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Protamine is a rapidly acting antidote that physically complexes unfractionated heparin (UFH) and reverses its anticoagulant effects. Protamine neutralizes the anti-IIa activity of low-molecular-weight heparin (LMWH) and incompletely neutralizes the anti-Xa activity of LMWH, which often normalizes the activated partial thromboplastin time (aPTT) and the thrombin time but minimally affects the anti–factor Xa activity and cannot be expected to limit hemmorhage. Protamine has no effect on heparin pentasaccharide fragments or analogs such as fondaparinux.


In 1868, Friedric Miescher discovered and named the basic protein that resides in the sperm of salmon as protamine.91 The antidotal properties of protamine were recognized in the late 1930s, leading to its approval as an antidote for heparin overdose in 1968.30 However, the largest body of literature pertaining to protamine originates from its use in neutralizing heparin after cardiopulmonary bypass and dialysis procedures.



The protamines are a group of simple basic cationic proteins found in fish sperm that bind to heparin to form a stable neutral salt. The effects of protamine sulfate and protamine chloride are comparable.62 The binding of heparin to protamine is stronger than the binding of heparin to antithrombin (AT), consequently protamine rapidly inactivates heparin and reverses its anticoagulant effects.45,86 Commercially available protamine sulfate is derived from the sperm of mature testes of salmon and related species. Upon hydrolysis, protamine yields basic amino acids, particularly arginine, proline, serine, and valine, but not tyrosine and tryptophan.

Related Protamine Variants

In animal studies, synthetic protamine variants, not available for clinical use, were effective in reversing the anticoagulant effects of LMWH, and are reported to be less toxic than protamine.13,49,98,99

Mechanism of Action

Heparins are large electronegative xenobiotics that are rapidly complexed by the electropositive protamine, forming an inactive salt. Heparin is an indirect anticoagulant, requiring a cofactor. This cofactor, AT, was formerly called AT III. Heparin alters the stereochemistry of AT, thereby catalyzing the subsequent inactivation of thrombin and other clotting factors.38 Only about one-third of an administered dose of UFH binds to AT, and this fraction is responsible for most of its anticoagulant effect.4,64 Low-molecular-weight heparin has a reduced ability to inactivate thrombin as a result of lesser AT binding, but the smaller fragments of LMWH inactivate factor Xa almost as well as the larger molecules of UFH, allowing for equivalent efficacy. Immunoelectrophoretic studies demonstrate that because of the net positive charge of protamine, it has a greater affinity for heparin than heparin for AT, producing a dissociation of the heparin–AT complex and favoring a protamine–heparin complex.83 This complex is removed by the reticuloendothelial system.3 The ability of protamine to bind to LMWH is limited ...

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