Rare Thrombotic Diseases Consortium

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder of hematopoiesis with an estimated incidence of 2 to 5 cases per million individuals in the United States. The disorder is characterized by intravascular hemolysis and manifested by episodic hemoglobinuria and venous thrombosis. The hemolysis is a result of the increased susceptibility of PNH red blood cells to complement, which can be exacerbated by infections, surgery, and other events that initiate complement activation. Thrombotic complications occur in about 40% of patients with PNH (1;2) and may affect unusual locations, including the hepatic veins (Budd-Chiari syndrome), portal vein, and cerebral veins. PNH may also occur in the setting of aplastic anemia or evolve into bone marrow aplasia (2;3). The disease affects men and women equally, and the median survival from the time of diagnosis is 10 to 15 years (1;3). A more recent study reported a longer median survival, of 23 years (2).

Pathophysiology

PNH is a clonal hematopoietic disorder, similar to myelodysplastic syndrome and chronic myelogenous leukemia. Cells from patients with PNH exhibit defective (or absent) surface expression of integral membrane proteins that are linked through a glycosylphosphatidylinositol (GPI) anchor (4). The gene responsible for the syndrome, identified in 1993, is essential for the synthesis of N-acetylglucosaminyl-phosphatidylinositol, an early intermediate in GPI-anchor biosynthesis (5;6). The increased cellular sensitivity to complement reflects the absence of two GPI-anchored complement regulatory proteins, CD59 (membrane inhibitor of reactive lysis) and CD55 (decay accelerating factor) (4).

Laboratory diagnosis

Most clinical laboratories use monoclonal antibodies against specific GPI-anchored proteins and flow cytometry to diagnose PNH. Antibodies against CD59 are used most commonly, since this molecule is present on all hematopoietic cell lineages. Granulocytes should also be analyzed, in addition to erythrocytes, since a recent hemolytic episode could lead to a false negative result if only erythrocytes are analyzed. Additional laboratory studies useful in the assessment of these patients include a complete blood count, reticulocyte count, LDH, and a bone marrow aspirate and biopsy.

Clinical management

The only curative treatment for PNH is allogeneic stem cell transplantation (7). In general, this approach is reserved for patients with more severe forms of the disease, since the clinical course in some individuals can be quite indolent. Recent encouraging results from a pilot trial of nonmyeloablative allogeneic hematopoietic cell transplantation in patients with PNH may offer a new approach for these patients (8). For patients who present with an acute life-threatening thrombotic occlusion, fibrinolytic therapy can be used, although the potential for hemorrhagic risks, especially if the patient is also thrombocytopenic, must be considered. Primary prophylaxis with warfarin has been shown to decrease thrombotic risk in patients with PNH (9), but management of warfarin in these patients can be difficult. All patients should receive folate supplementation, and iron supplementation should be provided for patients with absent iron stores. Immunosuppressive therapy (for example, antithymocyte globulin and/or cyclosporine) has been used successfully in some patients with PNH and pancytopenia. Recently, a humanized monoclonal antibody that blocks activation of the terminal components of complement was shown to reduce intravascular hemolysis, hemoglobinuria, and transfusion requirements (10).

References

(1) Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333:1253-58.

(2) Nishimura J, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine. 2004;83:193-207.

(3) Socie G, Mary JY, de Gramont A, Rio B, Leporrier M, Rose C et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996;348:573-77.

(4) Rosse WF, Ware RE. The molecular basis of paroxysmal nocturnal hemoglobinuria. Blood. 1995;86:3277-86.

(5) Miyata T, Takeda J, Iida Y, Yamada N, Inoue N, Takahashi M et al. The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis. Science. 1993;259:1318-20.

(6) Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993;73:703-11.

(7) Saso R, Marsh J, Cevreska L, Szer J, Gale RP, Rowlings PA et al. Bone marrow transplants for paroxysmal nocturnal hemoglobinuria. Br J Haematol. 1999;104:392-96.

(8) Takahashi Y, McCoy JPJr, Carvallo C, Rivera C, Igarashi T, Srinivasa R et al. In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation. Blood. 2004;103:1383-90.

(9) Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2003;102:3587-91.

(10) Hillmen P, Hall C, Marsh JCW, Elebute M, Bombara MP, Petro BE et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004;350:552-59.

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