Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematopoietic stem cell disorder that results in abnormal sensitivity of the red blood cell membrane to lysis by complement and therefore 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 live about 10–15 years following diagnosis; thrombosis is the primary cause of death.
Symptoms and Signs
Classically, patients report episodic hemoglobinuria resulting in reddish-brown urine. Hemoglobinuria is most often noticed in the first morning urine due to the drop in blood pH while sleeping (hypoventilation) that facilitates this hemolysis.
Besides anemia, these patients are prone to thrombosis, especially within mesenteric and hepatic veins, central nervous system 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 PNH per se, especially in the absence of a reticulocytosis or thrombosis.
Many patients with PNH have mild disease not requiring intervention. In severe cases and in those occurring in the setting of myelodysplasia or previous aplastic anemia, allogeneic hematopoietic stem cell transplantation may prove curative. In patients with severe hemolysis (usually requiring red cell transfusions) or thrombosis (or both), treatment with eculizumab is warranted.
Eculizumab is a humanized monoclonal antibody against complement protein C5. Binding of eculizumab to C5 prevents its cleavage so the membrane attack complex cannot assemble. Eculizumab improves quality of life and reduces hemolysis, transfusion requirements, fatigue, and thrombosis risk. Eculizumab is extremely expensive and increases the risk of Neisseria meningitidis infections; patients receiving the antibody must undergo meningococcal vaccination (including vaccines for serogroup B) and penicillin (or equivalent) meningococcal prophylaxis.
Iron replacement is indicated for treatment of iron deficiency when present, which may improve the anemia while also causing a transient increase in hemolysis. For unclear reasons, corticosteroids are effective in decreasing hemolysis.