Potentiation of factor H by heparin: A rate-limiting mechanism for inhibition of the alternative complement pathway

Boackle, Robert J.; Caughman, Gretchen B.; Vesely, Jana; Medgyesi, G; Fudenberg, H. Hugh

doi:10.1016/0161-5890(83)90139-6

Cited by 49 publications

(23 citation statements)

References 16 publications

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“…It was shown previously (27) that addition of heparin t serum increased the electrophoretic mobility of H. This wa also observed in this laboratory. However, electrophoreti analysis of SLE serum containing excess inhibitor showed I to have the same mobility as the H in NHS.…”

Section: Methodssupporting

confidence: 85%

“…Heparin, added to serum, has recently been shown to bind to H and potentia the ability of H to inactivate C3b (27). It was demonstrat further in the study that, as in SLE serum, inhibition conve-tase formation by heparin was not demonstrable in ti absence of H and the inhibitory effect of heparin could 1 restored by addition of purified H to the mixture.…”

Section: Methodsmentioning

confidence: 89%

“…In support of this hypothetical mechanism, soluble heparin has recently been shown to potentiate the ability of H to inactivate C3b (27). However, unlike heparin, the inhibitor in SLE serum appears to interact more loosely with H and does not change its electrophoretic or chromatographic properties.…”

Section: Methodsmentioning

confidence: 97%

“…As a result of these observations, the method used for surveying large numbers of serum specimens for free inhibitor used the low H target serum. 10 [25][26][27][28][29] and none contained preformed Ba. In NHS, a direct relationship between the quantity of Ba formed and of C3 converted at 5 mmn was observed (Fig.…”

Section: Methodsmentioning

confidence: 99%

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A circulating inhibitor of fluid-phase amplification. C3 convertase formation in systemic lupus erythematosus.

Waldo¹,

Forristal²,

Beischel³

et al. 1985

J. Clin. Invest.

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Section: Methodssupporting

confidence: 85%

Section: Methodsmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

A circulating inhibitor of fluid-phase amplification. C3 convertase formation in systemic lupus erythematosus.

Waldo¹,

Forristal²,

Beischel³

et al. 1985

J. Clin. Invest.

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“…The heparinoids used in this study are used clinically and known for a wide variety of biological effects. It has been known for years that heparin inhibits all pathways of complement by blocking MASPs, C1q and by the potentiation of factor H [13,27,28]. However, to our knowledge this is the first report that shows, in addition to heparin, that low molecular weight heparins, that are widely used clinically, inhibit all three complement ) and the alternative pathway (e,f).…”

Section: Discussionmentioning

confidence: 73%

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

Poppelaars

Damman

Vrij

et al. 2016

Clinical and Experimental Immunology

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1These authors contributed equally to this study. SummaryComplement 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 V 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.

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Biphasic response of complement to heparin: Fluid‐phase generation of neoantigens in human serum and in a reconstituted alternative pathway amplification cycle

et al. 1995

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We describe a study of the effects of heparin on complement activation through the use of assays for fragment C4d, fragment Bb, and the S-C5b-9 complex (S-MAC). In sera from healthy volunteers, virtually no change was observed in C4d either as a function of time or of heparin concentration, whereas changes in Bb and S-MAC were biphasic. This observation was explored in greater detail in the heparin concentration range 0.001-5.0 u/ml (5 x 10(-3) to 25 micrograms/ml). For both Bb and S-MAC, a significant (P < 0.05) increase in production was noted in the heparin concentration range, 0.01-0.5 u/ml (5 x 10(-2) to 2.5 micrograms/ml). At higher heparin concentrations, Bb and S-MAC production decreased markedly (P < 0.05). We reconstituted the alternative pathway amplification cycle (C3, factor B, and factor D) and studied Bb generation. With reactants at concentrations one tenth those of normal serum, we observed a maximum generation of 13.2 micrograms/ml Bb. Control and heparin at 5 x 10(-4) micrograms/ml generated Bb concentrations of 6.8 and 6.1 micrograms/ml, respectively, for a 2-min incubation; at 5 x 10(-3) micrograms/ml heparin, Bb was increased to 9.8 micrograms/ml. Using isoelectric focusing to study anionic pI shifts in heparin-bound factors B and D, it was found that factor B bound heparin only at the highest heparin concentration studied, i.e., 50 micrograms/ml; factor D, however, bound heparin at a much lower concentration (0.05 micrograms/ml). We conclude that, at low concentrations, heparin activates complement due to potentiation of the alternative pathway amplification cycle in the fluid phase.

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Potentiation of factor H by heparin: A rate-limiting mechanism for inhibition of the alternative complement pathway

Cited by 49 publications

References 16 publications

A circulating inhibitor of fluid-phase amplification. C3 convertase formation in systemic lupus erythematosus.

A circulating inhibitor of fluid-phase amplification. C3 convertase formation in systemic lupus erythematosus.

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

Biphasic response of complement to heparin: Fluid‐phase generation of neoantigens in human serum and in a reconstituted alternative pathway amplification cycle

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