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Pathogenesis of paroxysmal nocturnal hemoglobinuria

Author
Robert A Brodsky, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Alan G Rosmarin, MD

INTRODUCTION

Paroxysmal nocturnal hemoglobinuria (PNH) was one of the first hematologic disorders with a clear clinical description; the defining symptom, dark urine at night, was distinctive and easily observed. Subsequent investigations have clarified much of the pathogenesis of the disease, including the genetic defect and the mechanism of complement-mediated hemolysis. The mechanisms of other findings, such as pancytopenia and thrombosis, are less well understood and continue to be studied.

This topic discusses the pathogenesis of PNH. The clinical manifestations, diagnosis, and treatment of PNH are presented in detail separately. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)

PNH STEM CELL

PNH originates from an acquired genetic defect (mutation) in a multipotent hematopoietic stem cell, or in a hematopoietic progenitor cell that acquires stem cell properties and is able to survive, expand, and self-renew. PNH can arise de novo or in the setting of an underlying bone marrow disorder such as aplastic anemia (AA), myelodysplastic syndrome (MDS), or primary myelofibrosis (PMF) [1].

PIGA gene mutation — The acquired mutation in PNH occurs in the PIGA gene (phosphatidylinositol glycan anchor biosynthesis, class A; PIG-A; MIM311770), which is responsible for the first step in the synthesis of the glycosylphosphatidylinositol (GPI) anchor that attaches a subset of proteins to the cell surface (figure 1) [2].

The PIGA gene is located on the X chromosome. Therefore, a single "hit" (ie, a mutation in only one allele of the gene) will generate a PNH phenotype because males have only one X chromosome and females undergo X chromosome inactivation (lyonization) in every somatic cell, including hematopoietic stem cells [2].

               

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Literature review current through: Nov 2016. | This topic last updated: Thu Jun 02 00:00:00 GMT+00:00 2016.
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