Heparin-protamine complexes and C-reactive protein induce activation of the classical complement pathway: Studies in patients undergoing cardiac surgery and in vitro

The administration of protamine to patients undergoing cardiopulmonary bypa ss (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 complement activation. In 24 patients during myocardial revascularization, we measured complement, CRP, and complement-CRP complexes, reflecting CRP-mediated complement acti vation in vivo. We also incubated plasma from healthy volunteers and patien ts with heparin and protamine in vitro to study CRP-mediated complement act ivation. During CPB, CRP levels remained unchanged while C3 activation prod ucts increased. C4 activation occurred after protamine administration. CRP- complement complexes increased at the end of CPB and upon protamine adminis tration. Incubation of plasma with heparin and protamine in vitro generated complement-CRP complexes, which was blocked by phosphorylcholine and stimu lated by exogenous CRP. C4d-CRP complex formation after protamine administr ation correlated clinically with the incidence of postoperative arrhythmia. Protamine administration during cardiac surgery induces complement activati on which in part is CRP-dependent, and correlates with postoperative arrhyt hmia.