Some contribution may result from significant electropositivity of protamine. Mechanisms for these adverse effects are multifactorial. Adverse effects associated with protamine include both administration rate- and non–rate-related hypotension, 18, 24, 25, and 26, 29, 31, 43, 46, 79, 81 anaphylaxis, 42, 58 anaphylactoid reactions, 45, 65, 67 bradycardia, 1 thrombocytopenia, 90 thrombogenicity, 20 leukopenia, decreased oxygen consumption, 87, 89 acute respiratory distress syndrome (ARDS), 7, 83 pulmonary hypertension and pulmonary vasoconstriction, 13, 35 cardiovascular collapse, 56, 77 and dose dependent paradoxical anticoagulation with protamine excess. 38, 39, 59, 72 It is often difficult to separate the adverse effects caused by protamine from those of the protamine–heparin complex or those actually related to heparin. It is largely in this setting that the adverse effects of protamine are also documented and studied. Since the advent of CABG surgery, there have been approximately 100 deaths reported in total with the use of protamine in these circumstances. However, unlike previous years, only one-fourth of those cases are now CABGs and routinely expose patients to protamine. More than a million coronary revascularizations are performed each year in the United States. Protamine is routinely used in the neutralization of heparin at the completion of CABG surgery. 73 This complex is removed by the reticuloendothelial system.

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. 3, 55 LMWH 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. 32 Only about one-third of an administered dose of unfractionated heparin binds to AT, and this fraction is responsible for most of its anticoagulant effect. Heparin alters the stereochemistry of AT, thereby catalyzing the subsequent inactivation of thrombin and other clotting factors. This cofactor, AT, was formerly called antithrombin III. Heparin is an indirect anticoagulant, requiring a cofactor. Heparins are large electronegative xenobiotics that are rapidly complexed by the electropositive protamine, forming an inactive salt.

Protamine sulfate antidote