Heparin Reversal

Protamine is the only compound currently commercially available to reverse heparin. It is a polycationic compound containing predominantly arginine residues that bind the anionic residues (sulfhydryl and hydroxyl) of heparin. The ionic bond between heparin and protamine binds all the free heparin in the circulation. Heparin bound to AT-III may or may not be reversed by protamine. Protamine has a shorter half-life than heparin does. Hence, heparin bound to tissues may subsequently re-equilibrate into the circulation and contribute in a minor way to post-CPB bleeding, a phenomenon known as heparin rebound.

Protamine is derived from salmon milt. It is not a pure substance and can contain fish proteins, which may explain one of its side effects in patients who have a history of fish allergies. The optimal dosing regimen for protamine remains controversial. The fixed dosing regimen is derived from Bull and colleagues' original description,^[252] in which it was suggested that 1 mg of protamine will neutralize 100 IU of heparin. An additional 0.3 mg protamine/100 IU of heparin was recommended to address heparin rebound. However, this fixed-dose approach does not take several important factors into account: (1) hepatic and renal clearance of heparin and the heparin/AT-III complex during CPB, (2) the dose-dependent side effects of protamine, and (3) possible contribution of excess protamine to post-CPB bleeding. Thus, many institutions use a dosing regimen that allows administration of the minimal dose of protamine to reverse heparin. To accomplish this objective, a combination of the ACT and a heparin-protamine titration system (for example, the Hepcon system) is used (see later). Several studies have demonstrated reductions in postoperative bleeding and transfusions with this latter approach.^{[253] [254] [255]} Protamine reactions are not uncommon, can be life threatening, are associated with increased in-hospital mortality,^[256] and have been categorized into three groups.^[257] The first and most common side effect of protamine administration is systemic hypotension. This side effect occurs when protamine is administered too rapidly and results from histamine release from mast cells (as also occurs with other polycationic drugs administered rapidly, such as vancomycin). In addition, hypotension may be accompanied by decreased coronary perfusion pressure and myocardial ischemia or other manifestations of histamine release, such as flushing. Allergic and anaphylactoid reactions to protamine are less frequent but remain a serious side effect of protamine. True IgE-mediated, dose-independent allergic reactions to protamine occur in patients who have had previous exposure and are sensitized to the drug.^[258]

Anaphylactoid reactions may be manifested in an identical manner to allergic reactions, with mediator release induced by IgG and complement-dependent mechanisms. Type III reactions to protamine are characterized by pulmonary hypertension and vasoconstriction, with possible resultant right heart failure. This side effect is mediated by protamine-heparin complex-induced release of thromboxane A₂ from platelets and macrophages. Laboratory investigations^{[259] [260]} and more recently data from humans^{[39] [261]} have shown that this side effect is attenuated by pretreatment with cyclooxygenase (COX) inhibitors. The contribution of protamine (especially excess protamine) and heparin-protamine complexes to post-CPB bleeding is probably underappreciated. Platelet counts can decrease precipitously when protamine is administered following heparin.^{[262] [263]} Platelets are sequestered in the circulation, predominantly in the pulmonary circulation. Moreover, protamine may further alter platelet function by inducing platelet shrinkage and egress of large platelets from the circulation.^[264]

Although protamine remains the only widely used compound available to reverse heparin, other agents are being investigated. Heparinase hydrolyzes heparin, and the heparin fragments are rapidly cleared by the kidney. It is derived from bacteria and has progressed to phase III FDA-supervised studies. However, many investigators have expressed concern about its effects on endogenous heparan. Platelet factor IV, an endogenous platelet-derived inhibitor of heparin, is also being investigated. It can be genetically derived, but the dose required to neutralize the large doses of heparin needed for CPB may limit its potential. The side effects of polycationic compounds other than protamine (e.g., hexadimethrine) make them less desirable.