According to one theory, a clone of defective (GPI-negative) cells is characterized by increased resistance to apoptosis as compared with normal GPI-positive cells and gradually gains an advantage, leading to an exacerbation of clinical symptoms of the disease. 4 The researchers followed for the relationship with the immune attack of T lymphocytes and natural killer (NK) cells against the normal clone, 5-7 dysfunction of immunomodulating proteins anchored by GPI in the membrane of hematopoietic cells, 8 or secondary mutations causing proliferative predominance of the PNH clone. ![]() 3 It is suspected that this dominance may be associated with clonal selection of hematopoietic cells, whereby cells without GPI-AP over-proliferate in comparison with normal cells. The cause and pathobiological background of the increasing clone dominance of GPI-defective cells have not been fully elucidated. The deficiency of cell membrane proteins: CD55 / decay-accelerating factor (DAF) and CD59 / membrane inhibitor of reactive lysis (MIRL), which are inhibitors of the complement system, is of the greatest importance in the pathophysiology of PNH. The most common clinical symptoms are hemolytic anemia, bone marrow failure (BMF), thrombosis, as well as renal, heart, and lung failure, and several symptoms related to smooth muscle dystonia. Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disease associated with a defect in the synthesis of the glycosylphosphatidylinositol (GPI) anchor and the lack of GPI-anchored protein (GPI-AP) binding in the plasma membranes of the hematopoietic cells. The first approved proximal complement pathway inhibitors that primarily prevent extravascular hemolysis, pegcetacoplan, danikopan, and iptacopan, are presented and their potential benefits are highlighted. Among the new therapeutic agents, crovalimab and C5 inhibitors at a less advanced stage of research are discussed: tesidolumab, pozelimab, zilucoplan, nomacopan, and cemdisiran. 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. 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. 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. Some changes in cytokine and chemokine profiles in patients with PNH have been interpreted in the context of autoimmunity and apoptosis. 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. ![]() 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.
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