New insight into the effects of heparinoids on complement inhibition by C1-inhibitor
Corresponding Author
F. Poppelaars
Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groninge, Groningen
Correspondence: F. Poppelaars, Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Ingang 19, Huispostcode AA53, De Brug 4e verdieping. Hanzeplein 1, 9713 GZ, Postbus 30001, 9700 RB, Groningen, the Netherlands. E-mail: [email protected]Search for more papers by this authorJ. Damman
Department of Pathology, University of Amsterdam, Academic Medical Centre, Amsterdam
Search for more papers by this authorE. L. de Vrij
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Search for more papers by this authorJ. G. M. Burgerhof
Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
Search for more papers by this authorM. R. Daha
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
Search for more papers by this authorH. G. Leuvenink
Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Search for more papers by this authorM. E. Uknis
ViroPharma, Inc., Exton, PA, USA
These authors contributed equally to this study.
Search for more papers by this authorM. A. J. Seelen
Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groninge, Groningen
These authors contributed equally to this study.
Search for more papers by this authorCorresponding Author
F. Poppelaars
Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groninge, Groningen
Correspondence: F. Poppelaars, Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Ingang 19, Huispostcode AA53, De Brug 4e verdieping. Hanzeplein 1, 9713 GZ, Postbus 30001, 9700 RB, Groningen, the Netherlands. E-mail: [email protected]Search for more papers by this authorJ. Damman
Department of Pathology, University of Amsterdam, Academic Medical Centre, Amsterdam
Search for more papers by this authorE. L. de Vrij
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Search for more papers by this authorJ. G. M. Burgerhof
Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
Search for more papers by this authorM. R. Daha
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
Search for more papers by this authorH. G. Leuvenink
Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Search for more papers by this authorM. E. Uknis
ViroPharma, Inc., Exton, PA, USA
These authors contributed equally to this study.
Search for more papers by this authorM. A. J. Seelen
Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groninge, Groningen
These authors contributed equally to this study.
Search for more papers by this authorSummary
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.
Supporting Information
Additional Supporting information may be found in the online version of this article at the publisher's web-site:
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| cei12777-sup-0001-suppinfo01.pdf5.2 MB |
Table S1a. Percentage inhibition of classical pathway activity by C1-INH in combination with heparin, dalteparin, nadroparin or enoxaparin. The inhibition of C5b-9 deposition was calculated by dividing the optical density (OD) of the sample with heparinoid by the control, the sample without heparinoid or C1-INH. Data are expressed as the mean and standard error of the mean of three experiments. Table S1b. Percentage inhibition of lectin pathway activity by C1-INH in combination with heparin, dalteparin, nadroparin or enoxaparin. The inhibition of C5b-9 deposition was calculated by dividing the optical density (OD) of the sample with heparinoid by the control, the sample without heparinoid or C1-INH. Data are expressed as the mean and standard error of the mean of three experiments. Table S1c. Percentage inhibition of alternative pathway activity by C1-INH in combination with heparin, dalteparin, nadroparin or enoxaparin. The inhibition of C5b-9 deposition was calculated by dividing the optical density (OD) of the sample with heparinoid by the control, the sample without heparinoid or C1-INH. Data are expressed as the mean and standard error of the mean of three experiments. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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