Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab.
In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. There was no evidence of C3 on RBCs of untreated PNH patients; by contrast, in all patients on eculizumab (n = 41) a substantial fraction of RBCs had C3 bound on their surface, and this was entirely restricted to RBCs with the PNH phenotype (CD59(-)). The proportion of C3(+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom (51)Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess (51)Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.
Risitano
Antonio M
AM
Hematology, Department of Biochemistry and Medical Biotechnologies, Federico II University, Naples, Italy. amrisita@unina.it
Notaro
Rosario
R
Marando
Ludovica
L
Serio
Bianca
B
Ranaldi
Danilo
D
Seneca
Elisa
E
Ricci
Patrizia
P
Alfinito
Fiorella
F
Camera
Andrea
A
Gianfaldoni
Giacomo
G
Amendola
Angela
A
Boschetti
Carla
C
Di Bona
Eros
E
Fratellanza
Giorgio
G
Barbano
Filippo
F
Rodeghiero
Francesco
F
Zanella
Alberto
A
Iori
Anna Paola
AP
Selleri
Carmine
C
Luzzatto
Lucio
L
Rotoli
Bruno
B
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D002470:Cell Survival; D003176:Complement C3 / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006457:Hemoglobinuria, Paroxysmal / Q000276:immunology / Q000378:metabolism* / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D008297:Male
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003176:Complement C3; C481642:eculizumab