Terminal complement inhibitors have been the standard treatment for paroxysmal nocturnal hemoglobinuria (PNH). Breakthrough hemolysis is a complication that can occur with any complement inhibitor, and its management depends on the potential causes and severity of the hemolytic event.

Therapies that inhibit either the proximal or distal steps of the complement system are very effective against intravascular hemolysis and the symptoms of PNH. In most cases, we obtain a very good response to C5 inhibition, although many patients do not completely normalize their hemoglobin. Having some ongoing extravascular hemolysis despite C5 inhibition is not considered breakthrough hemolysis; instead, it is due to phagocytosis of red blood cells opsonized by complement degradation products by macrophages (extravascular hemolysis). This extravascular hemolysis is an expected iatrogenic consequence.

Breakthrough hemolysis is a drop in hemoglobin and hematocrit levels after achieving a response to complement inhibition and reaching a baseline. In other words, hematologic parameters deteriorate after being stable on therapy, either regularly toward the end of the cycle (ie, pharmacokinetic breakthrough) or unexpectedly because of a provoking factor (ie, pharmacodynamic breakthrough). Common provoking factors include amplifying conditions such as bacterial or viral infection or pregnancy.

Part of the approach to breakthrough hemolysis is proactive prevention by discussing the signs and symptoms of hemolysis with patients. We should ask patients with PNH to inform their physicians upon having dark urine or returning symptoms such as chest pain and abdominal pain. We should also inform patients with PNH about conditions that can trigger breakthrough hemolysis, such as pregnancy, severe infections, or invasive procedures.

However, not all breakthrough hemolysis is symptomatic. Subclinical laboratory breakthrough hemolysis may occur, with a slight increase in the lactate dehydrogenase (LDH) level and reticulocyte count and a slight decrease in hemoglobin without symptoms. In contrast, if a patient’s hemoglobin drops by more than 2 g/dL and their LDH increases by 5 to 10 times the normal upper limit, usually they are symptomatic.

For patients with breakthrough hemolysis, I measure CH50 (total complement activity). If the patient’s CH50 is more than approximately 5%, this indicates that the patient may need a higher dose or the more frequent administration of an anticomplement reagent (ie, the dose may not be high enough to suppress complement activity or pharmacokinetic breakthrough). For those with pharmacokinetic breakthroughs at the end of the dosing cycle, the hemolysis can be easily managed by either increasing the dose or shortening the dosing interval. For patients with ongoing hemolysis despite what appears to be adequate complement inhibition, I would add a proximal complement inhibitor.

During a breakthrough event, the frequent monitoring of patient symptoms and checking the trend in laboratory values are important, as we need to know the severity of the event and the mechanism of hemolysis. Suppose a patient has a dramatic decrease in hemoglobin or increased LDH. In that case, you must treat them like any other patient with anemia by the transfusion of red blood cells and removing the provoking factors.

My goal in treating patients with PNH is not necessarily to normalize hemoglobin. The critical first step is eliminating the need for blood transfusion and making the patient transfusion independent. If patients have a hemoglobin level between 10 g/dL and 12 g/dL, the symptoms related to anemia are generally modest. It is also worth noting that coexisting PNH and G6PD deficiency can result in more severe hemolysis. Hence, we need to be alert to the possibility of G6PD deficiency, particularly in people of African, Mediterranean, or Asian descent.