Paroxysmal nocturnal hemoglobinuria: advances in the understanding of pathophysiology, diagnosis, and treatment.

ABSTRACT

In recent years, "old" paroxysmal nocturnal hemoglobinuria (PNH) has achieved new advances in terms of the understanding of its pathophysiology, modern approach to diagnostics, optimization of therapy, and dynamic development of new therapeutic agents. This review emphasizes the greater than previously recognized importance of the reduced susceptibility of PNH stem cells to apoptosis in the selection of a defective clone. Some changes in cytokine and chemokine profiles in patients with PNH have been interpreted in the context of autoimmunity and apoptosis. The classification of PNH presentations, characteristics of the functions of selected glycosylphosphatidylinositol-anchored proteins, as well as pathologies associated with hemolysis, thrombosis, and bone marrow failure are described. The current diagnostic process for various forms of PNH is presented in detail, as well as its importance in the choice of treatment and prognosis of the disease course. Determinants of modern treatment, such as strategies (complement C5 inhibitors vs hematopoietic stem cell allotransplantation), the safety and efficacy of treatment with eculizumab or ravulizumab, policy of initiation and monitoring of treatment, the criteria for response to treatment and final outcomes of treatment are described. Among the new therapeutic agents, crovalimab and C5 inhibitors at a less advanced stage of research are discussed tesidolumab, pozelimab, zilucoplan, nomacopan, and cemdisiran. The first approved proximal complement pathway inhibitors that primarily prevent extravascular hemolysis, pegcetacoplan, danikopan, and iptacopan, are presented and their potential benefits are highlighted.