How to reverse Heparin (unfractionated heparin) anticoagulation?

From the Guidelines

Heparin can be reversed using protamine sulfate, which is the antidote for unfractionated heparin, at a dose of 1 mg per 100 units of heparin given in the previous 2-3 hours, with a maximum single dose not exceeding 50 mg, as recommended by the most recent guideline from the Neurocritical Care Society and the Society of Critical Care Medicine 1.

Key Considerations

• The dose of protamine should be calculated based on the amount of heparin administered in the previous 2-3 hours, with a recommended dose of 1 mg protamine per 100 units of heparin 1.
• The maximum single dose of protamine should not exceed 50 mg, and administration should be slow (over 1-3 minutes) to avoid adverse reactions including hypotension, bradycardia, and anaphylaxis.
• For continuous heparin infusions, the amount received in the previous 2-3 hours should be calculated to determine the appropriate dose of protamine.
• After administration, the patient's coagulation parameters (aPTT or anti-Xa levels) should be monitored to ensure adequate reversal.

Special Considerations

• Patients with fish allergies, prior protamine exposure, or those who have had vasectomies may be at higher risk for adverse reactions to protamine.
• For low molecular weight heparins like enoxaparin, protamine is partially effective, neutralizing about 60-80% of the anticoagulant activity, and may require higher relative doses.

Evidence Summary

The recommendation for reversing heparin with protamine sulfate is based on the most recent guideline from the Neurocritical Care Society and the Society of Critical Care Medicine 1, which provides a strong recommendation (moderate quality evidence) for the use of protamine sulfate to reverse heparin in the context of intracranial hemorrhage.

From the FDA Drug Label

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. To reverse heparin, protamine sulfate should be administered by slow infusion. The dose of protamine sulfate is based on the amount of heparin to be neutralized, with 1 mg of protamine sulfate neutralizing approximately 100 USP heparin units. No more than 50 mg of protamine sulfate should be given in any 10-minute period. The amount of protamine required decreases over time as heparin is metabolized 2.

From the Research

Reversing Heparin

• Heparin can be reversed using protamine sulphate, which is an effective inhibitor of heparin and is used clinically to neutralise both low molecular weight heparins (LMWH) and unfractionated heparin (UFH) 3.
• However, protamine sulphate does not fully counter the anti-Xa effect of LMWH, even in excess (>40 μg to 1 IU/ml) 3.
• The effectiveness of protamine sulphate neutralisation is largely dependent on molecular weight, with materials over 5000 Da being preferentially neutralised by protamine 3.
• LMWHs containing a larger proportion of small oligosaccharides will not be as effectively neutralised by protamine sulphate 3.

Alternative Anticoagulants

• Alternative anticoagulant and antithrombotic drugs have been developed, including argatroban and hirudin, which are already approved for alternative management of heparin-compromised patients 4.
• Specific anti-Xa drugs are also being developed, but their efficacy is limited and they can only be given in drug combinations 4.
• Other alternatives include synthetic and recombinant protein-derived anti-tissue factor agents, plasma-derived and recombinant serine protease inhibitors, and nucleic acid derivatives 4.

Clinical Use

• Unfractionated heparin and LMWHs collectively represent an important group of polypharmacologic drugs without which the management of thrombosis and vascular disorders would not be possible 4, 5.
• The use of LMWHs has continually increased due to expanded indications and growing awareness among clinicians 4.
• The development of an antidote and additional information on the mechanism of action of LMWHs may lead to their increased use in surgery patients 4.