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C H A P T E R 32

ACQUIRED DISORDERS OF RED CELL, WHITE CELL, AND

PLATELET PRODUCTION

Jaroslaw P. Maciejewski and Swapna Thota

ACQUIRED PURE RED CELL APLASIA The inhibitory activity is localized to the immunoglobulin (Ig)G
fraction and disappears upon remission. The antigenic targets for
Acquired pure red cell aplasia (PRCA) is characterized by the presence autoantibodies have not been well characterized, but various stages
of an acquired severe normochromic, most frequently normocytic of erythroid differentiation can be affected (also called PRCA type
anemia associated with a complete disappearance of reticulocytes and A), as seen in the reduction of burst-forming unit–erythroid or
erythroid precursors in the marrow and normal production of colony-forming unit–erythroid. In certain cases of antibody-mediated
myeloid cells and platelets. Consequently, it is presumed that the PRCA, the involvement of the complement system is a prerequisite
defect lies within erythroid precursors and not within stem cells as to disease causation. Perhaps the exception and a model for antibody-
seen in aplastic anemia. Initially described as progressive anemia with induced red cell aplasia is the identification of PRCA associated with
exclusive absence of erythroid series in the bone marrow, PRCA is a rare antierythropoietin antibodies (also called PRCA type B) in rare cases.
bone marrow failure disorder without geographic or racial predilec- Consistent with the specificity of the antibodies, myeloid colony
tion. All ages can be affected, but if present in children, it is called formation is not impaired, making it unlikely that a more ubiquitous
transient erythroblastopenia of childhood (TEC) and may be difficult inhibitory cytokine mediates the specific erythroid inhibition.
to distinguish from congenital causes of anemia, mainly Diamond- Experimental and clinical observations have suggested that PRCA
Blackfan anemia (DBA) (Chapter 29). Former nosology included may also be mediated by CTLs, which specifically recognize and kill
various terms such as erythrophthisis, chronic hypoplastic anemia, and erythroid precursors similar to CTL-mediated killing of cells in
pure red cell agenesis. aplastic anemia. Although such a T cell–mediated erythroid response
is likely to be polyclonal, rare instances of T-cell large granular lym-
phocyte (T-LGL) leukemia associated with PRCA or erythroid
ETIOLOGY AND CLASSIFICATION inhibition may represent an extreme form of the clonal continuum
of CTL responses (see T-LGL-associated PRCA). In addition to CTLs
Acquired forms of PRCA must be distinguished from congenital expressing α/β T-cell receptors (TCRs), T cells with a γ/δ TCR can
forms of PRCA, which usually manifest themselves early in life (see mediate PRCA. The antigens/antigenic peptides triggering such a
Chapter 29). Acquired PRCA occurring in childhood may be difficult response have not been well described. Similarly, natural killer (NK)
to distinguish from DBA. As an acquired disease, PRCA may be a cells have also been implicated in mediating cytotoxicity directed
primary disorder or secondary to a variety of systemic diseases, against erythroid precursors. NK cells, like γ/γ T lymphocytes
including a number of hematologic malignancies (Table 32.1). and unlike α/β CTLs, do not rely on major histocompatibility
complex (MHC)–restricted cytotoxicity, but may use killer-cell
immunoglobulin-like receptors (KIRs). KIRs inhibit cytolysis when
Pathogenesis they encounter a cell bearing human leukocyte antigen (HLA) class
I molecules. A lack of appropriate KIRs may predispose cells to
The inciting events in the development of PRCA are not known. increased attack by NK cells or γ/δ CTLs. Physiologic downregula-
However, as with idiopathic aplastic anemia, viruses or exposure to tion of KIRs has been implicated in the pathogenesis of PRCA in a
chemicals can serve as potential triggers (Fig. 32.1). Theoretically a patient with concomitant γ/δ T-LGL clonal proliferation. An alterna-
viral infection could lead to depletion of erythroid precursors. Studies tive NK-cell cytotoxic mechanism independent of KIR has been
of B19 parvovirus (discussed later) suggest such an etiology. Because reported in healthy individuals.
hematopoietic stem cells are not affected by B19 parvovirus, myeloid Peripheral Th lymphocyte polarization has been implicated in the
cells and platelets are normally produced, and upon clearance of the pathogenesis of PRCA. 56,57 Polarization toward the Th2 functional
virus, normal erythroid production can resume. Similarly, in immune- subtype during disease relapse and normalization of Th1/Th2 ratio
mediated PRCA, the mechanism of erythroid inhibition may vary after effective treatment has been reported in both monoclonal gam-
and may include (1) antibodies to proteins specific to erythroblasts, mopathy- and thymoma-associated PRCA.
(2) direct cytotoxic T lymphocyte (CTL)–mediated killing of ery-
throid precursors, and (3) production of soluble products by CTLs
such as inhibitory or proapoptotic cytokines that directly affect the PRIMARY PURE RED CELL APLASIA
erythroid series.
Historically, initial studies concentrated on examining the effects Primary PRCA occurs in the absence of any underlying disorder. It
of soluble serum inhibitors of erythropoiesis. These investigations may be acute and self-limited or may be a chronic and refractory
revealed a decline in erythroid colony formation in the presence of condition. Acute forms are uncommon. Most cases are protracted
patient serum or failure to induce erythroid colony formation in the and chronic, unlike TEC, which is an acute and self-limited disorder.
presence of erythropoietin. Such serum inhibitors can be found in Most of the cases of classic primary PRCA are autoimmune in origin,
40% of patients with PRCA. In 60% of patients, erythroid colony but a significant proportion will remain idiopathic in origin in spite
formation can be induced in vitro with hematopoietic growth factors. of an exhaustive workup.

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