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Protamine Sulfate
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Protamine Sulfate

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Protamine sulfate is a white or almost white powder that is slightly soluble in water, insoluble in ethanol and ether. Protamine sulfate is used as a medication to reverse the anticoagulant activity of heparin in case of threatening hemorrhage during delivery and heart surgery.

Application in reversing the anticoagulant activity of heparin

Protamine sulfate is an alkaline-strong, arginine-rich, positively-charged protein isolated from salmon sperm[1], which was approved for medical use in the United States in 1969. More information is as follow:

  • Mechanism of action

Protamine sulfate is a highly cationic peptide with strong alkalinity, while heparin is a complex anionic polysaccharide with strong acidity. It is generally accepted that, when protamine sulfate is used to reverse the anticoagulant activity of heparin, protamine sulfate can bind to heparin to form a stable ion pair that has no anticoagulant activity. Thus, protamine sulfate is frequently used to reverse the large doses of heparin administered during certain surgeries, especially heart surgery where anticoagulation is necessary to prevent clot formation within the cardiopulmonary bypass pump apparatus.

  • Neutralization effects of protamine sulfate on heparin from different sources

Currently available therapeutic heparin in Europe and the United States is derived from porcine mucosa (PM). The use of bovine mucosa (BM) or bovine lungs (BL) as an additional source for the production of heparin is now gaining attention. A study assessed the ability of protamine sulfate to neutralize the anticoagulant activity of heparin from PM, BM and BL. The results showed that differential amounts of heparin were neutralized by protamine sulfate, with neutralization of PM more effective than BL and BM (Table 1)[2].

Table 1. Selected heparins (four each of PM, BM and BL heparins) IU (AT: aIIa) required to precipitate 1 mg protamine sulfate

Selected heparins (four each of PM, BM and BL heparins) IU (AT: aIIa) required to precipitate 1 mg protamine sulfate
  • Side effects

Common side effects of protamine sulfate mainly include:

Decreased heart rate

Nausea or vomiting

Pulmonary hypertension

Shortness of breath

Sudden fall in blood pressure

Temporary flushing and a feeling of warmth

In addition, it is reported that protamine sulfate causes severe allergic reactions in patients who are allergic to fish, diabetics using insulin preparations containing protamine, and vasectomized or infertile men. These allergic reactions may cause respiratory difficulty, fatigue, and back pain in patients.

Alfa Chemistry offers high quality protamine sulfate. Please feel free to contact us for APIs or technical services.


  1. Miklosz, J., et al. Cardiovascular and respiratory toxicity of protamine sulfate in zebrafish and rodent models. Pharmaceutics. 2021, 13: 359.
  2. Hogwood, J., et al. Precipitation and neutralization of heparin from different sources by protamine sulfate. Pharmaceuticals. 2017, 10: 59.