How should heparin therapy be managed in patients with low anti-thrombin 3 (AT3) levels, particularly those with suspected or confirmed thrombosis and requiring anticoagulation?

Heparin and Antithrombin III Management

When heparin therapy fails to achieve adequate anticoagulation despite escalating doses, suspect antithrombin III (AT3) deficiency and consider AT3 supplementation, particularly when AT3 activity falls below 60-80%, though routine prophylactic AT3 repletion is not supported by current evidence.

Understanding the Heparin-AT3 Relationship

Heparin requires AT3 to exert its anticoagulant effect, increasing AT3's affinity for thrombin by approximately 1000-fold 1. Heparin resistance should be suspected when doses exceed 35,000 IU/day (or >600 U/kg) fail to achieve target activated clotting time (ACT) or activated partial thromboplastin time (aPTT) values 2, 3, 4.

When to Monitor AT3 Levels

Monitor AT3 activity in the following clinical scenarios:

• Patients requiring escalating heparin doses without achieving therapeutic anticoagulation targets 1
• Patients on ECMO support, especially those <1 year of age (highest risk group) 1
• Patients with suspected thrombosis despite adequate heparin dosing 1
• Cardiac surgery patients on cardiopulmonary bypass requiring ACT >400 seconds 3, 4
• Patients receiving asparaginase therapy or with disseminated intravascular coagulation 3

AT3 deficiency occurs frequently during ECMO support, with 71% of patients showing AT3 activity below 70% within 24-72 hours of ECMO initiation 1.

Target AT3 Levels and Supplementation Strategy

For ECMO Patients:

• Check AT3 levels at least daily along with anti-FXa levels, PT, PTT, fibrinogen, and platelet count 1
• Suspect AT3 deficiency when increasing heparin doses are needed to maintain target ACT (180-220 seconds) 1
• Target AT3 activity >50-80% when supplementation is considered, though the Extracorporeal Life Support Organization suggests this only when heparin is at maximum dose and anticoagulation goals are not met 1
• Maintain AT3 >1 U/mL (equivalent to >100%) in postcardiotomy ECMO patients with ongoing bleeding risk 1

For Non-ECMO Patients with Heparin Resistance:

• When AT3 activity is ≤60% and heparin resistance is confirmed, first reduce UFH to 500 IU/hour to prevent bleeding complications 3
• Administer AT3 concentrate to achieve AT3 activity >80% 3
• After AT3 normalization, adjust UFH dose to maintain aPTT 60-100 seconds (1.5-2.5 times control) 1, 3

Dosing of AT3 Concentrate:

• Initial dose: 500 units of AT3 concentrate 4
• If ACT remains subtherapeutic, administer second 500-unit dose 4
• In cardiac surgery patients, 85% achieved therapeutic ACT with 500 units, while 15% required 1000 units total 4
• Alternative: Fresh frozen plasma (2-4 units provides approximately 1000 units of AT3) 1, 5

Critical Evidence Regarding AT3 Repletion

The 2023 Anaesthesia guidelines provide the most recent high-quality recommendation: AT3 monitoring is suggested in patients with thrombosis, but current data does not support routine AT3 repletion 1. This represents a significant nuance:

• A prospective RCT in VV-ECMO patients found that AT3 supplementation (maintaining 80-120% activity) failed to decrease UFH requirements and showed no difference in bleeding, transfusions, or thrombosis compared to controls 1
• Most retrospective studies report AT3 supplementation did not achieve anticoagulation goals more quickly or decrease thrombotic risk 1
• AT3 supplementation may increase bleeding risk by potentiating unbound heparin activity 1

Alternative Anticoagulation When AT3 Deficiency Persists

When AT3 deficiency cannot be corrected or heparin resistance persists despite AT3 supplementation:

• Switch to direct thrombin inhibitors (lepirudin, argatroban, bivalirudin) that do not require AT3 for activity 1, 6
• Consider rivaroxaban (a direct factor Xa inhibitor) for patients with homozygous AT3 deficiency causing heparin-resistant thrombosis 7
• For cardiac surgery with heparin resistance, 85% of patients with subnormal AT3 achieved therapeutic ACT with AT3 concentrate, avoiding the need for alternative anticoagulants 4

Monitoring Strategy During AT3 Supplementation

Do not rely exclusively on ACT for anticoagulation management 1. Essential confirmatory tests include:

• Anti-FXa levels (target 0.3-0.7 U/mL for ECMO patients) 1
• aPTT (target 1.5-2.5 times control) 1, 3
• Repeat AT3 activity after supplementation to confirm correction 1
• Platelet count, fibrinogen, PT, hemoglobin 1

Critical Pitfalls to Avoid

• Never continue escalating heparin doses indefinitely without checking AT3 levels—this increases bleeding risk without improving anticoagulation 2, 3
• Do not administer AT3 concentrate without first reducing heparin dose to 500 IU/hour in non-ECMO patients, as this dramatically increases bleeding risk 3
• Avoid routine prophylactic AT3 supplementation in ECMO patients, as evidence shows no benefit and potential harm 1
• Remember that heparin resistance has multiple causes beyond AT3 deficiency, including fever, thrombosis, infection, myocardial infarction, and cancer—adjust heparin based on anti-FXa levels in these cases 2
• If heparin-induced thrombocytopenia (HIT) is suspected (platelet count <100,000/mm³ or recurrent thrombosis), immediately discontinue all heparin products and switch to direct thrombin inhibitors rather than supplementing AT3 1, 8, 2

Special Population: Cardiac Surgery

For patients undergoing cardiopulmonary bypass with heparin resistance:

• Heparin resistance occurs in approximately 20% of patients on heart-lung machines 3
• Most patients (85%) defined as heparin-resistant have subnormal AT3 activity (mean 67%) 4
• AT3 concentrate (500-1000 units) prolongs mean ACT from 492 to 789 seconds without additional heparin 4
• Mean heparin dose response increases from 36.5 to 69.3 s×U⁻¹×mL⁻¹ with AT3 treatment 4