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Paroxysmal Nocturnal Hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder characterized by intravascular hemolysis and hemoglobinuria, the latter accentuated during sleep. Leukopenia, thrombocytopenia, arterial and venous thromboses, and episodic crises are common. Diagnosis requires flow cytometry. Treatment is supportive and with eculizumab, a terminal complement inhibitor.
PNH is most common among men in their 20s, but it occurs in both sexes and at any age.
PNH is an acquired genetic mutation resulting in a membrane defect in stem cells and their progeny, including RBCs, WBCs, and platelets. It results in unusual sensitivity to normal C3 in the plasma, leading to ongoing intravascular hemolysis of RBCs and diminished production of WBCs and platelets by the bone marrow. The defect is a missing glycosyl-phosphatidyl-inositol anchor for membrane proteins caused by an abnormality of the PIGA gene, which is located on the X chromosome.
PNH is suspected in patients who have typical symptoms of anemia (eg, pallor, fatigue, dizziness, possible hypotension) or unexplained normocytic anemia with intravascular hemolysis, particularly if leukopenia or thrombocytopenia is present. Historically, if PNH was suspected, the sugar-water test was usually the first test done; it relies on enhanced hemolysis of C3-dependent systems in isotonic solutions of low ionic strength, is simple to do, and is sensitive. However, the test is nonspecific; positive results require confirmation by further testing. The most sensitive and specific test is determination of the absence of specific RBC or WBC membrane proteins (CD59 and CD55) by flow cytometry. An alternative is the acid hemolysis test (Ham test). Hemolysis usually occurs if blood is acidified with HCl, incubated for 1 h, and centrifuged. Bone marrow examination is not necessary but, if done to exclude other disorders, usually shows marrow hypoplasia. Gross hemoglobinuria is common during crises, and the urine may contain hemosiderin.
Treatment has been largely symptomatic. However, a new monoclonal antibody that is a terminal complement inhibitor, eculizumab, has remarkably changed the course of the disorder, reducing transfusion requirements, thromboembolism, and symptoms. Eculizumab increases the risk of meningococcal meningitis, so patients should receive the meningococcal vaccine at least 14 d prior to starting eculizumab.
Supportive measures include oral iron and folate supplementation and sometimes transfusions. Empiric use of corticosteroids (eg, prednisone 20 to 40 mg po once/day) controls symptoms and stabilizes RBC values in > 50% of patients. Generally, transfusions are reserved for crises. Transfusions containing plasma (and thus C3) should be avoided. Washing RBCs with saline before transfusion is no longer necessary. Heparin followed by warfarin may be required for thromboses but should be used cautiously. Most cases can be managed by these supportive measures for years to decades.
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