A new study has determined that rare variants of the complement factor H (CFH) gene, a complement regulator, were found at higher frequencies in patients with patients with paroxysmal nocturnal hemoglobinuria (PNH) than in healthy individuals.

The study, published in Blood, speculates that these rare variants may play a role in the physiology of PNH.

“Prata et al investigated the possible impact of these germline variants on disease outcomes, including pretreatment presentation and response to eculizumab,” the authors wrote. “Whereas the most common variants CFH p.His402Tyr and CR1 p.His1208Arg were not associated with a different disease presentation or response to eculizumab, rare CFH germline variants were associated with statistically significant worse event-free and failure-free survival.”

The research team screened 84 patients with PNH employing next generation sequencing, and found the higher frequencies of rare CFH variants. In their investigation of the impact of these variants, they discovered that all patients with these variants experienced red blood cell transfusions, thrombosis, or required a higher dose of eculizumab within 15 months of the start of their treatment.

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However, the authors note that the variants were not associated with either aplastic anemia or progression to any myeloid malignancy in the studied cohort.

The fact that patients carrying these rare variants might have a different response to standard anti-C5 complement treatment with eculizumab is critical information for clinicians. Proximal complement inhibitors are also being developed, and it will be essential to determine how the rare CFH variants could affect the response to these treatments.

The unique features of CFH variant activity and pharmacodynamic differences could lead to breakthrough hemolysis, a serious complication of PNH. The authors note that more functional data are required to further elucidate how variants of complement regulator genes, including CFH, will impact complement proximal inhibitor treatment among these patients.


Risitano AM. PNH and complement gene variants. Blood. Published online April 13, 2023. doi:10.1182/blood.2022019576