Protamine Sulfate

• Cationic Protein: Positively charged protein that binds negatively charged heparin, forming inactive complex and reversing anticoagulant effect
• Primary Uses: Reversal of unfractionated heparin (UFH) after procedures (cardiac surgery, PCI, dialysis) or in major bleeding; partial reversal of LMWH (e.g., enoxaparin)
• Dosing: Based on amount of heparin given and time since administration; classic initial dosing ~1 mg protamine per 100 units UFH remaining in circulation
• Administration: Must be given as slow IV infusion due to risk of severe hypotension, pulmonary vasoconstriction, and anaphylactoid reactions
• High-Risk Populations: History of protamine exposure (including NPH insulin), fish allergy, men with prior vasectomy—monitor closely for reactions
• LMWH Reversal: Only partially effective (~60-80% of anti-Xa activity neutralized)

• Generic Name: Protamine sulfate
• Brand Names: Protamine, generics

Heparin antagonist; cationic protein that neutralizes unfractionated heparin and partially reverses LMWH

Mechanism of Action:

• Protamine is a small, highly basic polypeptide that binds to heparin (strongly acidic/anionic glycosaminoglycan) through electrostatic interactions
• The protamine-heparin complex is inactive and removed by reticuloendothelial system, reversing heparin's anticoagulant effect
• For LMWH: Protamine neutralizes only part of anti-IIa and anti-Xa activity → reversal is incomplete (≈60-80% of anti-Xa)
• Excess protamine: When given in excess relative to heparin, protamine itself can have weak anticoagulant effects and prolong clotting times

Pharmacokinetics (IV):

• Onset: Anti-heparin effect is immediate after IV administration, with rapid normalization of ACT/aPTT if dosing appropriate
• Duration: Approximately 2 hours, though effect may dissipate sooner if heparin continues to be released from tissue depots or ongoing infusion
• Distribution: Confined largely to intravascular space; forms complexes with circulating heparin
• Clearance: Protamine-heparin complexes cleared by reticuloendothelial system; excess free protamine may persist transiently and exert anticoagulant effects

• UFH reversal post-procedure: After cardiopulmonary bypass and other surgical procedures
• Emergency UFH reversal: Major bleeding (intracranial hemorrhage, massive GI bleed, bleeding at procedural sites)
• Partial LMWH reversal: Enoxaparin in major bleeding or prior to emergent procedures
• Interventional cardiology: Reversal of UFH used during PCI
• Dialysis: Reversal of UFH from heparinized dialysis sessions

Available Forms:

• Injection: Typically 10 mg/mL solution (e.g., 50 mg in 5 mL vials) for IV administration
• For safety, protamine is usually further diluted in 50-100 mL normal saline and infused slowly over at least 10 minutes

Protamine Sulfate Dosing (Adult):

Contraindications:

• History of severe hypersensitivity or anaphylactic reaction to protamine

Major Precautions:

• Hypersensitivity risk: Patients with fish allergy, prior protamine exposure (including NPH insulin), or prior vasectomy have higher risk of hypersensitivity reactions
• Rapid infusion risks: Severe hypotension, bradycardia, pulmonary vasoconstriction, and right heart failure if given too quickly
• Excess dosing: Protamine beyond what's needed to neutralize heparin can paradoxically prolong clotting times and impair hemostasis
• Pulmonary hypertension: Use extreme caution in patients with pulmonary hypertension or significant right ventricular dysfunction

Common:

• Flushing, warmth, feeling of chest discomfort
• Mild hypotension, bradycardia
• Nausea, vomiting

Serious:

• Anaphylactic or anaphylactoid reactions (hypotension, bronchospasm, angioedema, shock)
• Acute pulmonary hypertension and right ventricular failure
• Severe hypotension and cardiovascular collapse

During and After Infusion:

• Continuous ECG and blood pressure monitoring
• Coagulation parameters (ACT, aPTT, anti-Xa where applicable) before and after reversal to gauge effectiveness
• Clinical assessment of bleeding vs thrombosis, surgical site hemostasis, drain output
• Signs of anaphylaxis or acute pulmonary hypertension: sudden hypoxemia, increased PA pressures (if monitored), bronchospasm, or shock

• 1. Lexicomp. (2024). Protamine: Drug information. Wolters Kluwer.
• 2. Farkas, J. (2022). Anticoagulant reversal. EMCrit Project / IBCC. https://emcrit.org/