What is the reversal protocol for heparin (unfractionated heparin) anticoagulation?

From the Guidelines

Protamine sulfate is the primary agent used for heparin reversal, and for unfractionated heparin (UFH), 1 mg of protamine should be administered for every 100 units of heparin received in the previous 2-3 hours, with a maximum single dose of 50 mg, as recommended by the most recent and highest quality study 1.

Key Considerations for Heparin Reversal

• The dose of protamine sulfate should be adjusted according to the time elapsed since the last heparin dose, with a recommended dose of 1 mg per 100 U heparin if given within 2-3 hours, as suggested by 1.
• If heparin is stopped for 30 to 60 minutes, the protamine sulfate dose is 0.5 to 0.75 mg per 100 U heparin, down to 0.375 to 0.5 mg per 100 U heparin after 60 to 120 minutes off heparin, as indicated by 1 and 1.
• Protamine sulfate should be administered slowly intravenously over 10 minutes to avoid hypotension and bradycardia, with a maximum infusion rate of 5 mg/min, as recommended by 1.

Monitoring and Safety Precautions

• Monitor activated partial thromboplastin time (aPTT) before and after administration to assess effectiveness, as suggested by 1.
• Be aware that protamine itself has some anticoagulant properties at high doses and can cause allergic reactions, particularly in patients with fish allergies, those who have received protamine-containing insulin, or those with previous protamine exposure, as noted by 1 and 1.
• Have resuscitation equipment available during administration due to the risk of anaphylaxis, as recommended by 1.

Additional Considerations

• For low molecular weight heparin (LMWH), use 1 mg of protamine per 1 mg of LMWH if given within 8 hours, or 0.5 mg of protamine per 1 mg of LMWH if given 8-12 hours prior, as suggested by the example answer.
• The decision to reverse heparin should be made on a case-by-case basis, taking into account the individual patient's risk of bleeding and thrombosis, as well as the clinical context, such as the presence of intracranial hemorrhage, as recommended by 1.

From the FDA Drug Label

Neutralization of Heparin Effect When clinical circumstances (bleeding) require reversal of the heparin effect, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period Each mg of protamine sulfate neutralizes approximately 100 USP heparin units.

The reversal of heparin can be achieved with protamine sulfate. The recommended dose is 1% solution by slow infusion, with no more than 50 mg administered in any 10-minute period. Each milligram of protamine sulfate neutralizes approximately 100 USP heparin units 2. It is essential to note that the amount of protamine required decreases over time as heparin is metabolized, and protamine should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available 2.

• Key points:
  • Protamine sulfate is used for heparin reversal
  • Dose: 1% solution by slow infusion
  • Maximum dose: 50 mg per 10-minute period
  • Each mg of protamine sulfate neutralizes approximately 100 USP heparin units
  • Administer with caution, as fatal reactions resembling anaphylaxis have been reported with protamine 2 2

From the Research

Reversal of Heparin

• Heparin reversal is a critical aspect of managing patients who have received heparin therapy, particularly in cases of bleeding or emergency surgery 3, 4, 5.
• Protamine is commonly used to reverse heparin, but its effectiveness can vary depending on the dose and the patient's condition 3, 4, 5.
• Studies have shown that protamine can be effective in reversing bleeding associated with low molecular weight heparin (LMWH), but it may not be effective in all patients 3.
• The dose of protamine required for reversal can be calculated using a mathematical formula based on activated clotting time (ACT) measurements, which can help reduce the risk of adverse effects 4.

Protamine Dose Calculation

• A study published in 2013 developed a method for calculating the protamine dose based on ACT measurements, which was shown to be effective in reducing the dose of protamine required for reversal 4.
• The formula takes into account the dose-response line and can be used to calculate the protamine dose required to neutralize heparin 4.
• Another study published in 2025 found that the protamine dose required for reversal was associated with significant reductions in activated partial thromboplastin time (aPTT) and international normalized ratio (INR) 5.

Alternative Reversal Agents

• Low molecular weight protamine has been proposed as a potential nontoxic heparin antagonist, which could reduce the risk of adverse effects associated with protamine use 6.
• Recombinant factor VIIa has been investigated as a potential antidote for LMWH-induced bleeding, but its effectiveness has been limited in some studies 7.
• Further research is needed to develop effective and safe reversal agents for heparin, particularly for patients who require emergency surgery or have experienced bleeding complications 3, 4, 5, 6, 7.