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

Clin Exp Immunol. 2016 Jun;184(3):378-88. doi: 10.1111/cei.12777. Epub 2016 Apr 13.


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.

Keywords: complement; complement 1-inhibitor; glycosaminoglycans; heparinoids; inhibition.

MeSH terms

  • Blood Coagulation / drug effects
  • Complement Activation / drug effects*
  • Complement C1 Inhibitor Protein / pharmacology*
  • Complement Pathway, Alternative / drug effects
  • Complement Pathway, Classical / drug effects
  • Complement Pathway, Mannose-Binding Lectin / drug effects
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Drug Synergism
  • Heparinoids / pharmacology*
  • Humans
  • Partial Thromboplastin Time


  • Complement C1 Inhibitor Protein
  • Drug Combinations
  • Heparinoids