DEFINITIONParoxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by episodes of intravascular hemolysis and hemo-globinuria, usually occurring at night. Thrombocytopenia, leu-kopenia, and recurrent venous thrombosis are also associated with PNH.PHYSICAL FINDINGS AND CLINICAL PRESENTATION Initial manifestations

Anemia symptoms (35%) Hemoglobinuria (25%) Bleeding (20%) Aplastic anemia (15%) GI symptoms (10%) Hemolytic anemia (10%) Iron de ciency anemia (5%) Venous thrombosis (5%) Infections (5%) Neurologic symptoms

Hemoglobinuria: typically, the rst morning void reveals dark urine with progressive clearing during the day (Fig. 3261). The cause for the circadian rhythm is unknown.

Hemolysis In addition to the circadian hemolysis and resulting he-moglobinuria, episodes of hemolytic exacerbations can ac-company infections, menstruation, transfusion, surgery, iron therapy, and vaccinations. Symptoms of severe hemolysis include chest, back, or abdominal pain, headache, fever, malaise, and fatigue.

Aplastic anemia: may be the presenting manifestation of PNH (therefore, PNH must be in the differential diagnosis of aplastic anemia) or may develop as a later complication of PNH.

Thrombosis Lower extremity deep venous thrombosis (DVT) Subclavian thrombosis Portal or mesenteric vein thrombosis Hepatic vein thrombosis (Budd-Chiari syndrome) Cerebrovascular thrombosis

Renal failure Acute renal failure associated with massive hemoglobin-uria (acute tubular necrosis) Progressive renal failure associated with thrombosis within renal small veins

Dysphagia Infections (associated with leukopenia or steroid treat-

ment) Physical ndings include the following:

Pallor (anemia) Jaundice (hemolysis) Splenomegaly Unilateral extremity swelling (DVT) Ascites (Budd-Chiari syndrome)

CAUSE AND PATHOGENESIS Complement-mediated hemolysis; the erythrocytes are ab-

normally sensitive to acidi ed serum. Patients have two populations of RBCs, some sensitive to

hemolysis (PNH III cells) but not others (PNH I cells) in variable proportions (10% to 75% PNH III cells). About 20% PNH III cells are required for hemoglobinuria to be detectable.

These protein de ciencies are the result of an acquired mu-tation located in the X chromosome, which regulates glyco-syl phosphatidylinositol (GPI).

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Chapter 326 Paroxysmal nocturnal hemoglobinuria

AAA B CFig 3261A, Urine samples from a patient with paroxysmal nocturnal hemoglobinuria within the short time span of 3 days. Extremely dark urine was rst ob-served in the morning, but this cleared in the course of the day. The term nocturnal is a re ection of this nding. Elevated lactate dehydrogenase and a normal creatine phosphokinase in this patient were suggestive of hemolysis and excluded myoglobinuria. Depending on the degree of oxi-dation of the hemoglobin, the urine can appear red or black. Several weeks later, the urine looked completely normal, suggesting to the eye that the hemoglobinuria is paroxysmal. However, biochemical evidence of hemoglobinuria persists, and hemosiderin was consistently present in the urine sediment. B, It is crucial to differentiate hemoglobinuria from hematuria. After centrifugation of the patients urine, the colorcaused by free hemoglobinremains in the supernatant. C, In contrast, after centrifugation of a specimen darkened caused by red cells, a red cell pellet ap-pears, and the supernatant is clear. These simple maneuvers can preempt unnecessary invasive urologic workups.(From Young NS, Gerson SL, High KA [eds]: Clinical Hematology. St. Louis, Mosby, 2006.)

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DIFFERENTIAL DIAGNOSIS Other hemolytic anemias

LABORATORY TESTS CBC: anemia, leukopenia, thrombocytopenia Reticulocytosis RBC smear: spherocytes Negative Coombs test Low leukocyte alkaline phosphatase Elevated LDH Low serum haptoglobin Low serum iron saturation, low ferritin Elevated urine hemoglobin Elevated urine urobilinogen Elevated urine hemosiderin Positive Ham test (acidi ed serum RBC lysis) Normoblastic hyperplasia on bone marrow aspirate or

biopsy Identi cation of GPI-anchored protein de ciency on hemato-

poietic cells using monoclonal antibodies or ow cytometry Cytogenetic studies are not diagnostic.

TREATMENT Androgenic steroids Prednisone Eculizumab, a humanized antibody that inhibits the activa-

tion of terminal complement components, reduces intravas-cular hemolysis, hemoglobinuria, and need for transfusion in patients with PNH.

Iron replacement Transfusions Treatment and prevention of thrombosis (heparin, warfarin) Avoidance of oral contraceptives Bone marrow transplantation

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