Proximal complement inhibitors have emerged as a potential option for addressing current limitations of terminal complement inhibitors, as they could prevent both intra- and extravascular hemolysis and improve anemia in patients with paroxysmal nocturnal hemoglobinuria (PNH).

In a review article recently published in Blood Reviews, a multinational panel of experts discussed the differences between the 2 approaches, highlighting biomarkers and laboratory tools for evaluating treatment efficacy.

“It is becoming clear that PNH is not just a disease mediated by terminal complement; as PNH blood cells lack the CD55 regulatory protein, proximal complement also plays a major role,” the experts explained. “Accordingly, the goals of treatment are evolving, and new treatment options that aim to maintain the benefits of terminal complement inhibitors while also improving hemoglobin levels are now emerging.”

Multiple parameters and biomarkers are needed to evaluate the level of intravascular and extravascular hemolysis in patients with PNH and provide a comprehensive picture of disease severity, progression, and long-term consequences.

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Assessing lactate dehydrogenase, bilirubin, haptoglobin, hemoglobin, absolute reticulocyte count, and PNH clone size is essential for monitoring patients with PNH, regardless of the treatment used. However, these parameters can be differentially affected by terminal and proximal complement inhibitors.

Also, the selection of biomarkers to monitor complement pathway blockade in patients with PNH should consider the type of complement inhibitor being administered, Kulasekararaj et al wrote. They recommend measuring CH50 values immediately before a dose is administered, as it may help define dosage. On the other hand, biomarkers of the proximal pathway include alternative complement assay, Bb fragments (ie, factor B cleavage fragments), and C3 and C3 opsonization.

Although promising, some of these markers, such as free C5 and the alternative complement assay, may have limited use in clinical practice due to concerns in preanalytical sampling and handling.

The use of proximal complement inhibitors may offer more convenient modes of administration and expand the treatment regimens available for patients with PNH. However, patients should be carefully monitored due to the current lack of long-term and real-world data on the safety of proximal complement inhibitors, the researchers wrote.


Kulasekararaj AG, Kuter DJ, Griffin M, Weitz IC, Röth A. Biomarkers and laboratory assessments for monitoring the treatment of patients with paroxysmal nocturnal hemoglobinuria: differences between terminal and proximal complement inhibition. Blood Rev. Published online January 14, 2023. doi:10.1016/j.blre.2023.101041