Paroxysmal nocturnal hemoglobinuria: a complement-mediated hemolytic anemia

Abstract

Paroxysmal nocturnal hemoglobinuria is manifests with a chronic hemolytic anemia from uncontrolled complement activation, a propensity for thrombosis and marrow failure. The hemolysis is largely mediated by the alternative pathway of complement. Clinical manifestations result from the lack of specific cell surface proteins, CD55 and CD59, on PNH cells. Complement inhibition by eculizumab leads to dramatic clinical improvement. While this therapeutic approach is effective, there is residual complement activity resulting from specific clinical scenarios as well as from upstream complement components that can account for suboptimal responses in some patients. Complement inhibition strategies are an area of active research.

Keywords: Alternative pathway of complement; Bone marrow failure; C1 inhibition; C3 blockade; Eculizumab; Hemolytic anemia; Humanized anti-C5 monoclonal antibody; Paroxysmal nocturnal hemoglobinuria.

Fig. 1

The complement cascade. The complement cascade is activated via the classical, lectin or alternative pathways. C3 is activated via C3 convertases. This step is regulated by the action of CD55, a glycosylphosphatidylinositol (GPI)-anchored protein. Subsequently, C5 is cleaved into C5a and C5b. C5a mediates a number of biological processes and C5b begins the terminal pathway of complement and the assembly of the membrane attack complex (MAC). The formation of the MAC is regulated by CD59, another GPI-anchored protein. Thrombin interacts with the complement cascade where it can directly cleave C3. Thrombin can also cleave C5 into C5a, which occurs independently of C3 and therefore represents a bypass of the 3 traditional complement activation pathways.

Fig. 2

The complement cascade, paroxysmal nocturnal hemoglobinuria (PNH), and eculizumab. PNH cells have a deficiency in glycosylphosphatidylinositol-anchored proteins on their cell surface. Absence of CD55 and CD59 leads to uncontrolled complement activation on the surface of PNH cells. Deficiency of CD59 increases MAC formation and induces intravascular hemolysis, which is central to the pathophysiology of PNH. Deficiency of CD55 leads to increased C3 convertase activity and C3d-associated extravascular hemolysis. Eculizumab therapy for PNH is a humanized monoclonal antibody that targets C5. By preventing C5 activation, eculizumab prevents the formation of the MAC, leading to a significant reduction in intravascular hemolysis of PNH cells. Use of eculizumab can lead to increased extravascular hemolysis.