoring includes:

• Activated Partial Thromboplastin Time (aPTT): target 1.5-2.5 times control value 4, 3
• Anti-Factor Xa levels: target 0.3-0.7 U/mL for patients on extracorporeal support 4, 3
• ACT: check at least every 30 minutes during cardiopulmonary bypass 3
• AT III levels: monitor at least daily during high-risk situations (ECMO, CPB) 4

---

Special Clinical Scenarios

Pregnancy and postpartum management:

• Postpartum antithrombotic prophylaxis is mandatory for women with AT III deficiency and family history of VTE 1, 2, 3

Perioperative management:

• Discontinue warfarin 4 days before procedure 2
• Bridge with full-dose heparin or LMWH 2
• Discontinue heparin 5 hours before procedure 2
• Resume both postoperatively until INR therapeutic for >48 hours 2

Cardiopulmonary bypass:

• Target ACT must be achieved before initiating bypass 3
• Administer additional heparin if ACT is below target 3
• AT III supplementation may be necessary to achieve adequate anticoagulation 4

ECMO support:

• Transfusion with fresh-frozen plasma or AT III supplementation should be given to correct AT III deficiency 4
• Maintain AT III levels >1 U/mL 4
• AT III deficiency is especially common in patients <1 year of age on ECMO 4

---

Critical Pitfalls to Avoid

Do not use AT III concentrate in sepsis:

• The KyberSept trial and Cochrane analysis showed no mortality benefit, especially with concomitant heparin use 2
• High-dose corticosteroids provide no benefit in septic patients with AT III deficiency 2

Do not use AT III concentrates in bleeding trauma patients 1

Rule out acquired causes before diagnosing hereditary deficiency:

• Liver dysfunction 1, 3
• Proteinuria/nephrotic syndrome 1, 3
• Disseminated intravascular coagulation (DIC) 1, 3
• Acute thrombosis 1, 3
• Recent surgery 1, 3
• Oral contraceptive use 1, 3

Consider poor gastrointestinal absorption:

• Patients who fail to reach therapeutic INR goals on warfarin may have absorption issues 5
• Consider switching to low molecular weight heparin or novel oral anticoagulants in refractory cases 5

---

Testing Recommendations

Test for AT III deficiency in:

• Patients with VTE at young age without identifiable risk factors, especially with strong family history 1
• First episode of VTE in absence of major reversible risk factor 1
• Recurrent VTE episodes 1
• First-degree relatives of individuals with confirmed AT III deficiency 1
• VTE at unusual body sites 1
• Thrombosis during pregnancy 1