Which anticoagulant can be reversed with prothrombin complex concentrate off‑label when the monoclonal antibody antidote (andexanet alfa) is unavailable?

Factor Xa Inhibitors Can Be Reversed Off-Label with PCC When Andexanet Alfa Is Unavailable

When the specific monoclonal antibody antidote andexanet alfa is not available, prothrombin complex concentrate (PCC) or activated PCC (aPCC) should be administered off-label to reverse Factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, and betrixaban) in patients with major bleeding. 1

Which Anticoagulants and Reversal Strategy

Factor Xa Inhibitors (Primary Answer)

• Apixaban, rivaroxaban, edoxaban, and betrixaban are the anticoagulants that can be reversed with PCC or aPCC off-label when andexanet alfa is unavailable 1
• The American College of Cardiology explicitly recommends: "If andexanet alfa is not available, administer PCC or aPCC" for all Factor Xa inhibitors 1

Dabigatran (Direct Thrombin Inhibitor)

• Dabigatran can also be reversed with PCC or aPCC off-label when its specific antidote idarucizumab is unavailable 1
• However, the monoclonal antibody mentioned in your question (andexanet alfa) is specifically for Factor Xa inhibitors, not dabigatran 1

Dosing Recommendations for Off-Label PCC Use

For Factor Xa Inhibitors

• No specific weight-based dosing is established in guidelines for off-label PCC use with Factor Xa inhibitors 1
• Refer to prescribing information for maximum units when using PCC or aPCC 1
• Clinical practice typically uses 25-50 U/kg based on extrapolation from other indications, with an initial dose of 25 U/kg suggested to minimize thromboembolic risk 2, 3

Comparison: VKA Reversal (On-Label PCC Use)

For context, when PCC is used on-label for vitamin K antagonist reversal, specific dosing exists 1:

• INR 2 to <4: 25 units/kg
• INR 4-6: 35 units/kg
• INR >6: 50 units/kg
• Alternative fixed-dose: 1000 units for non-intracranial major bleed, 1500 units for intracranial hemorrhage

Evidence Quality and Limitations

Why This Is Off-Label

• PCC does not fully normalize thrombin generation in the presence of Factor Xa inhibitors at therapeutic concentrations 4
• PCC only normalizes thrombin generation at very low Factor Xa inhibitor concentrations (<75 ng/mL for endogenous thrombin potential, <37.5 ng/mL for peak thrombin) 4
• In contrast, andexanet alfa normalizes thrombin generation over a wide range of apixaban and rivaroxaban concentrations (19-2000 ng/mL) 4

Clinical Effectiveness Despite Limitations

• Clinical hemostasis was achieved in 68.6% of patients with major bleeding on apixaban or rivaroxaban who received aPCC when andexanet alfa was unavailable 5
• aPCC appears more effective than non-activated PCC for Factor Xa inhibitor reversal in vitro, with superior restoration of clotting time and thrombin generation parameters 6, 7, 8
• Concentrations as low as 0.08-0.24 U/mL aPCC were sufficient to restore thromboelastometry parameters in vitro 6

Additional Considerations

Activated Charcoal

• Consider activated charcoal for known recent ingestion of Factor Xa inhibitors within 2-4 hours 1

Thromboembolic Risk

• Thromboembolic events occur in approximately 3.7-8% of patients receiving PCC 3
• In one study of aPCC for Factor Xa inhibitor reversal, 8.6% of patients experienced thromboembolic events during hospitalization 5
• Prompt resumption of anticoagulation after bleeding control significantly reduces thrombotic risk 2

Product Differences

• Beriplex/Kcentra (contains heparin) may be less effective than Cofact (heparin-free) for Factor Xa inhibitor reversal 7
• Both products are four-factor PCCs, but heparin content may reduce effectiveness 7

Laboratory Monitoring

• Standard INR testing is not reliable for monitoring Factor Xa inhibitor activity 3
• Agent-specific anti-Xa levels should be considered if available, though laboratory testing should not delay PCC administration in life-threatening bleeding 2, 3