Standard Protamine Dosing for Heparin Reversal
Administer 1 mg of protamine sulfate for every 100 units of unfractionated heparin given in the previous 2-3 hours, with a maximum single dose of 50 mg, delivered by slow IV injection over 10 minutes. 1, 2, 3
Core Dosing Algorithm
For Unfractionated Heparin (UFH)
Time-dependent dosing adjustments are critical:
- Within 30 minutes of heparin: Full dose of 1.0 mg protamine per 100 units heparin 1, 2
- 30-60 minutes after heparin: Reduce to 0.5-0.75 mg protamine per 100 units heparin 1, 2
- 60-120 minutes after heparin: Reduce to 0.375-0.5 mg protamine per 100 units heparin 1, 2
- >2-3 hours after heparin: Protamine likely not needed as heparin has been metabolized 1
The FDA label confirms that each mg of protamine neutralizes approximately 100 USP heparin units, and heparin has a half-life of approximately 30 minutes after IV injection. 3
Practical Example
For a patient who received 5,000 units of heparin IV within the last 30 minutes: 5,000 units ÷ 100 = 50 mg protamine (which equals the maximum single dose). 2
Critical Administration Guidelines
Slow IV infusion over 10 minutes minimum is mandatory to prevent severe hypotension, bradycardia, and anaphylactoid reactions. 1, 2, 3 The FDA explicitly warns that fatal anaphylaxis-like reactions have been reported with protamine, and resuscitation equipment must be immediately available. 3
Never exceed 50 mg in any 10-minute period. 1, 2, 3
Post-Administration Monitoring
Measure activated clotting time (ACT) or activated partial thromboplastin time (aPTT) 5-10 minutes after protamine administration to confirm adequate reversal. 1, 2 If ACT/aPTT remains elevated, administer additional protamine at 0.5 mg per 100 units of heparin. 1
Recent high-quality evidence from cardiac surgery demonstrates that a fixed 250 mg dose produces equivalent ACT values to ratio-based dosing in patients receiving >27,500 units of heparin, while conserving protamine. 4, 5 However, this approach is primarily validated in the cardiac surgery setting and should not replace standard dosing in general medical contexts.
Low Molecular Weight Heparin (LMWH) Reversal
For enoxaparin reversal:
- Within 8 hours: 1 mg protamine per 1 mg enoxaparin (maximum 50 mg) 6
- 8-12 hours: 0.5 mg protamine per 1 mg enoxaparin (maximum 50 mg) 6
Important caveat: Protamine only partially neutralizes LMWH's anti-Xa activity (approximately 60-75% reversal), and clinical effectiveness is variable. 6, 7 For life-threatening bleeding unresponsive to protamine, consider activated prothrombin complex concentrates or andexanet alfa. 6
Common Pitfalls to Avoid
Do NOT calculate protamine based on total cumulative heparin dose—only consider the dose given in the preceding 2-3 hours, as heparin is rapidly metabolized. 1 This is the most frequent dosing error.
Do NOT routinely reverse prophylactic subcutaneous heparin unless aPTT is significantly prolonged or active bleeding is present. 1
Do NOT administer rapidly—this causes severe hypotension and cardiovascular collapse. 1, 3
High-Risk Populations
Patients with the following are at increased risk for protamine hypersensitivity reactions and require heightened monitoring: 2, 6
- Fish allergies
- Previous protamine exposure
- Protamine-containing insulin use (NPH insulin)
- Vasectomized or infertile men
Protamine itself has weak anticoagulant properties at high doses, which may paradoxically worsen bleeding if overdosed. 6
Context-Specific Modifications
For cardiac surgery with cardiopulmonary bypass <90 minutes: The fixed-dose ratio method of 1.0-1.3 mg per 100 units is appropriate. 1 Recent data suggests even lower ratios (0.75 mg per 100 units) may be safe and reduce protamine-related complications. 8