Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening clonal hematopoietic stem cell disorder characterized by hemolytic anemia, bone marrow failure, and thrombosis. The absence of glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins, such as CD55 and CD59, leads to uncontrolled complement activation, chronic intravascular hemolysis, and severe complications. Thrombosis remains the leading cause of mortality, accounting for 40–67% of deaths in PNH patients.

High-sensitivity flow cytometry is the gold standard for detecting GPI-deficient cell populations and remains essential for both diagnosis and follow-up. Laboratory evaluation includes complete blood count, hemolysis parameters (LDH, bilirubin, haptoglobin, reticulocytes), and bone marrow examination. Clinical indications for testing are hemolysis, cytopenias, unexplained anemia, aplastic anemia, and thrombosis in atypical sites such as hepatic or cerebral veins. International guidelines (IPIG, ICCS, BCSH) recommend screening all patients with aplastic anemia for PNH clones at diagnosis.

Regular monitoring of hemolysis-related parameters is critical to identify high disease activity, defined as LDH ≥1.5 × ULN plus at least one symptom (fatigue, dyspnea, abdominal pain, hemoglobinuria, anemia, thrombosis). Eculizumab, a C5 inhibitor, was the first targeted therapy to significantly reduce intravascular hemolysis and thrombotic risk. Vaccination against Neisseria meningitidis is mandatory before treatment initiation. Ravulizumab, a long-acting C5 inhibitor, offers extended dosing intervals with comparable efficacy.

Recent therapeutic advances are transforming PNH management. Crovalimab, a next-generation C5 inhibitor, allows subcutaneous administration with longer dosing intervals. Biosimilar eculizumab (Bkemv) improves treatment accessibility. Proximal complement inhibitors, including iptacopan (oral Factor B inhibitor), danicopan (Factor D inhibitor), and pegcetacoplan (C3 inhibitor), target both intravascular and extravascular hemolysis, improving hemoglobin stabilization, transfusion independence, and quality of life. These agents are increasingly incorporated into personalized treatment strategies.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option but is associated with high treatment-related mortality. It should be reserved for patients with severe bone marrow failure or refractory disease when risks outweigh potential benefits.

The therapeutic landscape of PNH is undergoing a paradigm shift, with novel long-acting and oral complement inhibitors improving disease control and patient convenience. Early diagnosis through flow cytometry and individualized treatment selection remain essential for optimal outcomes. Although HSCT offers potential cure, complement inhibitors currently represent the cornerstone of PNH management.