New insight into the effects of heparinoids on complement inhibition by C1‐inhibitor |
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| Authors: | F. Poppelaars J. Damman E. L. de Vrij J. G. M. Burgerhof J. Saye M. R. Daha H. G. Leuvenink M. A. J. Seelen |
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| Affiliation: | 1. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groninge, Groningen;2. Department of Pathology, University of Amsterdam, Academic Medical Centre, Amsterdam;3. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;4. Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands;5. ViroPharma, Inc., Exton, PA, USA;6. Department of Nephrology, University of Leiden, Leiden University Medical Center, Leiden;7. Department of Surgery, University of Groningen, University Medical Center Groningen, the Netherlands |
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| 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. |
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| Keywords: | complement complement 1‐inhibitor glycosaminoglycans heparinoids inhibition |
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