Abstract
<jats:p>Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal disorder of hematopoietic stem cells characterized by complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure. The disease arises from somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene, which impair the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, leading to a deficiency of complement regulatory proteins such as, CD55 and CD59 on the surface of blood cells. This defect renders erythrocytes susceptible to uncontrolled complement activation and lysis. Beyond red cell destruction, PNH involves complex cellular and molecular mechanisms, including platelet activation, nitric oxide depletion, endothelial dysfunction, and immune escape of PNH clones in the bone marrow microenvironment. Over the past two decades, advances in the understanding of complement biology have transformed the therapeutic landscape of PNH. The introduction of terminal complement inhibitors, such as, eculizumab and ravulizumab, has dramatically improved survival and quality of life. However, limitations, including residual extravascular hemolysis and breakthrough episodes, have driven the development of proximal complement inhibitors targeting C3 (pegcetacoplan) and factors B and D (iptacopan, danicopan). Emerging RNA interference molecules and gene-editing strategies hold promise for deeper and potentially curative interventions.</jats:p>