The extent of breakthrough hemolysis that can occur with C3 or C5 blockade among patients with paroxysmal nocturnal hemoglobinuria (PNH) may vary as a result the intrinsic mechanisms of the complement system, thereby suggesting that a combined blockade approach may be beneficial for some patients, according to a review published in the New England Journal of Medicine.

The anti-C5 monoclonal antibody, eculizumab, is highly effective at improving anemia, reducing the risk of thrombosis, improving quality of life, and prolonging survival of patients with PNH. However, breakthrough hemolysis can occur, which presents as a reappearance of signs and symptoms.

“Breakthrough hemolysis may be attributed to suboptimal C5 inhibition,” the authors wrote in their report. This can occur if the levels of eculizumab are insufficient for complete blockade or if an event such as infection causes strong activation of the complement cascade that breaks through the C5 inhibition. Breakthrough hemolysis in this scenario is typically self-limited.

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However, when C5 is inhibited without blockade of C3, fragments of C3 can bind to PNH red cells, causing them to become targets for macrophages, ultimately resulting in extravascular hemolysis. It is believed that this mechanism is responsible for the up to 35% of patient with PNH who remain transfusion dependent despite eculizumab treatment.

Breakthrough hemolysis in the setting of only C3 inhibition can be much more profound than that which occurs with C5 blockade. The authors hypothesized that this difference is a result of intrinsic features associated with the complement system. When C5 is not inhibited, it recruits a single molecule of several downstream complement factors and ultimately results in the synthesis of a single MAC. In contrast, when C3 is not inhibited, its action is amplified through an enzyme cascade that results in the cleavage of multiple C5 molecules, thereby resulting in the production of multiple MAC copies. “As a consequence, breakthrough hemolysis can be massive,” the authors wrote.

Combined treatment of PNH with a C3 and a C5 inhibitor may therefore be beneficial for some patients. “With this approach,” the authors wrote, “the inhibition of either of the 2 pathways may not need to be complete.” They note that a major limitation of this strategy is the high cost of each inhibitor.

The authors concluded that the improved understanding of how partial inhibition of C3 or C5 can affect breakthrough hemolysis suggest that “the combined approach might prevent C3 binding to PNH red cells and thus extravascular hemolysis, in addition to preventing massive breakthrough hemolysis.”


Notaro R, Luzzatto L. Breakthrough hemolysis in PNH with proximal or terminal complement inhibition. N Engl J Med. 2022;387:160-166. doi: 10.1056/NEJMra2201664