Chapter 45: Paroxysmal Nocturnal Hemoglobinuria (PNH)

DEFINITION

• An acquired hematopoietic stem cell disorder characterized by deficiency of glycosyl phosphatidylinositol-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 leads to the complement-mediated intravascular hemolysis that is the clinical hallmark of the disease. Marrow failure and thrombophilia also complicate the disease.

• It is the only hemolytic anemia caused by an acquired intrinsic defect of the red cell.

ETIOLOGY AND PATHOGENESIS

• The disorder is a consequence of somatic mutation of PIGA, a gene on the X chromosome 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.

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

• More than 20 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 conclusively to contribute to disease pathology.

• Appears to arise as a monoclonal or oligoclonal abnormality of stem cells. Several populations of cells of different sensitivity to complement have been identified in some patients, and molecular analysis shows that the complement-sensitivity phenotype is determined by PIGA mutant genotype, confirming that the disease is oligoclonal in some patients.

• The oligoclonal nature of PNH suggests that a specific selection pressure is applied to the marrow that favors outgrowth of PIGA mutant stem cells present in the marrow when the selective pressure is applied. The association of PNH with aplastic anemia suggests that the selection pressure may be immune-mediated. The basis of the clonal selection and clonal expansion of the PIGA mutant cells is not known.

• The extent to which the mutant clone or clones expands varies greatly among patients. In some patients, a mutant clone may account for >90 percent of hematopoiesis, while in other patients, <10 percent of the blood cells are derived from a mutant clone. In general, the severity of the disease is directly related to the size of the mutant clone.

CLINICAL FEATURES

• Overt hemoglobinuria occurs irregularly in most patients, precipitated by a variety of events including infection, surgery, trauma, and stress.

• Nocturnal hemoglobinuria is relatively uncommon as a presenting symptom.

• Patients have chronic intravascular hemolytic anemia, which may be severe depending on the size of the mutant clone.

• Modest splenomegaly is observed in some patients.

• Iron deficiency is common as a consequence of iron loss in the urine, resulting from intravascular hemolysis.

• Marrow failure of varying degrees is present in all patients with PNH.

• PNH is closely associated with aplastic anemia and may be seen less commonly in association with low-risk myelodysplastic syndromes.

• Bleeding may occur secondary to thrombocytopenia.

• Thrombophilia is ...