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 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 complement 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 vitro 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 administration. Incubation of plasma with heparin and protamine in vitro generated complement-CRP complexes, which was blocked by phosphorylcholine and stimulated by exogenous CRP. C4d-CRP complex formation after protamine administration correlated clinically with the incidence of postoperative arrhythmia. Protamine administration during cardiac surgery induces complement activation which in part is CRP-dependent, and correlates with postoperative arrhythmia.

Small valve area index: its influence on early mortality after mitral valve replacement.

OBJECTIVE: To test the hypothesis that mitral valve prosthesis-patient mismatch increases postoperative mortality. METHODS AND RESULTS: The effect of mitral valve prosthesis-patient mismatch on survival in a cohort of consecutive patients after mitral valve replacement with a mechanical prosthesis was measured, focusing on the lower tail of the normal distribution curve of the prosthetic valve area index. For the calculation of the geometric valve area index (cm(2)/m(2) body surface area), we used specifications for the geometric valve area supplied by the manufacturer. The cut-off value of the 10th percentile of the valve area index was 1.919 cm(2)/m(2). The study population consisted of 428 adult patients who underwent mitral valve replacement by a Medtronic Hall (n=270, 63%) or a St. Jude Medical prosthesis (n=158, 37%). The size of the valves implanted ranged from 25 mm to 31 mm. The valve area index showed a normal distribution curve ranging from 1.43 to 2.98 cm(2)/m(2) with a mean of 2.2 cm(2)/m(2). Group 1 (n=33) had a valve area index <1.9 cm(2)/m(2) and group 2 (n=395), > or =1.9 cm(2)/m(2). The 30-day mortality was higher in group 1 than in group 2 (18.2 vs. 4.1%, P=0.005). Multivariate logistic regression analysis of the determinants of the 30-day mortality rendered a small valve area index (<1.9 cm(2)/m(2)) as an independent risk indicator: relative risk 4.3 (95% CI 1.6-9.5; P=0. 0043). The difference in overall survival between the two groups was entirely due to the high 30-day mortality in the patients with small valve area indices, congestive heart failure being the main cause of death. CONCLUSIONS: By concentrating on the extreme lower tail of the normal distribution of the valve area index, a strong and independent relation was found between relatively small valves (valve area index <1.9 cm(2)/m(2)) and 30-day mortality. We found no influence of valve size on late mortality beyond the first 30 days.

Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia.

BACKGROUND: Complement activation during cardiopulmonary bypass (CPB) surgery is considered to result from interaction of blood with the extracorporeal circuit. We investigated whether additional mechanisms may contribute to complement activation during and after CPB and, in particular, focused on a possible role of the acute-phase protein C-reactive protein (CRP). METHODS AND RESULTS: In 19 patients enrolled for myocardial revascularization, perioperative and postoperative levels of complement activation products, interleukin-6 (IL-6), CRP, and complement-CRP complexes, reflecting CRP-mediated complement activation in vivo, were measured and related to clinical symptoms. A biphasic activation of complement was observed. The ratio between the areas under the curve of perioperative and postoperative C3b/c and C4b/c were 3:2 and 1:46, respectively. IL-6 levels reached a maximum at 6 hours post-surgery. CRP levels peaked on the second postoperative day. Each complement-CRP complex had peak levels on the second or third postoperative day. By multivariate analysis, maximum levels of CRP on the second postoperative day were mainly explained by C4b/c levels after protamine administration, leukocyte count on the second postoperative day, and preoperative levels of CRP. Peak levels of C4b/c after protamine administration (P=.0073) and on the second postoperative day correlated with the occurrence of arrhythmia on the same day (P=.0065). CONCLUSIONS: Cardiac surgery with CPB causes a biphasic complement activation. The first phase occurs during CPB and results from the interaction of blood with the extracorporeal circuit. The second phase, which occurs during the first 5 days after surgery, involves CRP, is related to baseline CRP levels, and is associated with clinical symptoms such as arrhythmia.