Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a consequence of somatic mutations in the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene. Clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure. Treatment of PNH mainly relies on the use of complement-targeted therapy (C5 inhibitors), with the newest agents being explored against other factors involved in the complement cascade to alleviate unresolved intravascular hemolysis and extravascular hemolysis. This review summarizes the biology and current treatment strategies for PNH with the aim of reaching a general audience with an interest in hematologic disorders.

Keywords: biology; paroxysmal nocturnal hemoglobinuria; treatment.

Figure 1

Evidence and theories on PNH immunoselection. (A) Lack of costimulation in cell-to-cell interactions in T and NK cells. In the latter case, ULBP proteins, GPI-APs lacking in PNH, and MICA/B were identified as ligands of NKG2D NK cell receptor. (B) NKT cells are able to recognize lipid antigens from GPI-AP molecules, inherent lacking in PNH, presented on the surface of the cells through CD1d receptor. (C) Efficacy of anti-human thymocyte globulin (ATG) therapy. Main mechanisms of action of ATG include complement-dependent cytotoxicity, with the formation of the membrane attack complex (MAC), opsonization process, subsequent phagocytosis, and antibody-dependent cytotoxicity. (D) The discovery of several HLA combinations differently expressed between PNH patients and controls and the detection of mutations in HLA machinery in PIGA-mutated cells led to the hypothesis of the role of the immunopeptidome in the pathogenesis of PNH. Figure was generated with BioRender.com, accessed on 8 July 2023.