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.
Bruins
P
P
Department of Anesthesiology, Academic Medical Centre, Amsterdam, The Netherlands. pbruins@knmg.nl
te Velthuis
H
H
Eerenberg-Belmer
A J
AJ
Yazdanbakhsh
A P
AP
de Beaumont
E M
EM
Eijsman
L
L
Trouwborst
A
A
Hack
C E
CE
D000704:Analysis of Variance; D000925:Anticoagulants / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D002097:C-Reactive Protein / Q000494:pharmacology*; D002315:Cardiopulmonary Bypass; D003176:Complement C3 / Q000187:drug effects / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000187:drug effects*; D003165:Complement System Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006493:Heparin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D006494:Heparin Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009204:Myocardial Revascularization; D010767:Phosphorylcholine / Q000494:pharmacology; D011446:Prospective Studies; D011479:Protamines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
D000925:Anticoagulants; D003176:Complement C3; D003181:Complement C4; D006494:Heparin Antagonists; D011479:Protamines; C030101:protamine heparin aggregate; D010767:Phosphorylcholine; D006493:Heparin; D003165:Complement System Proteins; D002097:C-Reactive Protein