Narrative review: Paroxysmal nocturnal hemoglobinuria: The physiology of complement-related hemolytic anemia

Clinical Principles Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem-cell disorder caused by a somatic mutation in a gene known as phosphatidylinositol glycan class A (PIGA). It may arise de novo or in the setting of acquired aplastic anemia. Clinical presentation can include hemolytic anemia, hemoglobinuria, thrombosis, severe fatigue, abdominal pain, and esophageal spasm. Thrombosis, the leading cause of death from PNH, most commonly occurs in abdominal and cerebral veins. Therapeutic options include supportive care, bone marrow transplantation, and monoclonal antibody therapy with the terminal complement inhibitor eculizumab. Pathophysiologic Principles The product of the PIGA gene is required for the biosynthesis of a glycolipid anchor that attaches a class of membrane proteins known as glycosylphosphatidylinositol (GPI)anchored proteins to the cell surface. The absence of GPI-anchored proteins leads to complement-mediated intravascular hemolysis, because 2 important complement regulatory proteins (CD55 and CD59) are missing from PNH cells. Hemolysis in PNH occurs intravascularly. This leads to release of free hemoglobin, a potent nitric oxide scavenger. Depletion of nitric oxide at the tissue level contributes to fatigue, esophageal spasm, thrombosis, and male erectile dysfunction. Eculizumab decreases hemolysis in PNH by binding to C5 and blocking the terminal portion of the complement cascade.