Other Membrane Defects

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Chapter 455 Other Membrane Defects

George B. Segel

Paroxysmal Nocturnal Hemoglobinuria

Etiology

Paroxysmal nocturnal hemoglobinuria (PNH) reflects an abnormality of marrow stem cells that affects each blood cell lineage. The disease is not inherited; it is an acquired disorder of hematopoiesis characterized by a defect in proteins of the cell membrane that renders the red blood cells (RBCs) and other cells susceptible to damage by normal plasma complement proteins (see Fig. 455-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). The deficient membrane-associated proteins include decay-accelerating factor, the C8 binding protein, and other proteins that normally impede complement lysis at various steps. The underlying defect involves the glycolipid anchor that maintains these protective proteins on the cell surface. Various mutations in the PIGA gene that are involved in glycosylphosphatidylinositol biosynthesis have been identified in patients with PNH. More than one PIGA gene mutation often occurs in an individual patient, suggesting multiclonality. Glycosylphosphatidylinositol-deficient cells are found at low frequency in normal persons, suggesting that injury to the normal marrow stem cells provides a selective advantage to the progeny of PNH clones in the genesis of this disease.

Figure 455-1 Complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH). Red circles are haemoglobin. Blue circles are decay accelerating factor (CD55). Green circles are membrane inhibitor of reactive lysis (CD59). Bb, activated factor B; C3b, activated C3; C5b, activated C5; GPI, glycosyl phosphatidylinositol; MAC, membrane attack complex (consisting of C5b, C6, C7, C8, and several molecules of C9 [9n]; RBC, red blood cell.

(From Parker C: Eculizumab for paroxysmal nocturnal haemoglobinuria, Lancet 373:759–767, 2009.)

Clinical Manifestations

PNH is a rare disorder in children. Approximately 60% of pediatric patients have marrow failure, and the remainder have either intermittent or chronic anemia, often with prominent intravascular hemolysis. Nocturnal and morning hemoglobinuria is a classic finding in adults if hemolysis is worse during sleep. Chronic hemolysis is more common in PNH, despite its name. In addition to chronic hemolysis, thrombocytopenia and leukopenia are often characteristic. Thrombosis and thromboembolic phenomena are serious complications that may be related to altered glycoproteins on the platelet surface and resultant platelet activation and production of procoagulant microparticles. Furthermore, released free hemoglobin results in depletion of nitric oxide, fostering vasoconstriction and thrombosis and pain. Abdominal, back, and head pain may be prominent. Hypoplastic or aplastic pancytopenia can precede or follow the onset of PNH; PNH rarely progresses to acute myelogenous leukemia. Among 220 patients of all ages identified in French medical centers from 1950 to 1995, at the time of presentation, 93% had some blood abnormality (including 33% with anemia alone, 17% with anemia and thrombocytopenia, 7% with anemia and neutropenia, and 32% with pancytopenia), 13% had abdominal pain, and 6% had thrombosis. The mortality in PNH is related primarily to the development of aplastic anemia or thrombotic complications. The predicted survival rate for children before the development of eculizumab (see Treatment) was 80% at 5 yr, 60% at 10 yr, and 28% at 20 yr.

Laboratory Findings

The diagnosis of PNH was established classically by a positive result on either the acidified serum hemolysis (Ham) test or the sucrose lysis test. These tests activate the alternative and classic pathways of complement lysis, respectively. Hemosiderinuria is common and reflects chronic intravascular hemolysis. Markedly reduced levels of RBC acetylcholinesterase activity and decay-accelerating factor also are found. Flow cytometry currently is the diagnostic test of choice for PNH. With the use of anti-CD59 for RBCs and anti-CD55 and anti-CD59 for granulocytes, flow cytometry is more sensitive than the classic RBC lysis tests in detecting the reduced glycolipid-bound membrane proteins. Fluorescent aerolysin testing can heighten the sensitivity of detection by binding selectively to glycosylphosphatidylinositol anchors.

Treatment

Glucocorticoids such as prednisone (2 mg/kg/24 hr) have been used to treat acute hemolytic episodes, and dosage should be tapered as soon as the hemolysis abates. Prolonged anticoagulation therapy may be of benefit when thromboses occur; heparin and low molecular weight heparin can inhibit complement-mediated hemolysis. Because of chronic urinary loss of iron as hemosiderin, iron therapy may be necessary. Androgens (e.g., fluoxymesterone [Halotestin], antithymocyte globulin, cyclosporine, and growth factors (e.g., erythropoietin and granulocyte colony-stimulating factor) have been used to treat marrow failure. Bone marrow transplantation is successful in treating some cases; non-myeloablative transplantation can reduce transplant-related mortality and morbidity. Eculizumab, a humanized monoclonal antibody against complement protein C5, stabilizes hemoglobin levels, reduces the number of transfusions, decreases the rate of hemolysis, and decreases the risk of thrombosis in treated adults with PNH.

Acanthocytosis

Acanthocytosis is characterized by RBCs with irregular circumferential pointed projections (see Fig. 452-4E). This morphologic finding is seen with alterations in the cholesterol:phospholipid ratio in some patients with liver disease and in congenital abetalipoproteinemia associated with malabsorption, neuromuscular abnormalities, and retinitis pigmentosa (Chapters 80.3 and 622). It also is associated with the rare X-linked McLeod syndrome, which includes absence of the Kx (Kell) antigen, late-onset myopathy, neurologic abnormalities such as chorea, splenomegaly, and hemolysis with acanthocytosis.

In contrast, echinocytes or “burr cells” have a more regular distribution of projections or serrations along the surface of the RBCs. They often are seen as artifact and less often in end-stage renal disease and in some patients with liver disease.

Bibliography

Brodsky RA. Advances in the diagnosis and therapy of paroxysmal nocturnal hemoglobinuria. Blood Rev. 2008;22:65-74.

Gold MM, Shifteh K, Bello JA, et al. Chorea-acanthocytosis: a mimicker of Huntington disease. Case report and review of the literature. Neurologist. 2006;12:327-329.

Hillmen P, Young NS, Shubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233-1243.

Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet. 2009;373:759-767.

Rosse WF, Nishimura J. Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. Int J Hematol. 2003;77:113-120.

Smith LJ. Paroxysmal nocturnal hemoglobinuria. Clin Lab Sci. 2004;17:172-177.

Suenaga K, Kanda Y, Niiya H, et al. Successful application of nonmyeloablative transplantation for paroxysmal nocturnal hemoglobinuria. Exp Hematol. 2001;29:639-642.

Van den Heuvel-Eibrink MM, Bredius RG, te Winkel ML, et al. Childhood paroxysmal nocturnal hemoglobinuria (PHH): a report of 11 cases in the Netherlands. Br J Haematol. 2005;128:571-577.