PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Paroxysmal nocturnal hemoglobinuria is an acquired clonal stem cell disorder that results in abnormal sensitivity of the red blood cell membrane to lysis by complement. The underlying cause is a defect in the gene for phosphatidylinositol class A (PIC-A), which results in a deficiency of the glycosylphosphatidylinositol (GPI) anchor for cellular membrane proteins. In particular, the complement-regulating proteins CD55 and CD59 are deficient. Paroxysmal nocturnal hemoglobinuria should be suspected in confusing cases of hemolytic anemia or pancytopenia. The best screening test is flow cytometry to demonstrate deficiency of CD59 on red blood cells. This test has largely replaced the classic sucrose hemolysis test.
Clinical Findings
SYMPTOMS AND SIGNS
Classically, patients report episodic hemoglobinuria resulting in reddish brown urine. Hemoglobinuria is most often noticed in the first morning urine, probably because of its increased concentration. In addition to being prone to anemia, these patients are prone to thrombosis, especially mesenteric and hepatic vein thromboses. Other common sites of thrombosis include the central nervous system (saggital vein) and the skin, with formation of painful nodules. This hypercoagulopathy may be related to platelet activation by complement. As this is a stem cell disorder, paroxysmal nocturnal hemoglobinuria may progress either to aplastic anemia, to myelodysplasia, or to acute myelogenous leukemia.
LABORATORY FINDINGS
Anemia is of variable severity, and reticulocytosis may or may not be present. Abnormalities on the blood smear are nondiagnostic and may include macro-ovalocytes. Since the episodic hemolysis in paroxysmal nocturnal hemoglobinuria is intravascular, the finding of urine hemosiderin is a useful test. Serum LDH is characteristically elevated. Iron deficiency is commonly present and is related to chronic iron loss from hemoglobinuria, since hemolysis is primarily intravascular.
The white blood cell count and platelet count may be decreased. A decreased leukocyte alkaline phosphatase—evidence for a qualitative abnormality in the myeloid series—may be seen. Bone marrow morphology is variable and may show either generalized hypoplasia or erythroid hyperplasia. Flow cytometric assays may confirm the diagnosis by demonstrating the absence of CD59.
Treatment
Iron replacement is often indicated for treatment of iron deficiency. This may improve the anemia but may also cause a transient increase in hemolysis. For unclear reasons, prednisone is effective in decreasing hemolysis, and some patients can be managed effectively with alternate-day steroids. In severe cases and cases of transformation to myelodysplasia, allogeneic bone marrow transplantation has been used to treat the disorder. The anti-complement C5 antibody eculizumab has been shown to be effective in reducing hemolysis and transfusion requirements.

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