PROTAMINE 

 1. INTRODUCTION

Protamine sulfate is a strongly basic (cationic) polypeptide derived from fish sperm that is used primarily as a heparin antagonist.

  • Neutralizes unfractionated heparin (UFH) completely
  • Partially reverses low molecular weight heparin (LMWH)
  • Minimal effect on fondaparinux


2. MECHANISM OF ACTION

 Inhibits heparin-mediated activation of Antithrombin III

  • Restores activity of:
    • Thrombin (Factor IIa)
    • Factor Xa


 3. PHARMACOKINETICS

Parameter

Details

Route

IV only

Onset

Immediate (within 1–2 min)

Peak effect

~5 min

Duration

30–60 min

 Important:

  • Heparin may rebound after protamine wears off

 4. INDICATIONS 

Primary Indications

  1. Heparin reversal
    • Cardiac surgery (post-CPB)
    • ECMO decannulation
    • Dialysis-related bleeding
    • ICU bleeding on UFH
  1. Heparin overdose
  2. Urgent invasive procedures
    • CVC insertion in anticoagulated patient
    • Surgery

 5. DOSING 

 A. Unfractionated Heparin (UFH)
1 mg protamine neutralizes ~100 units of UFH

 Dose calculation:

  • If heparin given within last 30 min → full reversal
  • 30–60 min → 50% dose
  • 2 hours → minimal dose

Time since heparin

Protamine dose

< 30 min

1 mg per 100 units

30–60 min

0.5 mg per 100 units

60–120 min

0.25 mg per 100 units

 Max single dose: 50 mg


 B. LMWH (e.g., enoxaparin)-Only ~60–75% reversal

Situation

Dose

< 8 hr

1 mg protamine per 1 mg enoxaparin

8–12 hr

0.5 mg per 1 mg

>12 hr

Usually not needed

C. Fondaparinux

  • No effective reversal with protamine

6. ADMINISTRATION 

  • Route: Slow IV infusion
  • Rate: NOT > 5 mg/min

Rapid infusion → catastrophic reactions


 7. ADVERSE EFFECTS 

 A. Cardiovascular collapse

  • Severe hypotension
  • Bradycardia
  • Pulmonary hypertension

 B. Protamine reaction (ANAPHYLACTOID)

Mechanism:

  • Complement activation
  • Histamine release

Risk factors:

  • Previous protamine exposure
  • diabetes mellitus on NPH insulin
  • Fish allergy
  • Vasectomy (anti-protamine antibodies)

C. Pulmonary vasoconstriction

  • Acute pulmonary hypertension
  • Right ventricular failure
  • Seen especially post-cardiac surgery


D. Paradoxical anticoagulation

  • High dose protamine → anticoagulant effect

 8. PROTAMINE REACTION TYPES

Type

Mechanism

Features

Type I

Direct histamine release

Mild hypotension

Type II

IgE/IgG-mediated

Anaphylaxis

Type III

Complement activation

Pulmonary HTN, RV failure

2. PROPHYLACTIC REGIMENS

 A. Antihistamines

  • H1 blocker:
    • Chlorpheniramine 10 mg IV
      OR
    • Diphenhydramine 25–50 mg IV
  • H2 blocker:
    • Ranitidine 50 mg IV
      OR
    • Famotidine

Reduces histamine-mediated hypotension

 B. Corticosteroids

  • Hydrocortisone 100–200 mg IV
    OR
  • Methylprednisolone

 Prevents delayed / severe reactions (limited immediate effect but commonly used)

 C. Test dose 

  • Give 5–10 mg protamine slowly over 5–10 min
  • Observe for:
    • Hypotension
    • Bronchospasm
    • Pulmonary hypertension

 If tolerated → proceed with full dose

 D. Slow infusion 

  • Infusion rate: ≤ 5 mg/min
  • Dilute in NS and give via infusion pump

 This is the single most effective preventive measure