Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematopoietic stem cell disorder caused by somatic mutations of the PIGA gene on the X chromosome. PIGA encodes a phosphatidylinositol glycan needed for GPI-anchor synthesis, so PIGA-mutant cells lack all GPI-anchored proteins, including complement regulators CD55 (DAF) and CD59 (MIRL). The result is uncontrolled complement-mediated lysis of red cells, dysfunctional platelets, and a procoagulant state.

Three classical clinical scenarios are described: (1) classical PNH with intravascular hemolysis and thrombosis but normal marrow; (2) PNH in the setting of bone marrow failure, especially aplastic anemia, where smaller PNH clones evolve as the marrow is rescued; and (3) subclinical PNH detected by sensitive flow cytometry without overt symptoms.

Hemolysis manifests as fatigue, dark urine (especially morning), abdominal pain, and pulmonary hypertension via free hemoglobin scavenging nitric oxide. Thrombosis is the leading cause of mortality, often at unusual sites (hepatic — Budd-Chiari, mesenteric, cerebral). Diagnosis uses high-sensitivity flow cytometry with FLAER and quantification of GPI-deficient WBC and RBC clones. Eculizumab (humanized anti-C5) revolutionized treatment, with newer C5 inhibitors (ravulizumab, longer half-life) and proximal complement inhibitors (pegcetacoplan, iptacopan, danicopan) addressing extravascular hemolysis. Allogeneic HSCT remains the only curative option, mainly for marrow failure phenotype.