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  • Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem/progenitor cell (HSPC) disorder characterized by deficiency of glycosyl phosphatidylinositol (GPI)-anchored proteins (GPI-APs) on the surface of hematopoietic cells. Two complement regulatory proteins (CD55 and CD59) are GPI anchored, and deficiency of these two proteins on erythrocytes derived from the mutant HSPC leads to complement-mediated intravascular hemolysis that is the clinical hallmark of the disease. Marrow failure and thrombophilia also complicate the disease.


  • PNH is a consequence of somatic mutation of PIGA, an X chromosome gene that encodes a glycosyl transferase required for synthesis of the GPI anchor.

  • Women and men are equally affected because PIGA is subject to X inactivation in somatic tissues of females. Therefore, females, like males, have one functional PIGA in somatic tissues, resulting in an equal risk of inactivating PIGA in HSPC as a consequence of somatic mutation.

  • The somatic mutation arises in one or more HSPCs, and as a consequence, all of the progeny of the mutant cell are deficient in all GPI-APs that are normally expressed on hematopoietic cells.

  • More than 25 GPI-APs have been found to be deficient on the hematopoietic cells of PNH, but only deficiency of the complement regulatory proteins CD55 and CD59 has been shown unequivocally to contribute to disease pathology.

  • PNH arises as a monoclonal or oligoclonal abnormality of HSPC. Populations of cells of different sensitivity to complement have been identified among different patients and in individual patients. Molecular analysis shows that the complement-sensitivity phenotype is determined by PIGA mutant genotype. The oligoclonal nature of PNH in some patients has been confirmed by identifying multiple discrete PIGA mutations in cloned hematopoietic cells from blood and marrow.

  • The oligoclonal nature of PNH suggests that a selection pressure is applied to the marrow that favors the outgrowth of PIGA-mutant, GPI-AP–deficient HSPC. The association of PNH with aplastic anemia suggests that the selection pressure is immune mediated, but the basis of the clonal selection and clonal expansion of the PIGA-mutant HSPC is incompletely understood.

  • The extent to which the mutant clone (or clones) expands varies greatly among patients. In some patients, a mutant clone may account for more than 90% of hematopoiesis, whereas in other patients, less than 1% of the blood cells may be derived from the mutant clone. In general, the severity of the disease is directly related to the size of the mutant clone or clones.


  • Overt hemoglobinuria occurs irregularly in most patients, precipitated by a variety of events that activate the alternative pathway of complement, including infection, surgery, trauma, and stress.

  • Nocturnal hemoglobinuria is the presenting symptom in ~25% of cases.

  • Patients have chronic intravascular hemolytic anemia, which may be severe, depending on the size of the mutant clone and the PNH phenotype (based on degree of complement sensitivity).

  • Iron deficiency may be observed due to ...

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