Heparin antagonists

• Definition

• Heparin antagonists are agents that counteract or neutralize the anticoagulant effect of heparins (including unfractionated heparin and low molecular weight heparins).

• Their primary role is in the reversal of heparin-induced anticoagulation during emergency situations such as excessive bleeding, urgent surgery, or overdose.

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• Mechanism of Action

• The main clinically used heparin antagonist is protamine sulfate.

• Protamine is a low molecular weight, strongly basic protein derived from salmon sperm or produced synthetically.

• It binds to the strongly acidic heparin molecules via ionic interactions, forming a stable inactive complex that is cleared from circulation.

• The neutralization effect is rapid, occurring within minutes of administration.

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• Primary Agents

1. Protamine Sulfate

   • Mechanism: Forms stable complexes with heparin, neutralizing its anticoagulant effect.

   • Onset: Immediate (within ~5 minutes of IV injection).

   • Duration: ~2 hours; may require repeat dosing if heparin effect persists.

   • Neutralization:

     • UFH – fully reversed in a 1 mg protamine : 100 units heparin ratio

     • LMWH – partially reversed (about 60–80% activity neutralized)

     • Fondaparinux – not reversed by protamine

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• Indications for Use

• Life-threatening or uncontrolled bleeding during heparin therapy

• Reversal of heparin anticoagulation after cardiopulmonary bypass surgery

• Emergency reversal for urgent surgical procedures

• Heparin overdose (accidental or iatrogenic)

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• Dosage Guidelines (Protamine Sulfate)

• For UFH reversal:

  • Immediate reversal: 1 mg protamine for every 100 units of heparin administered in the previous 2–3 hours

  • Reduce dose if more than 15 minutes have passed since heparin administration (due to rapid clearance of heparin)

• For LMWH reversal:

  • 1 mg protamine per 1 mg enoxaparin (within 8 hours of dose) – may repeat 0.5 mg protamine per 1 mg enoxaparin if bleeding continues

• Administer slowly IV over 10 minutes to minimize risk of adverse reactions

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• Contraindications

• Known hypersensitivity to protamine or fish-derived products

• History of protamine reaction, particularly in patients previously exposed via insulin-protamine complexes or vasectomy (increased risk of anaphylaxis)

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• Adverse Effects

• Mild to severe hypotension due to histamine release or vasodilation

• Bradycardia

• Anaphylactic or anaphylactoid reactions – higher risk in fish allergy, prior protamine exposure, or diabetic patients using NPH insulin

• Pulmonary hypertension and right ventricular failure in severe cases

• Flushing, nausea, vomiting

• Paradoxical anticoagulant effect at very high doses due to interference with platelet function and fibrinogen polymerization

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• Precautions

• Administer slowly and under continuous hemodynamic monitoring

• Resuscitation equipment should be immediately available during administration

• Monitor coagulation parameters (aPTT, ACT) post-reversal to confirm efficacy

• Avoid overdose as it can cause anticoagulant effects

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• Drug Interactions

• May interfere with anticoagulant assays and give inaccurate laboratory results

• No significant metabolic drug-drug interactions, but effects are additive with other agents causing hypotension

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• Clinical Considerations

• Protamine is highly effective against UFH, less effective against LMWH, and ineffective against synthetic pentasaccharides like fondaparinux

• Use the minimal effective dose to reduce risk of adverse reactions

• In cases of delayed heparin clearance (renal impairment with LMWH), monitor for re-anticoagulation and consider repeat dosing

• Emergency reversal should always be weighed against thrombosis risk, especially in patients with recent vascular interventions