Paroxysmal nocturnal hemoglobinuria (PNH) is driven by uncontrolled complement activation that can lead to both intravascular and extravascular hemolysis, impacting disease manifestations and long-term complications. Understanding this underlying pathophysiology is key to selecting therapies that effectively control hemolysis and improve patient outcomes.

Patients with PNH have an acquired deficiency due to a mutation in the PIGA gene that puts their red blood cells (RBCs) at risk for hemolysis. When this gene is deficient, RBCs lack 2 molecules on their surface: CD55 and CD59. When these molecules are present on RBCs, complement does not cause damage; when they are missing, RBCs can be attacked by complement, causing them to lyse.

Clinically, this can result in patients having chronic low-grade hemolysis that is exacerbated by triggering events, such as surgery or infection, which can then activate complement to a much greater extent. Chronic intravascular hemolysis leads to the release of hemoglobin, and this can cause damage to the kidneys and other organs. It can also lead to iron deficiency, chronic anemia, fatigue, thrombosis, and a shortened survival.

Intravascular hemolysis occurs when RBCs are destroyed in the circulation, and the downstream effects can cause thrombosis and other symptoms of PNH. When you have intravascular hemolysis, your lactate dehydrogenase (LDH) is high because destruction occurs in the circulation. Extravascular hemolysis occurs when RBCs are destroyed outside the circulation in the liver and spleen. When you have extravascular hemolysis, RBC destruction occurs inside macrophages, so your LDH may be elevated, but not terribly high.

Haptoglobin, which binds free hemoglobin, gets reduced in intravascular hemolysis; this happens to a lesser extent in extravascular hemolysis. Another key distinction between intravascular and extravascular hemolysis is the effect of C3 convertase on the surface of RBCs. In patients with PNH and intravascular hemolysis, complement is activated and C3 gets added to RBCs, but then the complex continues to grow until the RBCs are destroyed by membrane attack complex formation. When intravascular hemolysis is inhibited with C5 inhibitors, the intravascular hemolysis is stopped and the RBCs do not carry the complement processing to its final extent. However, the RBCs remain coated with C3b and get removed by the macrophages in the liver and spleen, resulting in extravascular hemolysis.

In PNH, the underlying pathophysiology explains why controlling hemolysis—both intravascular and extravascular—is central to treatment, symptom control, thrombosis prevention, and long-term outcomes. Complement inhibition using C5 inhibitors nicely reduces intravascular hemolysis. LDH drops, hemoglobin rises, thrombosis risk decreases, transfusions decrease, and survival improves to near normal with the use of these agents. However, many patients on chronic C5 inhibitor therapy are still anemic because extravascular hemolysis continues in the liver and spleen. To target extravascular hemolysis, drugs that inhibit C3 or inhibit complement further upstream prevent C3 from binding to RBCs and can prevent both intravascular and extravascular hemolysis. Pegcetacoplan inhibits C3, danicopan inhibits factor D, and iptacopan inhibits factor B to turn off complement earlier in the cascade.

Another important consideration in PNH is the impact of hemolysis on iron balance. Untreated intravascular hemolysis causes iron loss in the urine, often leading to iron deficiency. However, chronic extravascular hemolysis leads to iron retention. Over time, iron levels creep up and can cause liver dysfunction. For patients on C5 inhibitors, simply altering the dose does not help because, even with perfect C5 inhibition, extravascular hemolysis will persist. This is a good rationale for considering alternative upstream agents that may also inhibit extravascular hemolysis.