A review of the pathophysiology of paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, ultra-rare disease characterized by chronic intravascular hemolysis. It is classically caused by an acquired mutation in the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) gene, though other gene mutations have been implicated. Whatever the initiating mutation, the result is a deficiency or loss of glycophosphatidylinositol (GPI) anchors from cell surfaces. These anchors are essential in binding proteins to cell membranes, with CD55 and CD59 being two important GPI-linked proteins lost in PNH. These ligands protect cells against complement; part of the innate immune system which promotes phagocytosis and lysis of invading pathogens. PNH cells appear to have a survival advantage over hematopoietic stem cells, often with the backdrop of bone marrow failure, leading to expansion of the PNH clone. Without the protection of CD55 and CD59, PNH red blood cells undergo complement-mediated hemolysis, causing a range of non-specific symptoms including anemia, fatigue, breathlessness and thrombosis. Untreated mortality can be high and before the advent of complement inhibitors treatment was limited to blood transfusions, anticoagulation, and bone marrow transplantation in a minority of patients. Complement inhibitors are now available which target components throughout the complement cascade and they have reduced PNH-associated morbidity and mortality. Treatment, however, carries the risk of infection, extravascular hemolysis and breakthrough hemolysis with some patients having better responses to others; perhaps in part due to polymorphisms of complement regulators. The aim of this review is to provide a thorough summary on the pathophysiology of not just the pathogenesis of PNH, but its clinical manifestations, treatment and their adverse effects, drawing on the impact of complement regulators, not covered in other review articles. Through reviewing the latest literature we have been able to identify areas where further ongoing research is required.