Protamine is routinely used in the neutralization of heparin at the completion of CABG surgery. More than a million coronary revascularizations are performed each year in the United States. However, unlike previous years, only one-fourth of those cases are now CABGs and routinely expose patients to protamine. Since the advent of CABG surgery, there have been approximately 100 deaths reported in total with the use of protamine in these circumstances. It is largely in this setting that the adverse effects of protamine are also documented and studied.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. 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.2,6,47,70,71
Mechanisms for these adverse effects are multifactorial. Some contribution may result from significant electropositivity of protamine. The protamine–heparin complex activates the arachidonic acid pathway, and the production of thromboxane A2 is at least partly responsible for some of the hemodynamic changes, including pulmonary hypertension.13,19,36,66,91 Pretreatment with indomethacin limits these effects.19,36,66,91 Free protamine or protamine complexed with heparin can convert l-arginine to nitric oxide (formerly called endothelium-derived relaxing factor), which in turn causes vasodilation and inhibits platelet aggregation and adhesion, potentially increasing bleeding risks.74 Methylene blue, via reduction in the amount and effect of nitric oxide, has been used with success to treat the vasoplegia secondary to a severe protamine reaction. Protamine in excess of heparin can enter the myocardium and decrease cyclic adenosine monophosphate (cAMP), causing myocardial depression.13,80 Protamine and protamine–heparin complexes can activate the complement pathway and contribute to vasoactive events.13,75 Protamine stimulates mast cells in the human heart and skin to release histamine.13,60 Protamine administered in the absence of heparin, or in an amount exceeding that necessary for heparin neutralization, can act as an anticoagulant through several mechanisms. Protamine can impair ADP induced platelet aggregation, clot initiation, clot kinetics, and platelet function, resulting in weaker clot formation.44,47,87 Additionally, protamine reduces factor V activation by both thrombin and factor Xa, decreases factor VII6,70,71 activation by tissue factor, and enhances tissue-type plasminogen activator mediated fibrinolysis. A trial of patients undergoing CABG reported higher rates of microvascular bleeding and coagulation factor replacement in patients receiving excess protamine.52
Risk factors for protamine induced adverse reactions include prior exposure to protamine in insulin, exposure during previous surgery with protamine reversal, vasectomy, fish allergy, or a rapid of protamine infusion rate.56,75 A prospective study reported a 0.06% incidence of anaphylactic reactions to protamine in all patients undergoing CABG, but a 2% incidence in diabetics using neutral protamine Hagedorn (NPH) insulin.12 A recent systematic review of the literature revealed an anaphylaxis incidence of 1%, but the authors were cautious in interpreting the results because of study heterogeneity.72 The resultant elevation of histamine concentrations, the activation of complement, and elevated IgE, IgA, and IgG concentrations are also suggested as possible mechanisms for the adverse effects.54,82,93,94 Diabetic patients receiving daily subcutaneous injections of a protamine containing insulin (NPH) have a 40% to 50% increased risk of immune-mediated adverse reactions, including anaphylaxis.28,30,34,42,51,81
Occasionally, patients manifesting a protamine allergy are incorrectly presumed to have insulin allergy.50 In diabetic patients receiving protamine insulin injections, the presence of serum antiprotamine IgE antibody is a significant risk factor for acute protamine reactions. Only patients with previous exposure to protamine insulin injections had serum antiprotamine IgE antibodies. However, in the group without previous protamine insulin exposure, antiprotamine IgG antibody was noted as a risk factor for protamine reactions.94 Either naturally occurring cross-reacting antibodies, or perhaps previously unrecognized protamine exposure, was responsible for the generation of these IgG antibodies.