What is the recommended reversal agent for heparin (unfractionated heparin) and low molecular weight heparin (LMWH)?

Reversal of Heparin Anticoagulation

Unfractionated Heparin (UFH) Reversal

Protamine sulfate is the definitive reversal agent for unfractionated heparin, administered as 1 mg protamine per 100 units of heparin given, with complete neutralization of anticoagulant effect. 1

Dosing Protocol for UFH Reversal

• Administer protamine sulfate by slow intravenous infusion at a dose of 1.0 to 1.3 mg per 100 units of heparin administered 2, 1
• No more than 50 mg should be given in any 10-minute period to minimize risk of adverse reactions 1
• The amount of protamine required decreases over time as heparin is metabolized; for dosing purposes, assume heparin has a half-life of approximately 30 minutes after IV injection 1

Monitoring and Confirmation

• Measure activated clotting time (ACT) or heparin level 5 to 10 minutes after protamine administration to confirm satisfactory reversal 2
• If residual heparin activity persists, additional protamine can be administered and reversal rechecked 2
• Recheck INR or ACT 30 minutes after protamine administration to assess degree of correction 3

Critical Safety Considerations

• Fatal anaphylactoid reactions have been reported with protamine; it should only be given when resuscitation techniques and treatment of anaphylactic shock are readily available 1
• Excess protamine itself induces a coagulopathy, so precise dosing is essential 2
• Anaphylactic reactions occur in approximately 3 per 100,000 doses via a non-IgE mechanism, possibly due to the solubilizer, and can result in cardiac arrest 2, 3

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Low Molecular Weight Heparin (LMWH) Reversal

Protamine sulfate only partially reverses LMWH anticoagulation, neutralizing approximately 60% of anti-factor Xa activity, making it less effective than for UFH reversal. 2, 4

Dosing for LMWH Reversal

• Administer protamine sulfate intravenously for LMWH-associated bleeding, though complete reversal is not achievable 2
• The typical approach is 1 mg protamine per 100 anti-Xa units (or 1 mg enoxaparin) administered, though evidence for optimal dosing is limited 2
• For life-threatening bleeding on LMWH, administer protamine sulfate by slow IV infusion in addition to cessation of LMWH 2

Clinical Effectiveness Considerations

• Protamine reverses the anti-IIa (thrombin) activity of LMWH but has minimal effect on anti-Xa activity, which is the predominant mechanism of LMWH 2
• In clinical studies, bleeding stopped in approximately 67% (8 of 12) of actively bleeding patients treated with protamine for LMWH reversal 5
• Anti-Xa levels are useful to assess anticoagulation before protamine but unhelpful in monitoring its reversal effect 5

Important Limitations

• Protamine should primarily be used for UFH due to complete reversal; for LMWH, protamine provides only partial reversal and clinical effectiveness varies 2
• The American Society of Hematology notes that protamine administration for LMWH-associated life-threatening bleeding is conditionally recommended based on very low certainty evidence, with the possibility of benefit warranting its use 2
• Better reversal agents for LMWH are needed, as protamine's incomplete reversal leaves residual anticoagulant effect 5, 4

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Clinical Algorithm for Heparin Reversal

For Active Major Bleeding on UFH:

1. Stop heparin immediately
2. Administer protamine sulfate 1 mg per 100 units of heparin given (maximum 50 mg per 10-minute period) 1
3. Check ACT or heparin level at 5-10 minutes 2
4. Repeat protamine if residual heparin activity persists 2
5. Have resuscitation equipment immediately available due to anaphylaxis risk 1

For Active Major Bleeding on LMWH:

1. Stop LMWH immediately
2. Consider protamine sulfate administration (1 mg per 1 mg enoxaparin or 100 anti-Xa units), recognizing only partial reversal 2
3. Provide supportive care with blood products as needed 2
4. Monitor clinically for bleeding cessation rather than relying on anti-Xa levels 5

Common Pitfalls to Avoid:

• Do not exceed 50 mg protamine in any 10-minute period to prevent protamine-induced toxicity 1
• Do not expect complete LMWH reversal with protamine—only 60% of anti-Xa activity is neutralized 2, 4
• Do not administer protamine without immediate access to resuscitation equipment due to anaphylaxis risk 1
• Avoid excess protamine dosing, as it causes its own coagulopathy 2