Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematopoietic stem cell disorder that results in abnormal sensitivity of the RBC membrane to lysis by complement and therefore hemolysis. The underlying cause is an acquired defect in the gene for phosphatidylinositol class A (PIG-A), which results in a deficiency of the glycosylphosphatidylinositol (GPI) anchor for cellular membrane proteins. In particular, the complement-regulating proteins CD55 and CD59 are deficient, which permits unregulated formation of the complement membrane attack complex on RBC membranes and intravascular hemolysis. Free hemoglobin is released into the blood that scavenges nitric oxide and promotes esophageal spasms, male erectile dysfunction, kidney damage, and thrombosis. Patients with significant PNH have shortened survival; thrombosis is the primary cause of death.
Classically, patients report episodic hemoglobinuria resulting in reddish-brown urine. Hemoglobinuria is most often noticed in the first morning urine due to the fall in blood pH while sleeping (hypoventilation) that facilitates this hemolysis. Besides anemia, these patients are prone to thrombosis, especially within mesenteric and hepatic veins, CNS veins (sagittal vein), and skin vessels (with formation of painful nodules). As this is a hematopoietic stem cell disorder, PNH may appear de novo or arise in the setting of aplastic anemia or myelodysplasia with possible progression to acute myeloid leukemia (AML). It is common that patients with idiopathic aplastic anemia have a small PNH clone (less than 2%) on blood or bone marrow analysis; this should not be considered true PNH per se, especially in the absence of a reticulocytosis or thrombosis.
Anemia is of variable severity and frequency, so reticulocytosis may or may not be present at any given time. Abnormalities on the blood smear are nondiagnostic but may include macro-ovalocytes and polychromasia. Since the episodic hemolysis is mainly intravascular, urine hemosiderin is a useful test. Serum LD is characteristically quite elevated. Iron deficiency is commonly present, related to chronic iron loss from hemoglobinuria.
The WBC count and platelet count may be decreased and are always decreased in the setting of aplastic anemia. The best screening test is flow cytometry of blood erythrocytes, granulocytes, and monocytes to demonstrate deficiency of CD55 and CD59. The proportion of erythrocytes deficient in these proteins might be low due to the ongoing destruction of affected erythrocytes. The FLAER assay (fluorescein-labeled proaerolysin) by flow cytometry is more sensitive. Bone marrow morphology is variable and may show either generalized hypoplasia or erythroid hyperplasia or both. The bone marrow karyotype may be either normal or demonstrate a clonal abnormality.