Protamine

Protamine

Protamine, a polycationic protein derived from salmon milt, possess strong alkalinity because of an amino acid composition consisting of 67% arginine.  In its natural state, the numerous positive charges on the protamine molecule bind with the negatively charged phosphate groups of the nucleoprotein material of salmon sperm.  Heparin, a polyanion, binds ionically to protamine to produce a stable precipitate.  Protamine contains two active sites, one that neutralizes heparin and another that exerts a mild anticoagulant effect, independent of heparin (Gravlee, Davis, & Utley,  1993).

The anticoagulant  effect of protamine has been demonstrated in vitro.  It is suggested that this anticoagulant effect only becomes important at doses approximating three times those required for neutralization of residual heparin.  Most patients will probably tolerate a protamine dose of 1-2 mg/kg without adverse effects on coagulation.  The clinician should be aware that protamine overdose can lead to further platelet dysfunction lasting several hours into the post-bypass period (Gravlee, Davis, & Utley,  1993).

At the conclusion of CPB, the residual amount of heparin should be assessed and appropriately neutralized.  The rate of heparin metabolism exhibits considerable interpatient variability, making accurate determination of residual heparin difficult.  Accurate calculation of the protamine dose is essential because unneutralized heparin can increase postoperative bleeding (Gravlee, Davis, & Utley,  1993).

Protamine is standardized against heparin preparations, so its potency may vary slightly.  One milligram of protamine neutralizes approximately 85 units of heparin (differing slightly for porcine mucosal versus bovine lung).  Protamine doses are usually calculated upon the ratio of 1-1.3  mg per 100 units of heparin, only binding effectively to circulating heparin (Gravlee, Davis, & Utley,  1993).

Adverse cardiopulmonary responses to protamine administration have been observed during the entire history of clinical cardiac surgery.  There are numerous suggested risk factors, including valvular heart disease (particularly mitral), preexisting pulmonary hypertension, bolus protamine administration, infusion rates greater than 5 mg/min., diabetes with prior NPH insulin exposure, specific brands of protamine, sterilization via ligation of the vas deferens, site of administration, and rate of administration (Gravlee, Davis, & Utley,  1993).

None of these predisposing risk factors are verified; however, protamine reactions are classified as follows:

• Pharmacologic histamine release.
• True anaphylaxis mediated by a specific antiprotamine  immunoglobin, (Ig) IE antibody.
• Thromboxane release leading to pulmonary vasoconstriction and bronchosconstriction

References

Horrow JC. Management of coagulopathy associated with cardiopulmonary bypass. In Gravlee GP, Davis RF, Utley JR eds. Cardiopulmonary Bypass: Principles and Practice. Baltimore, MD. Williams & Wilkens; 1993:436-466.