Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder 
characterized by chronic intravascular hemolysis as the primary clinical 
manifestation and morbidities that include anemia, thrombosis, renal impairment, 
pulmonary hypertension, and bone marrow failure. The prevalence of the PNH clone 
(from <1-100% PNH granulocytes) is approximately 16 per million, and careful 
monitoring is required. The average age of onset of the clinical disease is the 
early 30s, although it can present at all ages. PNH is caused by the acquisition 
of a somatic mutation of the gene phosphatidylinositol glycan anchor (PIG-A) in 
a multipotent hematopoietic stem cell (HSC), with clonal expansion of the 
mutated HSC. The mutation causes a deficiency in the synthesis of 
glycosylphosphatidylinositol (GPI). In cells derived from normal HSCs, the 
complement regulatory proteins CD55 and CD59 are anchored to the hematopoietic 
cell membrane surface via GPI, protecting the cells from complement-mediated 
lysis. However, in patients with PNH, these 2 proteins, along with numerous 
other GPI-linked proteins, are absent from the cell surface of red cells, 
granulocytes, monocytes, and platelets, resulting in complement-mediated 
intravascular hemolysis and other complications. Lysis of red blood cells is the 
most obvious manifestation, but as other cell lineages are also affected, this 
complement-mediated attack contributes to additional complications, such as 
thrombosis. Eculizumab, a humanized monoclonal antibody against the C5 
complement protein, is the only effective drug therapy for PNH patients. The 
antibody prevents cleavage of the C5 protein by C5 convertase, in turn 
preventing generation of C5b-9 and release of C5a, thereby protecting from 
hemolysis of cells lacking the CD59 surface protein and other complications 
associated with complement activation. Drs. Ilene C. Weitz, Anita Hill, and Jeff 
Szer discuss 3 recent cases of patients with PNH.