title: New insight into the effects of heparinoids on complement inhibition by C1-inhibitor.
abstract: Complement activation is of major importance in numerous pathological conditions. Therefore, targeted complement inhibition is a promising therapeutic strategy. C1-esterase inhibitor (C1-INH) controls activation of the classical pathway (CP) and the lectin pathway (LP). However, conflicting data exist on inhibition of the alternative pathway (AP) by C1-INH. The inhibitory capacity of C1-INH for the CP is potentiated by heparin and other glycosaminoglycans, but no data exist for the LP and AP. The current study investigates the effects of C1-INH in the presence or absence of different clinically used heparinoids on the CP, LP and AP. Furthermore, the combined effects of heparinoids and C1-INH on coagulation were investigated. C1-INH, heparinoids or combinations were analysed in a dose-dependent fashion in the presence of pooled serum. Functional complement activities were measured simultaneously using the Wielisa(®) -kit. The activated partial thrombin time was determined using an automated coagulation analyser. The results showed that all three complement pathways were inhibited significantly by C1-INH or heparinoids. Next to their individual effects on complement activation, heparinoids also enhanced the inhibitory capacity of C1-INH significantly on the CP and LP. For the AP, significant potentiation of C1-INH by heparinoids was found; however, this was restricted to certain concentration ranges. At low concentrations the effect on blood coagulation by combining heparinoids with C1-INH was minimal. In conclusion, our study shows significant potentiating effects of heparinoids on the inhibition of all complement pathways by C1-INH. Therefore, their combined use is a promising and a potentially cost-effective treatment option for complement-mediated diseases.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groninge, Groningen.
authors.forename: F
authors.initials: F
authors.lastname: Poppelaars
authors.affiliation: Department of Pathology, University of Amsterdam, Academic Medical Centre, Amsterdam.
authors.forename: J
authors.initials: J
authors.lastname: Damman
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: E L
authors.initials: EL
authors.lastname: de Vrij
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: J G M
authors.initials: JG
authors.lastname: Burgerhof
authors.affiliation: ViroPharma, Inc., Exton, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Saye
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groninge, Groningen.|Department of Nephrology, University of Leiden, Leiden University Medical Center, Leiden.
authors.forename: M R
authors.initials: MR
authors.lastname: Daha
authors.affiliation: Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: H G
authors.initials: HG
authors.lastname: Leuvenink
authors.affiliation: ViroPharma, Inc., Exton, PA, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Uknis
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groninge, Groningen.
authors.forename: M A J
authors.initials: MA
authors.lastname: Seelen
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects*; D050718:Complement C1 Inhibitor Protein / Q000494:pharmacology*; D003170:Complement Pathway, Alternative / Q000187:drug effects; D003171:Complement Pathway, Classical / Q000187:drug effects; D037582:Complement Pathway, Mannose-Binding Lectin / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D006496:Heparinoids / Q000494:pharmacology*; D006801:Humans; D010314:Partial Thromboplastin Time
chemical_list: D050718:Complement C1 Inhibitor Protein; D004338:Drug Combinations; D006496:Heparinoids
keywords: complement; complement 1-inhibitor; glycosaminoglycans; heparinoids; inhibition