Clinical Pearls & Morning Reports
There is often a delay in the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), because the condition is rare and is associated with unusual clinical features.Read the latest Case Record of the Massachussetts General Hospital.
Q: What is the underlying cause of PNH?
A: PNH is an acquired, life-threatening, clonal hematopoietic stem-cell disorder that is caused by an acquired mutation in the gene encoding phosphatidylinositol glycan class A (PIG-A). The mutation reduces or inhibits the expression of glycosylphosphatidylinositol (GPI)-anchored proteins on the surface of hematopoietic cells. The cell-surface markers CD55 and CD59 are the most widely expressed GPI-anchored proteins, and they function in complement regulation. The GPI-anchored proteins CD24 and CD14 are normally expressed on neutrophils and monocytes, respectively.
Q: What are some of the clinical and laboratory features of PNH?
A: Despite the name of the condition, the majority of affected patients do not report nocturnal hemoglobinuria. In PNH, intravascular hemolysis occurs, releasing free hemoglobin into the plasma. Unusual thromboses and bone marrow dysfunction (macrocytosis and thrombocytopenia) are both prominent features of PNH, but the mechanisms behind these processes are poorly understood. Thrombotic events occur in up to 40% of patients with PNH and are the leading cause of death associated with this condition.
A: Peripheral-blood flow cytometry is a sensitive and specific way to detect decreased expression of GPI-anchored proteins, and it allows for the measurement of the PNH clone. Monoclonal antibodies against specific GPI-anchored proteins (e.g., CD59, CD24, and CD14) and fluorescein-labeled proaerolysin (FLAER) staining are typically used in the analysis.
A: The two options for the treatment of classic PNH are eculizumab and allogeneic bone marrow transplantation. Eculizumab is a humanized monoclonal antibody that blocks conversion of C5 and formation of the membrane attack complex (C5–9) and protects PNH-associated erythrocytes from complement-mediated intravascular hemolysis. Treatment with eculizumab not only decreases the risk of thrombosis but also improves survival. Although bone marrow transplantation is the only potentially curative treatment for PNH, it is associated with clinically significant morbidity and mortality; the 5-year overall survival rate is 68%. Since eculizumab was introduced, bone marrow transplantation has been indicated only in patients with PNH who have concurrent severe aplastic anemia or myelodysplastic syndrome or in patients who do not have a response to eculizumab or are unable to obtain eculizumab because of its substantial cost.