Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired blood disorder characterized by the destruction of red blood cells due to defects in hematopoietic stem cells. This condition arises from somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene, leading to a deficiency of proteins crucial for protecting red blood cells from the complement system, resulting in hemolysis. Symptoms commonly include dark urine, jaundice, and complications such as thrombosis, anemia, and increased infection risk. Diagnosis typically involves flow cytometry to identify absent cell surface proteins. While PNH is a chronic condition, treatments aim to manage symptoms and complications, including blood transfusions and medications like eculizumab. Stem cell transplantation may offer a potential cure. The disorder is rare, affecting approximately 1 to 5 individuals per million, and tends to present in middle-aged adults. With appropriate treatment, many patients can lead meaningful lives, with median survival rates improving over the years.
Paroxysmal nocturnal hemoglobinuria
ALSO KNOWN AS: PNH
DEFINITION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare noninherited polyclonal genetic disorder caused by somatic mutations of the hematopoietic stem cells, which normally give rise to the trilineage cell lines including white blood cells, red blood cells, and platelets. The abnormal stem cells in PNH give rise to cells that are deficient in an anchor protein that normally bind certain proteins to cell membranes. Resultant complications can lead to hemolysis, aplastic anemia, venous thrombosis, and acute leukemia.
Risk Factors
PNH is a rare disorder, with a general prevalence of about 1 to 5 people in 1 million, as reported by the National Organization for Rare Disorders (NORD) in 2024. It frequently affects those who are middle-aged and affects both sexes at all age ranges. It is usually diagnosed in those with an existing diagnosis of myelodysplastic syndrome or aplastic anemia, the latter of which is a risk factor for the development of PNH.
Etiology and Genetics
PNH is an acquired disorder due to somatic mutations of the phosphatidylinositol glycan class A (PIGA) gene on the X chromosome of hematopoietic stem cells. This defect leads to an absent or defective protein product that normally is involved in the synthesis of the glycosyl-phosphatidylinositol (GPI) anchor protein that is required for binding of cell membrane surface proteins. The majority of PIGA defects are due to frame-shift mutations that end with an early stop codon, leading to a lack of the protein product. Substitution mutations are also possible that may lead to protein products that are less effective in the synthesis of the GPI anchor. NORD stated in 2014 that PNH patients are believed have more than one type of mutation, leading to a polyclonal population of stem cells admixed with a population of normal stem cells. Most of these mutations are unique to each patient.
Because this defect occurs in hematopoietic stem cells, all cell lines are affected, including red blood cells, white blood cells, and platelets. The critical cell membrane surface proteins that are lacking on red blood cells include the decay-accelerating factor (also known as CD55), membrane inhibitor of reactive (also known as CD59), restriction factor (HRF), and C8 binding protein. These surface proteins normally interact and slow down the complement process, notably through proteins C3b and C4b. Their absence therefore leads to the unhampered destruction of the red cell membrane by the complement system, leading to intravascular hemolysis.
Though the PIGA gene defect appears to be a necessary component for the development of PNH, it is not clear if this is sufficient, since PIGA mutations have been found in small numbers in many, if not most, normal individuals. The abnormal population increases in aplastic anemia and becomes overwhelmingly large in PNH. The Luzzatto-Young hypothesis on the development of PNH notes that the processes that lead to aplastic anemia tend to suppress the proliferation of normal cells and not defective cells, therefore leading to the preferential selection of defective cells characteristic of PNH.
Symptoms
One of the defining manifestations of PNH is dark urine in the morning, which is due to the leakage of hemoglobin from breakdown of red blood cells. Other symptoms vary depending on the degree of disease progression. Yellowing of the skin (jaundice) can occur with prolonged red blood cell breakdown; bleeding can occur with an abnormally low platelet count; risks for infections can occur with low white blood cell count; and headache, abdominal pain, and skin findings can occur due to vessel thrombosis.
Screening and Diagnosis
The principal diagnostic test of PNH is flow cytometry, which is able to detect the CD55 and CD59 glycoproteins on the surface of red blood cells. The absence or the reduced expression of both such glycoproteins, along with clinical and laboratory features, is diagnostic of PNH. Another more specific method is using fluorescently labeled inactive bacterial toxin aerolysin, which normally initiates hemolysis by binding to GPI anchors on RBCs. The lack of such binding suggests an absence of GPI and is also diagnostic of PNH.
Treatment and Therapy
Therapy for PNH includes addressing clinical issues related to anemia, leukopenia, thrombocytopenia, and thrombosis. Blood or platelet transfusions are indicated in clinically indicated anemia or thrombocytopenia. Other therapies such as folic acid, glucocorticoids, and eculizumab (an agent that inhibits terminal complement pathway activation) have been used. Treatment of thrombosis includes thrombolysis to break up blood clots in life-threatening thrombosis or with anticoagulation agents such as heparin or warfarin for preventive measures. Hematopoietic stem cell transplants and medical agents such as cyclosporine or antithymocyte globulin have been used to address the issue of aplastic anemia. Stem cell transplantation is the only known cure. is theoretically possible since the PIGA gene was cloned in 1993.
Prevention and Outcomes
Although PNH is a chronic disorder, many patients are able to live for extended periods of time, and spontaneous recovery is possible. Studies have found the median survival after the onset of disease to be twenty-two years, with longer lifespans for those diagnosed after the 1990s and into the twenty-first century. The majority of deaths and morbidity are related to complications from venous thrombosis.
Bibliography
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