Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of hematopoietic stem cells, not an inherited hemoglobin disorder. A somatic mutation in the PIGA gene prevents affected cells from making normal glycosylphosphatidylinositol (GPI) anchors. Without these anchors, blood cells cannot display the complement-regulating proteins CD55 and CD59 normally. Loss of this surface protection leaves the clone vulnerable to uncontrolled complement activity. Red cells can then rupture within the circulation, producing intravascular hemolysis and releasing free hemoglobin into plasma and urine. Free hemoglobin binds nitric oxide. Nitric-oxide depletion helps explain abdominal pain, dysphagia or esophageal spasm, erectile dysfunction and pulmonary hypertension. Complement-mediated red-cell destruction also causes anemia and may injure the kidneys. PNH can coexist with aplastic anemia or another marrow-failure disorder, so neutropenia and thrombocytopenia may accompany anemia even though hemolysis is central to classic PNH. Organize the clinical pattern into three linked problems: intravascular hemolysis, thrombosis and bone-marrow dysfunction. Thrombosis may occur in usual or unusual sites, including hepatic, portal, mesenteric and cerebral veins. The disease name is misleading: hemolysis is not confined to nighttime. Dark urine may be...