Chapter 43: Paroxysmal Nocturnal Hemoglobinuria

DEFINITION

• 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 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 (ie, somatic) mutation that is intrinsic to the red cell. The defect has its origins in the HSPC from which the circulating red cells are derived.

ETIOLOGY AND PATHOGENESIS

• 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 only one functional PIGA in somatic tissues, including HSPC, that may undergo PIGA mutation.

• The somatic mutation arises in one or more HSPC, and as a consequence, all of the progeny of the mutant 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.

• PNH arises as a monoclonal or oligoclonal abnormality of HSPC. 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 may be oligoclonal in some patients composed of PNH clones bearing different PIGA mutations.

• The oligoclonal nature of PNH suggests that a specific selection pressure is applied to the marrow that favors outgrowth of PIGA mutant HSPC present in the marrow when the selective pressure is applied. The association of PNH with aplastic anemia suggests that the selection pressure is immune-mediated. 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, more than 10% 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.

• Iron deficiency may be observed due to iron loss ...