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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Journal of Hematology & Oncology 1/2017

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

Journal of Hematology & Oncology > Ausgabe 1/2017
Michela Sica, Tommaso Rondelli, Patrizia Ricci, Maria De Angioletti, Antonio M. Risitano, Rosario Notaro
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13045-017-0496-x) contains supplementary material, which is available to authorized users.
Preliminary results of this work have been presented at the XV Meeting of the European Hematology Association (Barcelona, Spain; 2010) and at the XI Congress of the Italian Society of Experimental Hematology (Torino, Italy; 2010).



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.


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.


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.


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.

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Additional file 1: Figure S1. In vivo C3 binding on red cells of PNH patients on eculizumab. Figure S2. Effect of spontaneous complement activation on PNH red cells. (PDF 1927 kb)
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