When does a PNH clone have clinical significance?

ABSTRACT

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired blood disease caused by somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene required to produce glycophosphatidyl inositol (GPI) anchors. Although PNH cells are readily identified by flow cytometry due to their deficiency of GPI-anchored proteins, the assessment of the clinical significance of a PNH clone is more nuanced. The interpretation of results requires an understanding of PNH pathogenesis and its relationship to immune-mediated bone marrow failure. Only about one-third of patients with PNH clones have classical PNH disease with overt hemolysis, its associated symptoms, and the highly prothrombotic state characteristic of PNH. Patients with classical PNH benefit the most from complement inhibitors. In contrast, two-thirds of PNH clones occur in patients whose clinical presentation is that of bone marrow failure with few, if any, PNH-related symptoms. The clinical presentations are closely associated with PNH clone size. Although exceptions occur, bone marrow failure patients usually have smaller, subclinical PNH clones. This review addresses the common scenarios that arise in evaluating the clinical significance of PNH clones and provides practical guidelines for approaching a patient with a positive PNH result.