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Introduction

  1. Pharmacology. Protamine is a cationic protein, obtained from fish sperm, that rapidly binds to and inactivates heparin by forming a stable salt. It also partially neutralizes low-molecular-weight heparins (LMWHs) and can act as an anticoagulant by inhibiting thromboplastin. Onset of action occurs within 30-60 seconds and lasts up to 2 hours.
  2. Indications
    1. Reversal of the anticoagulant effects of heparin after inadvertent excessive dosing. Note: Protamine generally is not needed for the treatment of bleeding during heparin therapy, because discontinuation of the heparin is usually sufficient.
    2. Reversal of regional anticoagulation in the hemodialysis circuit in patients with a contraindication to anticoagulation (eg, active GI or CNS bleeding).
    3. Reversal of the anticoagulant effects of LMWHs in patients with emergent and clinically significant bleeding. Note: Protamine has partial and unpredictable reversal effects on LMWHs.
  3. Contraindications
    1. Black Box Warning. Known hypersensitivity to protamine. Patients with diabetes who have used protamine insulin may be at the greatest risk for hypersensitivity reactions.
    2. Protamine reconstituted with benzyl alcohol should not be used in neonates because of suspected toxicity from the alcohol.
  4. Adverse effects
    1. Black Box Warning. Rapid intravenous administration (more than 5 mg/min) and high doses (more than 50mg at once) are associated with hypotension, bradycardia, and anaphylactoid reactions. Have epinephrine, diphenhydramine, and cimetidine or another histamine2 (H2) blocker ready.
    2. Rebound anticoagulation may occur within 8 hours of protamine administration.
    3. Excessive doses may cause anticoagulation and increase the risk of bleeding.
    4. Use in pregnancy. FDA Category C (indeterminate). A maternal hypersensitivity reaction or hypotension can result in placental ischemia. However, this does not preclude its acute, short-term use for a seriously symptomatic patient (Introduction).
  5. Drug or laboratory interactions. No known drug interactions, other than the reversal of heparin effects.
  6. Dosage and method of administration. Administer protamine by slow intravenous injection, not to exceed 50 mg in a 10-minute period or 5 mg/min.
    1. Heparin Reversal. The dose of protamine depends on the total dose and the time since the administration of heparin.
      1. If immediately after heparin administration, give 1-1.5 mg of protamine for each 100 units of heparin.
      2. If 30-60 minutes after heparin administration, give 0.5-0.75 mg of protamine for each 100 units of heparin.
      3. If 60-120 minutes after heparin administration, give 0.375-0.5 mg of protamine for each 100 units of heparin.
      4. If more than 2 hours after heparin administration, give 0.25-0.375 mg of protamine for each 100 units of heparin.
      5. If heparin was administered by continuous infusion, give 25-50 mg of protamine.
      6. If the quantity of heparin administered is unknown, give an empiric dose of 25-50 mg.
      7. Additional doses are determined by the activated partial thromboplastin time (aPTT) after 5-15 minutes and again at 2-8 hours post protamine dose.
    2. LMWH Reversal
      1. Dalteparin or tinzaparin. If within 8 hours of the last dose, give 1 mg of protamine for every 100 international units (IU) of dalteparin or tinzaparin. If 8-12 hours has elapsed since the last dose, give 0.5 mg of protamine for every 100 IU of dalteparin or tinzaparin. If longer than 12 hours since the last dose, protamine may not be effective. If the aPTT remains prolonged 2-4 hours after the initial dose, give an additional 0.5 mg of protamine for every 100 IU.
      2. Enoxaparin. If within 8 hours of the last dose, give 1 mg of protamine for each 1 mg of enoxaparin. If 8-12 hours have elapsed since the last dose, give 0.5 mg of protamine for each 1 mg of enoxaparin. If longer than 12 hours since the last dose of enoxaparin, protamine may not be effective. If the aPTT remains prolonged 2-4 hours after the initial dose, give an additional 0.5 mg of protamine for each 1 mg of enoxaparin.
      3. If the quantity of LMWH administered is unknown, give an empiric dose of 25-50 mg IV over 10 minutes.
      4. Anti-factor Xa activity levels and aPTT values are usually not completely reversed, but may be used to guide dosing. Measure 5-15 minutes after protamine administration and again at 4-6 hours.
      5. LMWHs have longer half-lives (4-6 hours) and accumulate with renal insufficiency; therefore, coagulopathies may persist, and protamine should be considered even several hours after the overdose.
      6. The ratios of anti-factor Xa to anti-factor IIa vary for LMWH products; if they are high, as with an LMW heparinoid (eg, danaparoid), protamine may be ineffective.