What is the composition and mechanism of action of protamine?

From the Guidelines

Protamine is a polycationic protein that neutralizes the anticoagulant action of heparin by binding ionically to it.

Composition and Mechanism of Action

• Protamine contains 2 active sites, 1 that neutralizes heparin and 1 that exerts an anticoagulant effect that is independent of heparin 1.
• The anticoagulant effect of protamine is mild and only clinically apparent at doses that are several-fold higher than those required for heparin neutralization 1.
• One milligram of protamine neutralizes ≈85 U heparin 1.

Dosing Strategies

• There are 3 strategies used for protamine dosing, which mirror the strategies for heparin dosing: a fixed-dose ratio of protamine to heparin, the HDRC method, and the heparin-protamine titration method 1.
• A fixed-dose ratio of protamine to heparin is suitable for operations with a short duration of CPB (<90 minutes), with 1.0 to 1.3 mg protamine administered for each 100 U heparin administered 1.
• For operations with longer durations of CPB, it is recommended that the dose of protamine for heparin reversal be estimated with the ACT-HDRC method or the heparin-protamine titration method 1.
• Protamine should be given in a ratio of 0.8-1.0 of the initial doses of heparin to avoid excessive administration and perioperative bleeding 1.

Reversal of Low Molecular Weight Heparin (LMWH)

• Protamine only partially reverses the anticoagulant effect of LMWH, and its use is reasonable to partially reverse the anticoagulant effect of LMWH 1.
• If LMWH was given within 8 h, protamine sulfate should be administered in a dose of 1 mg per 100 anti-Xa units of LMWH up to a maximum single dose of 50 mg 1.

From the FDA Drug Label

CLINICAL PHARMACOLOGY: When administered alone, protamine has an anticoagulant effect. However, when it is given in the presence of heparin (which is strongly acidic), a stable salt is formed and the anticoagulant activity of both drugs is lost. Protamine sulfate has a rapid onset of action. Neutralization of heparin occurs within five minutes after intravenous administration of an appropriate dose of protamine sulfate. Although the metabolic fate of the heparin-protamine complex has not been elucidated, it has been postulated that protamine sulfate in the heparin-protamine complex may be partially metabolized or may be attacked by fibrinolysin, thus freeing heparin. The composition of protamine is a salt, specifically protamine sulfate. The mechanism of action of protamine involves forming a stable salt with heparin, which neutralizes the anticoagulant activity of heparin. Key points about protamine include:

• Anticoagulant effect when administered alone
• Neutralization of heparin when given in the presence of heparin
• Rapid onset of action, with neutralization occurring within five minutes 2

From the Research

Composition of Protamine

• Protamine is a highly basic protein isolated from salmon sperm 3 or produced through recombinant biotechnology 4.
• It is a positively charged polypeptide 5 and a low molecular weight polycationic amine 6.

Mechanism of Action of Protamine

• Protamine binds to heparin in a nonspecific electrostatic interaction to reverse its anticoagulant effects 3.
• It dissociates the heparin-antithrombin III (AT III) complex, forming the inactive heparin-protamine complex 4.
• Protamine has dose-dependent anticoagulant properties, interfering with coagulation factors and platelet function, stimulating fibrinolysis, and leading to thrombocytopenia and reduction in thrombin-related platelet aggregation 4.
• It down-regulates thrombin generation by inhibiting factor V activation 5.
• Protamine inhibits thrombin-induced platelet aggregation 7.

Effects of Protamine on the Body

• Protamine administration is associated with a spectrum of adverse reactions, ranging from vasodilation to life-threatening cardiopulmonary dysfunction and shock 3.
• It can produce actions on cardiac muscle, reducing blood pressure, heart rate, and cardiac output, and increasing the Q-aT interval of the electrocardiogram 6.
• Protamine may produce aberrant conduction within the heart, resulting in deleterious effects in heart function, especially in conditions associated with myocardial disease 6.