Paroxysmal Nocturnal Hemoglobinuria (PNH)
 

 

Uploaded: 2008-10-16, Updated: 2008-10-16

The Key Features

  • qPIGA mutation in hematopoietic stem cells

  • GPI deficient on the cell surface of RBC and WBC, resulting in deficiency of CD55 and CD59

  • Clinical triads: intravascular hemolysis, aplastic anemia,  thrombosis

  • Best tests: flow cytometry

DEFINITION

  • Nonmalignant clonal expansion of one or several hematopoietic stem cells that have acquired a somatic mutation of PIGA, an X-linked gene involved in the first step in biosynthesis of glycosyl phosphatidylinositol (GPI).

  • All hematopoietic cells are deficient in GPI-anchored complement-regulating surface proteins

    • CD55: decay-accelerating factor (DAF)

    • CD59: membrane inhibitor of reactive lysis (MIRL)

    • HRF: homologous restriction factor (C8 binding protein)

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  • Deficiency of the GPI anchor proteins accounts for the intravascular hemolysis that is the primary clinical manifestation of the disease.

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  • Frequently associated bone marrow failure, particularly aplastic anemia.

  • Major cause of morbidity and mortality in PNH: thrombophilia

PATHOPHYSIOLOGY

  • The enzyme PIGA (phosphatidylinositol glycan A) is essential in synthesizing GPI;

  • PIGA mutation leads to a defect in GPI anchor, CD55, CD59 and HRF, which protect the cell from destruction by the complement system;

  • Without these anchors, the cells are more easily targeted by the complement proteins.

CLINICAL FEATURES

  • 1-5 per million;

  • Sudden, recurring episodes of symptoms, which may be triggered by stresses, infections or physical exertion;

  • Dark urine in the morning;

  • Anemia: fatigue, weakness, pallor, shortness of breath, and an increased heart rate. Infections due to a deficiency of white blood cells.

  • Thrombosis, especially in large abdominal veins;

  • In association with other bone marrow disorders and Increased risk of developing leukemia;

CLASSIFICATION

  • Classic PNH

    • Intravascular hemolysis: reticulocytosis, high LDH and indirect bilirubin, and low serum haptoglobin;

    • Bone marrow: hypercellular with erythroid hyperplasia and rather normal morphology, but without nonrandom karyotypic abnormalities;

    • No evidence of other defined bone marrow abnormality.

  • PNH in the setting of another specified bone marrow disorder

    • Cinical and laboratory evidence of hemolysis;

    • Concomitantly or history of a defined bone marrow abnormality: aplastic anemia, myelodysplastic syndrome (MDS), or other myelopathy (eg, myelofibrosis).

  • PNH-subclinical (PNH-sc) in the setting of another specified bone marrow disorder

    • No clinical or laboratory evidence of hemolysis;

    • Small populations of GPI-AP–deficient RBCs or granulocytes are detected by very sensitive flow cytometric analysis;

    • In association with bone marrow failure syndromes, particularly aplastic anemia and refractory anemia-MDS.

MINIMAL ESSENTIAL DIAGNOSTIC CRITERIA

  • Evidence of a population of peripheral blood cells (erythrocytes, granulocytes, or preferably both) deficient in GPI-APs by flow cytometric analysis or the FLAER assay (fluorescently labeled aerolysin);

  • Complete blood count, reticulocyte count, serum concentration of lactate dehydrogenase (LDH), bilirubin (fractionated), and haptoglobin;

  • Bone marrow aspirate, biopsy, and cytogenetics.

MANAGEMENT

  • Blood tests: CBC, reticulocyte count, LDH, bilirubin, and haptoglobin, DAT or direct Coombs' test);

  • Serum iron studies (iron concentration, total iron binding capacity, transferrin saturation index, and ferritin concentration);

  • Suga/sucrose lysis test: for screening,  RBC in low ionic strength solution and observed for hemolysis;

  • Ham's acid hemolysis: more specific, performed if the sugar test is positive;

  • Flow cytometric analysis of RBC and granulocytes for CD55 and CD59. Type I cells have normal levels of CD55 and CD59, type II have reduced levels and type III have absent levels.

TREATMENT AND PROGNOSIS

  • Corticosteroids: for both chronic hemolysis and acute hemolytic exacerbations, still a subject of debate;

  • Androgens: either alone or in combination with steroids;

  • Iron replacement:  patients frequently become iron deficient as a result of both hemoglobinuria and hemosiderinuria;

  • Transfusion: may ameliorate hemolysis by suppressing erythropoiesis;

  • Splenectomy

  • Wculizumab, C5-inhibitor monoclonal Ab

REFERENCES

  • Charles Parker, Mitsuhiro Omine, Stephen Richards, Jun-ichi Nishimura, Monica Bessler, Russell Ware, Peter Hillmen, Lucio Luzzatto, Neal Young, Taroh Kinoshita, Wendell Rosse, Gerard Socié, and for the International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005 December 1; 106(12): 3699–3709.