Frequency and Specificity of Protamine Antibodies in Diabetic and Control Subjects

Protamines are cationic fish chromosomal proteins that retard absorption of isophane (NPH) insulins. Protamines are also administered in large doses for heparin neutralization in cardiac procedures. This study used a rapid enzyme-linked immunosorbent assay to examine frequency of protamine antibodies in diabetic and control populations. Antigen specificity of the IgG binding to protamine-coated plates was verified by competitive inhibition with other protamines, histone, glucagon, thyroid-stimulating hormone, arginine, and lysine. All antibodies tested cross-reacted completely with all protamines. Only 4 of 18 had any cross-reactivity with histones. None cross-reacted with the other inhibitors. In population surveys, 122 (38%) of 319 NPH insulin-treated diabetic subjects, 3 (8%) of 39 diabetic subjects treated with protamine-free lente insulins, and 5 (2.5%) of 202 normal control subjects had protamine antibody. No correlation was found between insulin and protamine antibodies. Because more than one-third of insulin-treated diabetic subjects have circulating IgG specific for protamine, they are potentially at risk for acute immunologic or anaphylactoid reactions when protamine is administered for heparin neutralization.