Paroxysmal nocturnal hemoglobinuria overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Paroxysmal nocturnal hemoglobinuria is a rare, acquired, potentially life-threatening disease of the blood characterised by hemolytic anemia, thrombosis and red urine due to breakdown of red blood cells. PNH is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane.
Historical Perspective
Paroxysmal nocturnal hemoglobinuria was first described by the European physicians in the 19th century. The hypothesis of hemolysis of red blood cells due to the increased plasma acidity in the night time was described by Dr. Strübing in 1815. From 1911 to 1950, more studies were conducted in order to establish the full description of PNH.
Classification
Paroxysmal nocturnal hemoglobinuria may be classified according to the diagnosis results into three subtypes. The subtypes of PNH include classic PNH, secondary PNH, or subclinical PNH.
Pathophysiology
Paroxysmal nocturnal hemoglobinuria is believed to be caused by a genetic mutation and complement mediated hemolysis. A mutation in PIGA gene (Posphatidylinositol Glycan anchor biosynthesis, class A) is considered the main pathogenic factor in development of PNH because PIGA gene is responsible for the GPI anchor synthesis. The PIGA gene mutation is most common a frameshift mutation which results in a misfolded protein product which is nonfunctional proteins and degraded by proteasomes. Other genetic mutation may also cause PNH like TET2, SUZ12, U2AF1, and JAK2. The anemia in PNH is due to complement mediated hemolysis of RBCs which are defective in the CD59//CD55 markers which are important in inactivating the complement system and protecting the RBCs. Paroxysmal nocturnal hemoglobinuria may be associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.
Causes
Common causes of paroxysmal nocturnal hemoglobinuria include a somatic mutation in the PIGA gene. Other causes include mutations in genes of TET2, SUZ12, U2AF1, and JAK2.
Differentiating Paroxysmal Nocturnal Hemoglobinuria from Other Diseases
Epidemiology and Demographics
The incidence of paroxysmal nocturnal hemoglobinuria is approximately 0.13 per 100,000 individuals worldwide. Paroxysmal nocturnal hemoglobinuria commonly affects adults. However, some cases of PNH in the childhood have been reported.
Risk Factors
There are no established risk factors for paroxysmal nocturnal hemoglobinuria. However, PNH is usually associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.
Screening
According to the American society of hematology, screening for paroxysmal nocturnal hemolglobinuria is recommended among patients with hemoglobinuria, cytopenia, suspected myelodysplasia, negative direct coombs test intravascular hemolytic anemia, refractory anemia, and aplastic anemia with no apparent sign of intravascular hemolysis.
Natural History, Complications, and Prognosis
If left untreated, patients with paroxysmal nocturnal hemoglobinuria may progress to develop thrombosis which is a main cause of death in PNH. Common complications include intracranial thrombosis, splenic vein thrombosis, and portal vein thrombosis. Prognosis of paroxysmal nocturnal hemoglobinuria is good as long as anti-complemant therapy eculizumab is taken regularly.