Paroxysmal Nocturnal Hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria is a peculiar acquired clonal genetic disease caused by somatic mutation of the X‐linked PIGA gene in a hematopoietic stem cell. Loss‐of‐function mutation in PIGA gene causes a lack or a decreased biosynthesis of glycosylphosphatidylinositol (GPI), which in turn results in a complete or a partial deficiency in the cell surface expression of GPI‐anchored proteins, such as CD59 and CD55. The PIGA ‐mutant stem cell clone becomes dominant in hematopoiesis due to an autoimmune‐mediated decrease of normal hematopoietic stem cells and/or an acquisition of benign tumour characteristics after additional genetic change(s) such that it causes ectopic expression of HMGA2 gene known to cause benign tumours. Mutant red blood cells lacking CD59 and CD55 are highly sensitive to complement and are lysed upon activation of complement during infection and other events, resulting in haemolytic anemia and hemoglobinuria. A humanised monoclonal antibody against fifth component of complement C5 that inhibits activation of C5 is now in clinical use to prevent intravascular haemolysis. Key Concepts: Paroxysmal nocturnal hemoglobinuria is an acquired genetic disease due to somatic mutation in the X‐linked PIGA gene that occurs in the hematopoietic stem cell. Loss‐of‐function somatic PIGA mutation causes a defective biosynthesis of glycosylphosphatidylinositol (GPI). The defective biosynthesis in GPI that anchors many proteins onto the plasma membrane, leads to defective cell surface expression of GPI‐anchored proteins. The PIGA ‐defective mutant clone expands and dominates hematopoietic cells in bone marrow and the peripheral blood. The clonal expansion is mediated by an autoimmune‐mediated decrease of normal hematopoietic stem cells and/or an acquisition of benign tumour characteristics. A lack of GPI‐anchored proteins makes red blood cells sensitive to homologous complement due to a loss of complement regulators, CD59 and CD55. Complement‐mediated haemolysis of GPI‐deficient red blood cells results in haemolytic anemia and hemoglobinuria. A humanised anti‐C5 monoclonal antibody is in clinical use to prevent intravascular haemolysis.