title: Heparin-protamine complexes and C-reactive protein induce activation of the classical complement pathway: studies in patients undergoing cardiac surgery and in vitro.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Academic Medical Centre, Amsterdam, The Netherlands. pbruins@knmg.nl
authors.forename: P
authors.initials: P
authors.lastname: Bruins
authors.forename: H
authors.initials: H
authors.lastname: te Velthuis
authors.forename: A J
authors.initials: AJ
authors.lastname: Eerenberg-Belmer
authors.forename: A P
authors.initials: AP
authors.lastname: Yazdanbakhsh
authors.forename: E M
authors.initials: EM
authors.lastname: de Beaumont
authors.forename: L
authors.initials: L
authors.lastname: Eijsman
authors.forename: A
authors.initials: A
authors.lastname: Trouwborst
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
mesh_terms: 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*
chemical_list: 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