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542 Part VI: The Erythrocyte Chapter 36: Pure Red Cell Aplasia 543

of red cell failure is best understood for T cell–mediated autoimmune In one man with red cell aplasia and LGL, erythropoiesis was inhibited
destruction and persistent B19 parvovirus infection. by non–MHC (major histocompatibility) antigen-restricted γδ T cells
that lysed CFU-E. T cells downregulated class I histocompatibility anti-
gens and thus were unable to engage the natural killer cell’s inhibitory
ETIOLOGY AND PATHOGENESIS receptors. 137
Immune-Mediated Erythropoietic Failure
Clinical and laboratory evidence supports both antibody and cellular Persistent B19 Parvovirus Infection
mechanisms of inhibition of erythropoiesis. Red cell aplasia is associ- B19 parvovirus specifically infects and is toxic to erythroid progenitor
ated with autoimmune diseases, such as rheumatoid arthritis, systemic cells. Parvovirus infection normally is terminated within 1 to 2 weeks
lupus erythematosus, myasthenia gravis, autoimmune hemolytic ane- of infection by the humoral immune response. Linear neutralizing
mia, acquired hypoimmunoglobulinemia, autoimmune polyglandular epitopes are localized to a relatively small region of the capsid protein.
145
syndrome, and especially thymoma, and with lymphoproliferative pro- In the absence of an effective antibody response, infection persists and
cesses, such as chronic lymphocytic leukemia (CLL) and Hodgkin dis- causes pure red cell aplasia. 65,145 Erythropoietic failure may be the only
ease, in which immune dysregulation is common. Serum inhibitors can evidence of parvoviral infection. Persistence of B19 parvovirus infection
be detected in the laboratory. Krantz and colleagues showed that immu- may occur in the setting of immunodeficiency (Chap. 80), most com-
noglobulin fractions from the patient’s blood inhibited heme synthesis monly caused by chemotherapeutic and immunosuppressive drugs,
146
and red cell progenitor assays in vitro. Antibodies that inhibit BFU-E human immunodeficiency virus 1 infection, and occasionally with
87
147
and CFU-E colony formation are present frequently in patients with Nezelof syndrome’s subtle immunologic abnormalities. Parvovirus at
148
red cell aplasia. A pathophysiologic role can be inferred, first from the one time may have accounted for approximately 15 percent of severe
response of patients to specific treatments directed at antibodies, such anemia in patients with AIDS, but highly effective antiretroviral drug
149
as plasmapheresis and a monoclonal antibody to a cluster of differentia- regimens have reduced its role. 150,151 Persistent B19 parvovirus infection
tion molecule expressed on the surface of all mature B cells, CD20, and can occur in the fetus exposed during the midtrimester of pregnancy
second from decreased or absent plasma antibody in recovered patients. (Chap. 55). The infection can cause hydrops fetalis as a result of viral
Antibodies may be involved in the red cell aplasia of pregnancy. 105 cytotoxicity for erythroid progenitors in the fetal liver and death of the
Autoantibodies to erythropoietin rarely have caused this dis- newborn as a result of severe anemia and congestive heart failure. In
65
ease. 106,107 More frequently, red cell aplasia secondary to antibodies is rare instances, parvovirus-infected or hydropic infants rescued by red
elicited by administration of recombinant erythropoietin to patients cell transfusion show congenital red cell aplasia or dyserythropoietic
undergoing renal dialysis. 108–113 Anemia can be profound, and some anemia. 33
patients remain transfusion dependent despite discontinuation of hor-
mone therapy. Glycosylation of recombinant erythropoietin is different Intrinsic Cellular Defects Leading to Failed Red Blood Cell
from the native molecule, but antibodies are directed against conforma- Production
tional epitopes of the protein and not to the sugar moieties. Erythropoi- Red cell aplasia can be the first or the major manifestation of myelodys-
etin immunogenicity associates with human leukocyte antigen (HLA) plasia. Discrete genetic defects can lead to failure of erythropoiesis.
152
specificities. The second example of antibodies of known specificity Activating point mutations in N-RAS, an oncogene in the RAS family
114
causing red cell aplasia occurs after hematopoietic stem cell transplanta- occur in some cases of myelodysplastic syndrome. 153,154 Mutant N-RAS
tion using donors mismatched at a major ABO locus, which can lead to in vitro can induce a proliferative defect in erythroid progenitor cells.
155
delayed donor erythroid engraftment or late erythropoietic failure. 115–118 Loss of the RPS14 gene in 5q− deletions leads to red cell aplasia in this
In most instances, however, the target antigen(s) responsible for this myelodysplastic syndrome. 22,156 In vitro colony formation may distin-
outcome is(are) not known. guish such intrinsic cellular defects from immune mediated marrow
Suppression of erythropoiesis by T cells may be more common failure, with higher BFU-E numbers predicting response to immuno-
than antibody inhibition as a mechanism of erythropoietic failure. suppressive therapies. 157
119
Suggestive clinical observations include the frequent association of red
cell aplasia with CLL (Chap. 92) in approximately 6 percent of cases ;
120
CLL is also associated with autoimmune hemolytic anemia and idio- Medications
pathic thrombocytopenic purpura and with large granular lympho- Idiosyncratic drug reactions account for a far smaller proportion of red
121
cytic leukemia (LGL; Chap. 94) in approximately 7 percent of cases. In cell aplasia than of agranulocytosis (Chap. 65). Case reports have impli-
122
a series of 47 red cell aplasia patients, four had CLL and nine had LGL. cated various agents, such as diphenylhydantoin, sulfa and sulfonamide
123
More sensitive flow cytometric and molecular methods may detect drugs, azathioprine, allopurinol, isoniazid, procainamide, ticlopidine,
clonal T-cell expansion in patients with normal numbers of circulating ribavirin, and penicillamine. Causality is impossible to assign from case
lymphocytes. 124,125 An attractive molecular mechanism underlying CD8 reports; with nonsteroidal antiinflammatory drugs, gold, and colchic-
cell expansion is signal transducer and activator of transcription 3 gene ine, the underlying rheumatic syndrome may be the etiologic link.
mutations (STAT3), leading to constitutive activation of a clone of cyto-
toxic T cells, which is relatively frequent in patients with large granular
lymphocytosis and has been described in patients with pure red cell CLINICAL FEATURES
126
aplasia. 127–129 Functionally, lymphocytes from patients with idiopathic Symptomatic anemia in the older patient may manifest as pallor,
pure red cell aplasia 130–132 or red cell aplasia associated with CLL, 133,134 fatigue, lassitude, pulsatile tinnitus, and anginal chest pain (Chap. 34).
LGL, 135–137 thymoma, other lymphoid malignancies, 139,140 Epstein- Iatrogenic Cushing syndrome and the physical stigmata of secondary
138
Barr virus infection, and human T-cell leukemia virus 1 infection hemochromatosis are seen in patients after prolonged glucocorticoid
141
142
suppressed erythropoiesis in colony assays. Several mechanisms of administration and long-term red cell transfusion therapy. Concomi-
cell killing have been suggested. 122,143 When effector cells show histo- tant diseases include CLL and lymphomas, collagen vascular disorders,
compatibility locus A class I–restricted killing, recognition of a spe- myasthenia gravis, especially in the setting of thymoma, and some
cific antigen peptide is implied by a T cell with an αβ T-cell receptor. cancers. Red cell aplasia also occurs with pregnancy. Persistent B19
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