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CHAPTER 40 Although treatment with eculizumab favorably modifies the natural history

PAROXYSMAL NOCTURNAL of PNH, it has no effect on the underlying disease process (i.e., the PIGA-mu-
tant hematopoietic stem cell clone). The PIGA-mutant mutant clone can be
HEMOGLOBINURIA eradicated and normal hematopoiesis restored by allogeneic hematopoietic
stem cell transplantation, but the relatively benign natural history of PNH in
patients treated with eculizumab has tempered enthusiasm for transplanta-
tion because of concerns about subjecting patients to the risk of treatment-re-
Charles J. Parker lated morbidity.

SUMMARY DEFINITION AND HISTORY

In contrast to all other intrinsic abnormalities of the erythrocyte, paroxysmal Although commonly regarded as a type of hemolytic anemia, parox-
nocturnal hemoglobinuria (PNH) is an acquired, not an inherited, disorder. ysmal nocturnal hemoglobinuria (PNH) is properly categorized as
PNH arises as a consequence of somatic mutation, involving one or more a hematopoietic stem cell disorder. PNH arises as a result of clonal
hematopoietic stem cells, of PIGA, a gene located on the X chromosome that expansion of one or several hematopoietic stem cells that have acquired
is required for synthesis of the glycosylphosphatidylinositol (GPI) moiety that a somatic mutation of the X-chromosome gene PIGA (phosphatidyli-
anchors some proteins to the cell surface. Consequently, all GPI-anchored nositol glycan class A). As a consequence of mutant PIGA, any progeny
proteins (GPI-APs) that are normally expressed are deficient on the mutant of affected stem cells (erythrocytes, granulocytes, monocytes, platelets,
hematopoietic stem cells and their progeny. The complement-mediated intra- and lymphocytes) are deficient in all glycosylphosphatidylinositol-an-
chored proteins (GPI-APs) that are normally expressed on hematopoi-
vascular hemolytic anemia and the resulting hemoglobinuria that are the etic cells. The clinical manifestations of PNH are hemolytic anemia,
clinical hallmarks of PNH are a consequence of deficiency of the GPI-anchored thrombophilia, and marrow failure, but only the hemolytic anemia is
complement regulatory proteins, CD55 and CD59. Although PNH is a neoplas- unequivocally a consequence of somatic mutation of PIGA. It is not a
tic (clonal) disease, it is not a malignant disease in that there is no exagger- malignant neoplasm in the classical sense of uncontrolled proliferation
ated proliferation of neoplastic cells and replacement of marrow or spread to of cells, spread to tissues other than marrow, or spatial replacement of
other tissues, and the extent to which the mutant clones expand varies greatly hematopoiesis. Its effects can be lethal and it can uncommonly undergo
among patients. Thus, the blood cells of patients with PNH are a mosaic of clonal evolution to acute myelogenous leukemia.
phenotypically normal and abnormal cells. The size of the mutant clone is an Comprehensive, scholarly reviews of the history of PNH have been
1–4
important determinant of the clinical manifestations of the disease, which published. The first published clinical description of PNH is attrib-
include hemolysis, thrombophilia, and, in many patients, pancytopenia as a uted to William Gull in 1866, but he failed to distinguish definitively
result of marrow failure. The diagnosis of PNH is confirmed using flow cytom- PNH from paroxysmal cold hemoglobinuria. Paul Strübing, in 1882,
clearly recognized PNH as a distinct entity and undertook prescient
etry to detect and quantify the percentage of blood erythrocytes and leuko- experiments designed to test his hypothesis that the nocturnal hemo-
cytes (i. e., neutrophils and monocytes) that lack GPI-APs measured as intensity globinuria was a consequence of acidification of plasma that occurred
of CD55 and CD59 on the cell surface. The intravascular hemolysis of PNH when carbon dioxide and lactic acid accumulated because of slowing of
can be controlled with eculizumab, a humanized monoclonal antibody that respiration during sleep. In 1911, A.A. Hijmans van den Berg demon-
blocks formation of the cytolytic membrane attack complex of complement. strated that the hemolysis of PNH is caused by a defect in the red cell
rather than by the presence of an abnormal plasma factor (as is the case
with paroxysmal cold hemoglobinuria; Chap. 54). Thomas Hale Ham
is credited with discovering, in the late 1930s, that complement medi-
ates the hemolysis of PNH erythrocytes, although it was not until the
alternative pathway of complement was identified and characterized in
Acronyms and Abbreviations: APC, alternative pathway of complement; the mid-1950s by Louis Pillemer that the basis of Ham’s original obser-
CD55, an antigen encoding DAF; CD59, an antigen encoding MAC-inhibitory vations became apparent. Ham developed the acidified serum lysis test
protein; DAF, decay-accelerating factor; GPI, glycosylphosphatidylinositol; (Ham test) that, along with the sucrose lysis test (sugar water test) of
GPI-APs, glycosylphosphatidylinositol-anchored proteins; GVHD, graft- Robert Hartmann and David Jenkins, was used as the standard diag-
versus-host disease; HLA, human leukocyte antigen; INR, international nostic test for PNH until being supplanted in the early 1990s by flow
normalized ratio of prothrombin assay data; LDH, lactate dehydrogenase; cytometry. Both Hartmann and William Crosby brought attention to
MAC, membrane attack complex of complement; MDS, myelodysplastic the important role that thrombosis (particularly the Budd-Chiari syn-
syndrome; MIRL, membrane inhibitor of reactive lysis; PIGA, phosphati- drome) plays in the natural history of PNH, and John Dacie and his
student and colleague S.M. Lewis were the first to systematically charac-
dylinositol glycan class A; PMN, polymorphonuclear cell; PNH, paroxysmal terize the relationship between PNH and marrow failure.
nocturnal hemoglobinuria; PNH-sc, subclinical PNH; RA, refractory anemia;
RAEB, refractory anemia with excess of blasts; RAEB-t, refractory anemia
with excess of blasts in transformation; RA-PNH+, RA with a population of EPIDEMIOLOGY
PNH cells; RA-PNH−, RA without a population of PNH cells; RARS, refractory The prevalence of PNH is not known with certainty. Prevalence esti-
anemia with ringed sideroblasts; RBCs, red blood cells; RCMD, refractory mates are influenced by bias in study design and results differ consid-
cytopenias with multilineage dysplasia; WHO, World Health Organization. erably, in large part, because of the heterogeneous nature of the disease.
The blood of patients with PNH is a mosaic of normal and abnormal

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