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520 Part VI: The Erythrocyte Chapter 35: Aplastic Anemia: Acquired and Inherited 521

or flow cytometry will uncover a population of leukemic lymphoblasts. The relationship of PNH to aplastic anemia remains enigmatic.
In other cases, the acute leukemia may appear later. Hairy-cell leuke- Because hematopoietic stem cells lacking the phosphatidylinositol-
mia, Hodgkin disease, or another lymphoma subtype, rarely, may be anchored proteins are present in many or all normal persons in very
preceded by a period of marrow hypoplasia. Immunophenotyping small numbers, it is not surprising that more than 50 percent of
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of marrow and blood cells by flow cytometry for CD25 may uncover patients with aplastic anemia may have a PNH cell population as
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the presence of hairy cells. Other clinical features may be distinctive detected by immunophenotyping. The probability of patients with
(Chap. 93). Organomegaly such as lymphadenopathy, hepatomegaly, aplastic anemia developing a clinical syndrome consistent with PNH is
or splenomegaly are inconsistent with the atrophic (hypoproliferative) 10 to 20 percent, and this is not a consequence of immunosuppressive
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features of aplastic anemia. Large granular lymphocytic leukemia has treatment. Patients also may present with the hemolytic anemia of
also been associated with aplastic anemia. Rare cases of typical acquired PNH and later develop progressive marrow failure so that any pathoge-
aplastic anemia have been followed by t(9;22)-positive acute lympho- netic explanation should consider both types of development of aplastic
cytic leukemia (ALL) or chronic myelogenous leukemia (CML). 136 marrows in PNH. The PIG-A mutation may confer either a prolifera-
tive or survival advantage to PNH cells. 144,145 A survival advantage could
RELATIONSHIP AMONG APLASTIC result if the anchor protein or one of its ligands served as an epitope
ANEMIA, PAROXYSMAL NOCTURNAL for the T-lymphocyte cytotoxicity, which induces the marrow aplasia.
In this case, the presenting event could either reflect cytopenias or the
HEMOGLOBINURIA, AND CLONAL MYELOID sensitivity of red cells to complement lysis and hemolysis, depending on
DISEASES the intrinsic proliferative potential of the PNH clone.
In addition to the diagnostic difficulties occasionally presented by Within our current state of knowledge, aplastic anemia is an
patients with hypoplastic myelodysplastic syndromes, hypoplastic autoimmune process, and any residual hematopoiesis is presumably
acute myelogenous leukemia (AML), or PNH with hypocellular mar- polyclonal. This is a critical distinction from hypoplastic leukemia and
rows, there may be a more fundamental relationship among these PNH, which are clonal (neoplastic) diseases. The environment of the
three diseases and aplastic anemia. The development of clonal cytoge- aplastic marrow, however, may favor the eventual evolution of a mutant
netic abnormalities such as monosomy 7 or trisomy 8 in a patient with (malignant) clone, especially if immunotherapy is used, whereas
aplastic anemia portends the evolution of a myelodysplastic syndrome hematopoietic stem cell transplantation may either ablate threatening
or acute leukemia. Occasionally, these cytogenetic markers have been minor clones or establish more robust hematopoiesis, an environment
transient, and in cases with disappearance of monosomy 7, hematologic less conducive to clonal evolution.
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improvement has occurred as well. Persistent monosomy 7 carries a
poor prognosis as compared to trisomy 8. 138,139 TREATMENT
As many as 20 percent of patients with aplastic anemia have a
5-year probability of developing myelodysplasia. If one excludes Approach to Therapy
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any transformation to a clonal myeloid disorder that occurs up to Severe anemia, bleeding from thrombocytopenia, and, uncommonly
6 months after treatment to avoid misdiagnosis among the hypoplastic at the time of diagnosis, infection secondary to granulocytopenia
clonal myeloid diseases, the frequency of a clonal disorder was nearly and monocytopenia require prompt attention to remove potential
15 times greater in patients treated with immunosuppression as com- life-threatening conditions and improve patient comfort (Table 35–5).
pared to those treated with marrow transplantation after 39 months of More specific treatment of the marrow aplasia involves two principal
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observation. This finding suggests either that immune suppression by options: (1) syngeneic or allogeneic hematopoietic stem cell transplan-
anti–T-cell therapy enhances the evolution of a neoplastic clone or that tation or (2) combination immunosuppressive therapy with ATG and
it does not suppress the intrinsic tendency of aplastic anemia to evolve cyclosporine. The selection of the specific mode of treatment depends
to a clonal disease, but provides the increased longevity of the patient
required to express that potential. The latter interpretation is more likely
as patients successfully treated solely with androgens develop clonal dis-
ease as frequently as those treated with immunosuppression. Trans-
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plantation may reduce the potential to clonal evolution in patients with TABLE 35–5. Initial Management of Aplastic Anemia
aplastic anemia by reestablishing robust lymphohematopoiesis. • Discontinue any potential offending drug and use an alternative
Telomere shortening also may play a pathogenetic role in the class of agents if essential.
evolution of aplastic anemia into myelodysplasia. Patients with aplas- • Anemia: transfusion of leukocyte-depleted, irradiated red cells
tic anemia have shorter telomere lengths than matched controls, and as required for very severe anemia.
patients with aplastic anemia with persistent cytopenias had greater • Very severe thrombocytopenia or thrombocytopenic bleed-
telomere shortening over time than matched controls. Three of five ing: consider ε-aminocaproic acid; transfusion of platelets as
patients with telomere lengths less than 5 kb developed clonal cytoge- required.
netic changes, whereas patients with longer telomeres did not develop • Severe neutropenia; use infection precautions.
such diseases. 23,142
The findings of mutated genes considered driver mutations in mye- • Fever (suspected infection): microbial cultures; broad-spectrum
lodysplastic syndrome or AML (see “Marrow Findings: Cytogenetic and antibiotics if specific organism not identified, granulocyte
colony-stimulating factor (G-CSF) in dire cases. If child or small
Genetic Studies” earlier) in nearly 20 percent of a population of patients adult with profound infection (e.g., Gram-negative bacteria, fun-
with clinical aplastic anemia indicates that clonal hematopoiesis may gus, persistent positive blood cultures) can consider neutrophil
develop or be present surreptitiously. The precise relationships to the transfusion from a G-CSF pretreated donor.
aplastic anemia lesion is uncertain but could be caused the outgrowth • Immediate assessment for allogeneic stem cell transplantation:
of a clone of cells in the background of severally suppressed polyclonal Histocompatibility testing of patient, parents, and siblings.
hematopoietic stem cells. These findings were more common in patients Search databases for unrelated donor, if appropriate.
with a long duration of disease and with shorter telomeres. 132a

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