Researchers reported that transfusion-independent patients with paroxysmal nocturnal hemoglobinuria (PNH) are vulnerable to the progressive deposition of iron in the reticuloendothelial system, according to a letter to the editor of HemaSphere. 

PNH is characterized by bone marrow failure. Eculizumab is the mainstay treatment for this disorder; it works by reducing intravascular hemolysis, which if left untreated can lead to urinary iron loss and subsequent iron deficiency. 

Hepcidin is the main regulator of iron homeostasis and it controls both the absorption and recycling of iron. Scientists recently discovered that the hormone erythroferrone is the main erythroid regulator of hepcidin. 

When patients with PNH experience hyperferritinemia, it is typically caused by a decline in renal iron loss or an increase in iron deposition in the reticuloendothelial system via C3d-mediated extravascular hemolysis. Although scientists have a reasonable grasp of how eculizumab affects iron metabolism, the roles of hepcidin and erythroferrone are less understood. 

Read more about PNH etiology 

The authors of the study thus sought to further investigate the role that eculizumab—and to a lesser extent, hepcidin and erythroferrone—have on iron metabolism. They recruited 13 transfusion-independent patients with PNH not treated with a complement inhibitor, as well as 23 transfusion-independent patients with PNH treated with eculizumab for at least 6 months.

The research team analyzed the association between hemolysis (both intravascular and extravascular) in these patients and iron parameters such as serum hepcidin and erythroferrone. 

The researchers reported that patients with PNH on eculizumab do indeed develop hyperferritinemia on a frequent basis compared with the control group. In addition, they found that C3d-mediated extravascular hemolysis was closely associated with iron accumulation in the reticuloendothelial system. 

“In conclusion . . . we postulate that in transfusion-independent PNH patients on eculizumab, the combination of a decline of renal iron loss as well as the emergence of extravascular hemolysis leading to increased reticuloendothelial system-iron influx and erythropoiesis-mediated suppressed hepcidin contribute to progressive iron deposition in the reticuloendothelial system,” Schaap and colleagues wrote. 


Schaap CM, Schols SEM, Preijers FWMB, et al. Effect of eculizumab on iron metabolism in transfusion-independent patients with paroxysmal nocturnal hemoglobinuria. HemaSphere. Published online May 2023. doi:10.1097/HS9.0000000000000878