New insight into the effects of heparinoids on complement inhibition by C1-inhibitor

F. Poppelaars*, J. Damman, E. L. de Vrij, J. G. M. Burgerhof, J. Saye, M. R. Daha, H. G. Leuvenink, M. E. Uknis, M. A. J. Seelen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Scopus)

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 dosedependent fashion in the presence of pooled serum. Functional complement activities were measured simultaneously using the Wielisa (R)-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.

Original languageEnglish
Pages (from-to)378-388
Number of pages11
JournalClinical and Experimental Immunology
Volume184
Issue number3
DOIs
Publication statusPublished - Jun-2016

Keywords

  • complement
  • complement 1-inhibitor
  • glycosaminoglycans
  • heparinoids
  • inhibition
  • C1 INHIBITOR
  • HEREDITARY ANGIOEDEMA
  • TARGETING COMPLEMENT
  • PREDOMINANT ROLE
  • ACTIVATION
  • TRANSPLANTATION
  • PATHWAY
  • GENERATION
  • PLASMA
  • LECTIN

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