Most instances of breakthrough hemolysis are caused by a provoking factor, including a complement-amplifying condition, with the most common being bacterial or viral infection, pregnancy, surgery, and trauma. Fortunately, most provoking factors are temporary, and most cases are self-limited.

In my practice, breakthrough hemolysis is not very common. Still, it does happen in a small percentage of patients, perhaps 5% to 15% of individuals with PNH who receive a distal complement inhibitor (ie, a C5 inhibitor, eculizumab, or ravulizumab). I suspect that the rate of breakthrough hemolysis may be even lower in patients with PNH who are on proximal complement inhibitors because the use of these agents is less established and the data are more limited. We have had pegcetacoplan for only a few years, and iptacopan was introduced even more recently. Although blocking a proximal step in the complement cascade may be associated with less breakthrough hemolysis, by reducing extravascular hemolysis, proximal complement inhibition may generate a larger population of circulating PNH red blood cells that are susceptible to hemolysis by complement-amplifying conditions.

Not all hemolysis in PNH is due to complement-amplifying conditions. Other factors can also provoke hemolysis in PNH. For example, G6PD deficiency in red blood cells makes red blood cells more susceptible to oxidative injury in patients with PNH, even those receiving treatment with anticomplement reagents.

If a patient with PNH does not respond to an anticomplement reagent, we may consider a different complement inhibitor. Let us consider a patient with PNH with a hemoglobin of 7 g/dL or 8 g/dL and an elevated lactate dehydrogenase (LDH) that is 5 to 10 times the normal level, requiring frequent transfusions. After 3 months of C5 inhibition, if the patient’s hemoglobin is in the range of 9 g/dL or 10 g/dL, their LDH is 4 times the normal level, and their reticulocyte count is 5%, then this is a good response, but it is not a complete response. In this situation, you might consider switching to a proximal complement inhibitor.