Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder of hemopoietic stem cells resulting in intravascular complement-mediated cell lysis on an irregular basis. As a result, patients often manifest a variable anemia and may also display mild granulocytopenia and thrombocytopenia on CBC examination. In this disorder, all marrow components (erythrocytes, platelets and granulocytes) are affected. The defect occurs at the cell membrane where the absence of the anchoring protein glycosylphosphatidylinositol (GPI) results in a lack of certain membrane surface proteins. Membrane inhibitor of reactive lysis (CD59) is one of these membrane proteins that inhibits complement-mediated cell lysis; therefore, its deficiency on affected PNH cells leads to an amplification of surface-bound complement mediated cellular destruction. The lack of CD59 on platelets also leads to their propensity towards hypercoagulability. The lack of GPI anchoring protein results in the loss of many membrane surface proteins to include CD59, alkaline phosphatase, acetylcholinesterase and decay accelerating factor (DAF or CD55). As stated above, PNH is an acquired disorder with an abnormal stem cell clone arising from a single cell usually in marrow that has been damaged. Many persons afflicted with this disorder also have a past history of or later develop aplastic anemia.

The classic symptom of passing red or brownish colored urine upon arising from sleep does not occur in all patients. Therefore, this disorder should be suspected in patients with an unexplained intravascular hemolysis, especially when there is associated thrombocytopenia, leukopenia, hemosiderinuria, a low leukocyte alkaline phosphatase level, and a low red blood cell acetylcholinesterase level.

Complications of this disorder include hemolytic anemia, venous thrombosis including the Budd-Chiari syndrome, hemorrhage secondary to thrombocytopenia, headache, a propensity to progress to acute leukemia or myelofibrosis, and renal abnormalities. Some of the more common renal abnormalities include hyposthenuria, decreasing creatinine clearance, acute renal failure, and enlarged kidneys with cortical infarcts, cortical thinning, and papillary necrosis noted on radiologic studies. Patients may become iron deficient from the chronic loss of iron through the urine, and in that case, cells will be microcytic and hypochromic. It is of note that many patients do not manifest hemoglobinuria; however, hemosiderinuria is noted in most cases.

The best screening tests are examination of the urine for hemosiderin and the complete Ham acid hemolysis test. The sucrose lysis test may also be used to aid in establishing the diagnosis as it is more sensitive but less specific than the Ham test. As stated above, a low leukocyte alkaline phosphatase, a low red blood cell acetylcholinesterase level, and hemosiderinuria in a patient with signs of hemolysis should raise the possibility of PNH as the underlying diagnosis. Flow cytometry of erythrocytes using anti-CD59 or of granulocytes using either anti-CD59 or anti CD55 may become more available in the future and would be a more effective means of establishing the diagnosis of PNH. These receptors would be absent on cells of persons afflicted with PNH.

Therapy for the resultant anemia is with transfusions to both raise the hemoglobin level and to suppress marrow function during acute exacerbations. Transfusion therapy may infrequently cause worsening hemolysis. If this occurs, washed red blood cells rather than whole blood may be used. Steroids (prednisone 15-30mg on alternate days) may abort acute hemolytic episodes, and higher doses (0.5-1.0 mg/kg) may prove beneficial in treating thrombosis. The androgenic hormones Danocrine or danazol may help stimulate marrow function and decrease complement-mediated cellular destruction. Iron deficiency may be treated with oral iron; however, this may result in the production of large young red cells that are extremely sensitive to the action of complement and therefore result in an acute hemolytic event. This may be suppressed by giving concomitant prednisone therapy (60 mg/day). As with all chronic hemolytic states, folic acid therapy may serve to supplement body stores during excessive erythropoiesis. Thrombotic episodes should be treated aggressively with heparin and Coumadin therapy. Marrow hypoplasia may be treated with antithymocyte globulin plus prednisone. In severe cases, bone marrow transplantation may be offered.