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.