The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab

Abstract

Paroxysmal nocturnal hemoglobinuria is a rare disorder of hemopoietic stem cells. Affected individuals have a triad of clinical associations - intravascular hemolysis, an increased risk of thromboembolism, and bone marrow failure. Most of the symptoms experienced in this disease occur due to the absence of complement regulatory proteins on the surface of the red blood cells. Complement activation is thus not checked and causes destruction of these cells. Eculizumab is a monoclonal antibody treatment which specifically binds to the complement protein C5, preventing its cleavage, and so halts the complement cascade and prevents the formation of the terminal complement proteins. Eculizumab prevents intravascular hemolysis, stabilizes hemoglobin levels, reduces or stops the need for blood transfusions, and improves fatigue and patient quality of life as well as reducing pulmonary hypertension, decreasing the risk of thrombosis and protecting against worsening renal function. It is not a curative therapy but has a great benefit on those with this rare debilitating condition.

Keywords: eculizumab; hemolysis; paroxysmal nocturnal hemoglobinuria.

Figure 1

Glycophosphatidylinositol biosynthesis: an illustration showing the stepwise addition of sugar residues and the sites at which PIG-A and PIG-M are required. Abbreviations: M, mannose; NA, N-acetylglucosamine; PI, phosphatidylinositol.

Figure 2

The complement cascade showing the proximal and the terminal complement components which lead to the formation of the membrane attack complex which in turn causes hemolysis of erythrocytes in paroxysmal nocturnal hemoglobinuria.

Figure 3

PNH red blood cell analysis showing type III paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes which express no CD59 (shown on the x axis), type II PNH erythrocytes with reduced levels of CD59 and type I erythrocytes with normal levels of CD59.

Figure 4

Eculizumab binding to C5 inhibiting formation of the membrane attack complex and release of C5a.