Although commonly regarded as a type of hemolytic anemia, Paroxysmal Nocturnal Hemoglobinuria is in reality a hemopoietic stem cell disorder characterized by the formation of defective platelets, granulocyte, and possibly lymphocytes as well as abnormal erythrocytes. The abnormality of red cells predisposes them to intravascular complement mediated lysis, wich waxes and wanes in severity.
PNH is an acquired disorder, studies have all shown that PNH cells are usualy a clone. Thus, PNH presumably arises, like a neoplasm, from the transformation of a single cell. The abnormal clone appears to arise most commonly in a damaged marrow. The classical abnormality of PNH erythrocytes is their increased sensitivity to complement mediated lysis.
A large number of membrane protein deficiencies have been observed in PNH. These include deficiencies of acetyl cholinesterase, DAF (decay accelarating factor), CD59 antigen, CD58 antigen, CD14 antigen etc... The absence of the CD59 antigen plays the most critical role.
Granulocytes and platelets, like red cells, shown increased sensitivity to complement mediated lysis.
Hemoglobinuria
In most patients with PNH, hemoglobinuria occurs irregularly. Bouts of hemolysis may be initiated by infections, surgery, and possibly even strenous exercise. The injection of contrast dyes, may precipitate hemolysis by activating complement.
Chronic Hemolysis
Patients with PNH manifest all clinical and laboratory signs of chronic hemolytic anemia. Weakness, dyspnea, and pallor are common. Splenomegaly is present in some patients, but the enlargement of the spleen is usually quiet modest.
Iron Deficiendy
Iron deficiency is often a manifestation of PNH because of iron loss in the urine
Bleeding
Thrombocytopenia may be very severe, and extensive hemorrhagic complications may be part of the clinical presentation.
Thrombosis
The reason for this is not entirely clear, but it may be related to activation of platelets by complement or to the intravascular release of ADP from red cells, leading to platelet aggregation. The Budd Chiari syndrome, has been observed repeatedly. Pulmonary hipertension has been attributed to widespread thromboses in the pulmonary microvasculature. Both arterial and venous thromboses have been reported.
Renal Manifestations
Hyposthenuria, abnormal tubular function and declining creatinine clearence are common features. Acute and chronic renal failure may occur.
Neurologic Manifestations
Severe headaches or pains in the eyes occur in patiets with PNH. These complications may be due small venous occlusions.
Diagnosis rests on the clinical picture and clinical laboratory measurement of a population of circulating cells with unusual sensitivity to complement mediated lysis. This may be demonstrated in the sugar water test; the patients serum is mixed with 5% dextrose in water and incubated with the patient's cells. In PNH, hemolysis ensues. In Ham's test, patient's cells are incubated in acidified serum. Under these conditions the alternative complement pathway is triggered, and lysis of PNH, but not normal, cells follows.
Hemolysis is controlled in some patients with prednisone therapy. A dose of 15 - 40 mg every other day has been reported to decrease the rate of hemolysis. In Patients with anemia, androgens may be effective.
Acutely, iron replacement may result in increased hemolysis because of the formation and release of new sensitive red cells.
Marrow transplatation is an effective, albeit high risk method for the treatment of PNH.
Use of prophylatic anticoagulants in PNH has been advocated, but there in no clear cut evidence of beneficial effect.
(1)Paroxysmal Nocturnal Hemoglobinuria.in Ernest Beutler, Marshall A. Lichtman et al. (eds.): Hematology. 5th ed. New York, McGraw-Hill,1995, p. 252-257.
(2)Alan D. schreiber:Autoimune hemolytic anemia. In Bennett J. C., Plum F. (eds). Cecil Textbook of Medicine. 20th edition. W.B. Saunders, 1996, p. 866-867.
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