What is the recommended agent for heparin reversal?

Heparin Reversal Agent

Protamine sulfate is the recommended agent for heparin reversal, administered at a dose of 1 mg per 100 units of heparin given in the previous 2-3 hours with a maximum single dose of 50 mg. 1

Unfractionated Heparin (UFH) Reversal

Indications for Reversal

• Urgently reverse anticoagulation when intracranial hemorrhage develops during full-dose heparin infusion 1
• Major bleeding on therapeutic heparin
• Emergency surgery requiring normal coagulation
• Heparin overdose with bleeding complications

Dosing Protocol

1. Initial dose calculation:

   • 1 mg protamine for every 100 units of heparin administered in the previous 2-3 hours 1, 2
   • Maximum single dose: 50 mg 1, 2

2. Administration method:

   • Administer by slow IV injection over approximately 10 minutes to minimize adverse effects 1
   • Rapid administration can cause hypotension, bradycardia, and anaphylactoid reactions

3. Monitoring and additional dosing:

   • Check aPTT 5-10 minutes after protamine administration to confirm reversal 1
   • If aPTT remains elevated, administer additional protamine at 0.5 mg per 100 units of unfractionated heparin 1

4. Time-based considerations:

   • The amount of protamine required decreases over time as heparin is metabolized 2
   • For dosing purposes, assume heparin has a half-life of about 30 minutes after IV injection 2

Low Molecular Weight Heparin (LMWH) Reversal

Indications for Reversal

• Major bleeding on therapeutic LMWH
• Intracranial hemorrhage while on LMWH 1

Dosing Protocol for LMWH

1. For enoxaparin:

   • If given within 8 hours: 1 mg protamine per 1 mg of enoxaparin (maximum 50 mg) 1, 3
   • If given within 8-12 hours: 0.5 mg protamine per 1 mg of enoxaparin 1, 3
   • After 12 hours (3-5 half-lives): protamine likely not needed 1, 3

2. For dalteparin, nadroparin, and tinzaparin:

   • 1 mg protamine per 100 anti-Xa units of LMWH administered (maximum 50 mg) 1

3. For persistent bleeding:

   • Consider redosing protamine (0.5 mg per 100 anti-Xa units or per 1 mg of enoxaparin) 1, 3

Important Caveats and Limitations

Efficacy Considerations

• Protamine only partially reverses LMWH (approximately 60-75% of anti-Xa activity) 3, 4
• Clinical effectiveness in LMWH reversal is variable, with bleeding continuing in some patients despite protamine administration 5
• Protamine has negligible effects on pentasaccharides (e.g., fondaparinux) 4

Safety Considerations

• Fatal reactions resembling anaphylaxis have been reported with protamine 2
• Administer only when resuscitation techniques and treatment for anaphylactoid shock are readily available 2
• Higher risk of adverse reactions in patients with:
  • Fish allergies
  • Previous protamine exposure (including NPH insulin)
  • Vasectomized men

Special Situations

• Prophylactic subcutaneous heparin:

  • Routine reversal not recommended 1
  • Consider reversal only if aPTT is significantly prolonged 1

• Pentasaccharides (e.g., fondaparinux):

  • Protamine is NOT effective and should not be used 1
  • For reversal of pentasaccharides, consider activated PCC (20 IU/kg) or rFVIIa (90 μg/kg) if necessary 1

Alternative Approaches

• For cardiac surgery, a fixed 250 mg protamine dose may be as effective as ratio-based dosing while conserving protamine supply 6
• Novel heparin antagonists based on virus-like particles are being investigated and may provide more consistent reversal than protamine 7

By following these evidence-based guidelines for protamine administration, clinicians can effectively manage heparin-associated bleeding while minimizing the risks associated with reversal agents.