Heparin-protamine Complexes and C-reactive Protein Induce Activation of the Classical Complement Pathway: Studies in Patients Undergoing Cardiac Surgery and In Vitro

circulation Summary The administration of protamine to patients undergoing cardiopul-monary bypass (CPB) to neutralize heparin and to reduce the risk of bleeding, induces activation of the classical complement pathway mainly by heparin-protamine complexes. We investigated whether C-reactive protein (CRP) contributes to protamine-induced comple-ment activation. In 24 patients during myocardial revascularization, we measured complement, CRP, and complement-CRP complexes, reflecting CRP-mediated complement activation in vivo. We also incubated plasma from healthy volunteers and patients with heparin and protamine in vi-tro to study CRP-mediated complement activation. During CPB, CRP levels remained unchanged while C3 activation products increased. C4 activation occurred after protamine administration. CRP-complement complexes increased at the end of CPB and upon protamine administra-tion. Incubation of plasma with heparin and protamine in vitro generat-ed complement-CRP complexes, which was blocked by phosphoryl-choline and stimulated by exogenous CRP. C4d-CRP complex forma-tion after protamine administration correlated clinically with the inci-dence of postoperative arrhythmia. Protamine administration during cardiac surgery induces comple-ment activation which in part is CRP-dependent, and correlates with postoperative arrhythmia