What is the dose of protamine sulfate (Protamine) for reversal of heparin?

Protamine Sulfate Dosing for Heparin Reversal

For unfractionated heparin reversal, protamine sulfate should be administered at a dose of 1 mg for every 100 units of heparin given in the previous 2-3 hours, with a maximum single dose of 50 mg. 1, 2, 3

Unfractionated Heparin Reversal Protocol

Initial Dosing

• Calculate dose based on timing of last heparin administration:
  • Within 2-3 hours: 1 mg protamine per 100 units of heparin 1
  • 30-60 minutes after heparin: 0.5-0.75 mg per 100 units 1, 2
  • 60-120 minutes after heparin: 0.375-0.5 mg per 100 units 1, 2

  • 120 minutes after heparin: 0.25-0.375 mg per 100 units 1, 2

Administration Method

• Administer by slow intravenous injection over 10 minutes 1, 3
• Never exceed 5 mg/min infusion rate 1
• Maximum single dose: 50 mg 1, 3

Monitoring and Additional Dosing

• Check activated partial thromboplastin time (aPTT) 5-10 minutes after administration 2
• If aPTT remains elevated, administer additional protamine at 0.5 mg per 100 units of unfractionated heparin 1

Low Molecular Weight Heparin (LMWH) Reversal

While protamine is less effective for LMWH (neutralizes only 60-75% of anti-Xa activity) 2, it remains the recommended agent:

Enoxaparin

• If given within 8 hours: 1 mg protamine per 1 mg enoxaparin (maximum 50 mg) 1, 2
• If given within 8-12 hours: 0.5 mg protamine per 1 mg enoxaparin 1
• After 3-5 half-lives: Protamine likely not needed 1

Dalteparin, Nadroparin, Tinzaparin

• 1 mg protamine per 100 anti-Xa units of LMWH (maximum 50 mg) 1, 2

For Persistent Bleeding with LMWH

• Consider redosing with 0.5 mg protamine per 100 anti-Xa units or per 1 mg enoxaparin 1

Important Precautions

• Protamine itself can cause anticoagulation in excess doses by inhibiting factor V activation 2
• Potential adverse effects include hypotension, bradycardia, and anaphylactoid reactions, especially with rapid administration 2
• Protamine is ineffective for pentasaccharides (e.g., fondaparinux) 1, 2
• For prophylactic subcutaneous heparin, routine reversal is not necessary unless aPTT is significantly prolonged 1, 2

Clinical Considerations

• Recent evidence suggests fixed protamine dosing (250 mg) may be comparable to ratio-based dosing in certain cardiac surgery settings, but the standard ratio-based approach remains recommended for most clinical scenarios 4
• Anti-Xa levels can be useful to assess anticoagulation before protamine administration but may not accurately reflect clinical effectiveness of reversal 5
• Always have resuscitation equipment available when administering protamine due to risk of severe reactions 2