Paroxysmal Nocturnal Hemoglobinuria (PNH): A Life Threatening Disease Caused by Unregulated Complement Activation

In clinical terms, paroxysmal nocturnal hemoglobinuria (PNH) is synonymous with glycosylphosphatidylinositol (GPI) deficiency, and is an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic stem cells. 5

PNH is a rare disease with an estimated annual incidence of 4 per million. 1 The condition is a progressive and debilitating hematopoietic stem cell disorder characterized by chronic hemolysis. Periods of hemolysis could be initiated by infection, surgery, whole blood transfusion, injection of contrast dyes or even severe exercise. 2 Early identification of PNH in patients may contribute to improved long-term outcomes with this serious disease; however, PNH can be a life threatening condition with 35 percent of patients dying within 5 years of diagnosis.

Thrombosis is the leading cause of death in PNH. Pulmonary embolism and deep vein thrombosis are among the most commonly reported thrombotic events. 4 The risk of these adverse events exist in PNH regardless of clone size, lack of transfusion history, severity of anemia, anticoagulant therapy or level of hemolysis. 6

The disease may undergo partial remissions and exacerbations. In over half of patients, both the proportion of abnormal cells and the clinical severity decrease with time. In approximately 3-5 percent of PNH patients, the disease progresses to acute leukemia. 2

Several complement defense proteins are decreased or absent in PNH:

● DAF, CD55 (decay accelerating factor),

● MIRL, CD59 (membrane inhibitor of reactive lysis),

● C8-binding protein (homologous restriction factor).

Other proteins that are deficient in PNH include:

● CD58 (leukocyte function antigen 3),

● CD14 (endotoxin-binding protein receptor),

● CD24, and CD16a (Fcγ receptor). 2

The pioneering use of the therapeutic monoclonal antibody eculizumab, which binds to and prevents the activation of the complement protein C5, represents a significant advance in treatment for patients with PNH and is the standard therapy for hemolytic PNH. The only curative procedure for PNH is bone marrow transplantation although for the majority of patients the associated risks are too great to justify transplantation.

The availability of a diagnostic flow cytometry assay means that a definitive diagnosis of PNH can be established rapidly in most cases, resulting in improved patient management and prognosis. 3

1. Johnson RJ, Hillmen P: Paroxysmal nocturnal haemoglobinuria: Nature’s gene therapy? Mol Pathol 2002; 55:145-152.
2. McPherson & Pincus: Henry’s Clinical Diagnosis and Management by Laboratory Methods, 21st ed. Copyright©2006W. B. Saunders Company. p. 216.
3. Richards SJ, Barnett D. The role of flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria in the clinical laboratory. Clin Lab Med. 2007 Sep;27(3):577-90, vii.
4. Hillmen P, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood, 2007;110:4123-4128.
5. Richards SJ. Recent advances in the diagnosis, monitoring, and management of patients with paroxysmal nocturnal hemoglobinuria. Cytometry B Clin Cytom 2007; 72(5): 291-8
6. Hill A, Richards SJ, Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2007 May;137(3):181-92. Review.