How I treat paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, complement-mediated hemolytic anemia with protean manifestations. PNH can present as a hemolytic anemia, a form of bone marrow failure, a thrombophilia, or any combination of the above. Terminal complement inhibition is highly effective for treating intravascular hemolysis from PNH and virtually eliminates the risk of thrombosis, but is not effective for treating bone marrow failure. Here, I present a variety of clinical vignettes that highlight the clinical heterogeneity of PNH and the attributes and limitations of the 2 US Food and Drug Administration-approved C5 inhibitors (eculizumab and ravulizumab) to treat PNH. I review the concept of pharmacokinetic and pharmacodynamic breakthrough hemolysis and briefly discuss new complement inhibitors upstream of C5 that are in clinical development. Last, I discuss the rare indications for bone marrow transplantation in patients with PNH.

Graphical abstract

Figure 1.

Mechanisms of hemolysis in PNH. (A) Loss of CD55 and CD59 on PNH red cells leaves them vulnerable to complement-mediated intravascular hemolysis. (B) PNH red cells from patients with PNH treated with C5 inhibition (eculizumab or ravulizumab) often become coated with C3 fragments that serve as opsonins and lead to extravascular hemolysis in the spleen and liver. C5 inhibition compensates for the loss of CD59 and prevents intravascular hemolysis; however, CD55, upstream to C5 is important for accelerating decay of the C3 convertase. The lack of CD55 from PNH red cells leads to the accumulation of C3b and its processed forms iC3b and C3dg. (C) Pharmacokinetic intravascular hemolysis caused by insufficient drug dosing allows free C5 levels to rise. (D) Pharmacodynamic intravascular hemolysis. Complement amplifying conditions (pregnancy, infection, major surgery) can result in excess C3b accumulation on PNH red cells that leads to a conformational change in C5 and decrease the binding of eculizumab or ravulizumab to C5, resulting in breakthrough hemolysis even in the absence of a rise in free C5.