Protamine Sulfate
Protamini sulfas
Also known as: Prosulf · protamine sulphate · protamini sulfas · sulfato de protamina · Protamine sulfate
Reviewed by the VetSheet Veterinary TeamUpdated Apr 5, 2026Evidence-based veterinary reference
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Dosing by species
🌎 NA — North America🌍 EU — Europe
Dogs
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| Heparin overdosage | 1-1.5 mg protamine sulfate to antagonize each mg (100 units) of heparin via slow IV injection. Reduce dose as time increases between heparin dose and start of treatment (after 30 minutes give only 0.5 mg). | IV | Single dose | — | 🌎 NA |
| Heparin overdosage | Administer 1 mg protamine for each 100 Units of heparin to be inactivated. Decrease protamine dose by ½ for every 30 minutes that have lapsed since heparin was administered | IV | Single dose | — | 🌎 NA |
- Heparin overdosage: Give slowly.
- Heparin overdosage: May be ineffective if heparin was given deep SC. Do not give faster than 50 mg over 10 minutes.
Cats
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| Heparin overdosage | 1-1.5 mg protamine sulfate to antagonize each mg (100 units) of heparin via slow IV injection. Reduce dose as time increases between heparin dose and start of treatment (after 30 minutes give only 0.5 mg). | IV | Single dose | — | 🌎 NA |
| Heparin overdosage | Administer 1 mg protamine for each 100 Units of heparin to be inactivated. Decrease protamine dose by ½ for every 30 minutes that have lapsed since heparin was administered | IV | Single dose | — | 🌎 NA |
- Heparin overdosage: Give slowly.
- Heparin overdosage: May be ineffective if heparin was given deep SC. Do not give faster than 50 mg over 10 minutes.
Cattle
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| Bracken Fern (Pteridium spp.) poisoning | 1 injection of 10 mL of 1% protamine sulfate IV | IV | Single dose | — | 🌎 NA |
- Bracken Fern (Pteridium spp.) poisoning: In combination with whole blood (2.25-4.5 L)
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Overview
Protamine sulfate is a simple, low molecular weight, cationic protein originally derived from the sperm or mature testes of salmon and related fish species. In veterinary medicine, it is primarily utilized as a specific, life-saving antidote for heparin overdose when significant, uncontrolled bleeding occurs.
Key clinical points:
- Unfractionated vs. LMWH: While protamine completely neutralizes unfractionated heparin, it only partially neutralizes the anti-Xa activity of low molecular weight heparins (LMWH) like dalteparin or enoxaparin. However, it still improves microvascular bleeding in LMWH overdoses.
- Alternative Uses: It has been suggested as an adjunctive treatment for Bracken Fern (Pteridium spp.) toxicity in ruminants.
Clinical Pearl: Because protamine is a foreign protein, hypersensitivity reactions (including anaphylaxis) are possible, particularly in patients with previous exposure or fish allergies.
Mechanism of action
Protamine works via direct acid-base neutralization.
- Mechanism: Heparin is a strongly acidic molecule, while protamine is strongly basic.
- Pathway: Protamine → binds directly to circulating heparin → forms an inactive, stable salt complex → neutralizes heparin's anticoagulant activity.
Pharmacology Note: Protamine possesses weak intrinsic anticoagulant activity of its own. If administered in large doses without heparin present, it can theoretically interfere with coagulation, though this rarely causes clinical hemorrhage.
Safety & warnings
Contraindications
- Known hypersensitivity or intolerance to protamine
- Hypersensitivity to protamine
- Conditions where heparin has not been administered
Adverse effects
- Acute hypotension (if given too rapidly)
- Bradycardia
- Pulmonary hypertension
- Dyspnea
- Hypersensitivity/Anaphylaxis
- Heparin 'rebound' effect (bleeding hours after neutralization)
- Anaphylactoid reactions
- Paradoxical bleeding (at high doses)
Precautions
Administration Warnings
- Rate of Injection: Must be administered via slow IV injection (over 1-3 minutes). Rapid IV injection can cause severe acute hypotension, bradycardia, pulmonary hypertension, and dyspnea. Do not exceed a rate of 50 mg over a 10-minute period.
- Heparin Rebound: A 'rebound' effect may occur where anticoagulation and bleeding resume several hours after apparent neutralization. This is likely due to the release of heparin from extravascular compartments or degradation of the protamine-heparin complex by fibrinolysin.
- Pregnancy: FDA Category C. Use only if clearly needed.
Drug interactions
Forms a stable salt, causing the loss of anticoagulant activity of both compounds (therapeutic intent).
Monitoring
- Coagulation parameters (e.g., aPTT, ACT) to assess heparin neutralization
- Blood pressure (monitor for hypotension during administration)
- Heart rate and rhythm (monitor for bradycardia)
- Respiratory rate and effort
- Signs of recurrent bleeding (heparin rebound effect) for several hours post-administration
- Coagulation times (aPTT, ACT)
- Signs of anaphylaxis during administration
Pharmacokinetics
Half-life
Absorption
Binds to heparin within 5 minutes after IV injection.
Distribution
Forms a complex with heparin in the intravascular space.
Metabolism
The exact metabolic fate is unknown, but evidence suggests the heparin-protamine complex is partially metabolized and/or degraded by fibrinolysin, which can free previously bound heparin.
Elimination
Clearance mechanisms are not fully defined, but degradation of the complex can lead to a clinical 'rebound' effect.
Overdose
Because protamine has inherent, albeit weak, anticoagulant activity, massive overdoses could theoretically result in hemorrhage.
However, clinical data in humans suggests that significant overdoses (600-800 mg) typically result in only mild, transient effects on coagulation. The LD50 of protamine in mice is reported to be 100 mg/kg. Treatment of overdose should be supportive.
Available products
Formulations
- Injection: 10 mg/mL
- 10 mg/ml injectable solution
Human-labeled
- Protamine Sulfate Injection: 10 mg/mL preservative-free in 5 mL and 25 mL vials
- Protamine sulphate 10 mg/ml solution for injection
Regulatory status
POM (Prescription Only Medicine)
POM (Prescription Only Medicine)
No regulatory data for: 🇺🇸 US · 🇭🇰 HK · 🇹🇼 TW · 🇯🇵 JP · 🇰🇷 KR · 🇦🇺 AU
Storage & stability
Powder for injection: Store at room temperature (15-30°C). Liquid injection: Store in the refrigerator (2-8°C); avoid freezing (though stable at room temperature for at least 2 weeks). Reconstituted powder: Use immediately if mixed with Sterile Water for Injection, or within 72 hours if mixed with Bacteriostatic Water for Injection. Compatible with D5W, normal saline, cimetidine, and verapamil.
Client information
Important Information for Pet Owners
- Emergency Use Only: Protamine sulfate is a specialized rescue medication used exclusively in a hospital setting to treat severe bleeding caused by an overdose of heparin.
- Intensive Monitoring: Your pet will be closely monitored in the ICU while receiving this drug, as it can cause sudden drops in blood pressure or heart rate if given too quickly.
- Rebound Bleeding: Even after successful treatment, your pet will need to be observed for several hours, as the bleeding effects of heparin can sometimes 'rebound' and return.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturer’s current label.