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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2017

Open Access 01-12-2017 | Research

Eculizumab treatment: stochastic occurrence of C3 binding to individual PNH erythrocytes

Authors: Michela Sica, Tommaso Rondelli, Patrizia Ricci, Maria De Angioletti, Antonio M. Risitano, Rosario Notaro

Published in: Journal of Hematology & Oncology | Issue 1/2017

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Abstract

Background

C5 blockade by eculizumab prevents complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). However, C3-bound PNH red blood cells (RBCs), arising in almost all treated patients, may undergo extravascular hemolysis reducing clinical benefits. Despite the uniform deficiency of CD55 and of CD59, there are always two distinct populations of PNH RBCs, with (C3+) and without (C3−) C3 binding.

Methods

To investigate this paradox, the phenomenon has been modeled in vitro by incubating RBCs from eculizumab untreated PNH patients with compatible sera containing eculizumab, and by assessing the C3 binding after activation of complement alternative pathway.

Results

When RBCs from untreated patients were exposed in vitro to activated complement in the context of C5-blockade, there was the prompt appearance of a distinct C3+ PNH RBC population whose size increased with time and also with the rate of complement activation. Eventually, all PNH RBCs become C3+ to the same extent, without differences between old and young (reticulocytes) PNH RBCs.

Conclusions

This study indicates that the distinct (C3+ and C3−) PNH RBC populations are not intrinsically different; rather, they result from a stochastic all-or-nothing phenomenon linked to the time-dependent cumulative probability of each individual PNH red cell to be exposed to levels of complement activation able to trigger C3 binding. These findings may envision novel approaches to reduce C3 opsonization and the subsequent extravascular hemolysis in PNH patients on eculizumab.
Appendix
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Metadata
Title
Eculizumab treatment: stochastic occurrence of C3 binding to individual PNH erythrocytes
Authors
Michela Sica
Tommaso Rondelli
Patrizia Ricci
Maria De Angioletti
Antonio M. Risitano
Rosario Notaro
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-017-0496-x

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