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CHAPTER 35 or polyblastic myelogenous leukemia. Several uncommon inherited disorders,

APLASTIC ANEMIA: including Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis con-
genita and others have as a primary manifestation aplastic hematopoiesis.
ACQUIRED AND INHERITED

ACQUIRED APLASTIC ANEMIA
George B. Segel and Marshall A. Lichtman
DEFINITION AND HISTORY
Aplastic anemia is a clinical syndrome that results from a marked dimi-
SUMMARY nution of marrow blood cell production. The decrease in hematopoiesis
results in reticulocytopenia, anemia, granulocytopenia, monocytope-
Acquired aplastic anemia is a clinical syndrome in which there is a deficiency nia, and thrombocytopenia. The diagnosis usually requires the presence
of red cells, neutrophils, monocytes, and platelets in the blood, and fatty of pancytopenia with a neutrophil count fewer than 1500/μL (1.5 ×
10 /L), a platelet count fewer than 50,000/μL (50 × 10 /L), a hemoglobin
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replacement of the marrow with a near absence of hematopoietic precursor concentration less than 10 g/dL (100 g/L), and an absolute reticulocyte
cells. Reticulocytopenia is a constant feature. Neutropenia, monocytopenia, count fewer than 40,000/μL (40 × 10 /L), accompanied by a hypocel-
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and thrombocytopenia, when severe, are life-threatening because of the risk lular marrow without abnormal or malignant cells or fibrosis. For the
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of infection and bleeding, complicated by severe anemia. Most cases occur purpose of therapeutic decision making, comparative clinical trials, and
without an evident precipitating cause and are caused by autoreactive cyto- international sharing of data, the disease has been stratified into mod-
toxic T lymphocytes that suppress or destroy primitive CD34+ multipotential erately severe, severe, and very severe acquired aplastic anemia based
hematopoietic cells. The disorder also can occur after (1) prolonged high-dose on the blood counts (especially the neutrophil count) and the degree
exposure to certain toxic chemicals (e.g., benzene), (2) after specific viral of marrow hypocellularity (Table 35–1). Most cases of aplastic anemia
infections (e.g., Epstein-Barr virus), (3) as an idiosyncratic response to cer- are acquired; fewer cases are the result of an inherited disorder, such
tain pharmaceuticals (e.g., ticlopidine, chloramphenicol), (4) as a feature of as Fanconi anemia, Shwachman-Diamond syndrome, and others (see
a connective tissue or autoimmune disorder (e.g., lupus erythematosus), or, “Hereditary Aplastic Anemia” below). 2
Aplastic anemia was first recognized by Paul Ehrlich in 1888. He
(5) rarely, in association with pregnancy. The final common pathway may described a young, pregnant woman who died of severe anemia and
be through cytotoxic T-cell autoreactivity, whether idiopathic or associated neutropenia. Thrombocytopenia was difficult to measure and the role
with an inciting agent since they all respond in a similar fashion to immu- of blood dust (platelets) was controversial at that time. Autopsy exami-
nosuppressive therapy. The differential diagnosis of acquired aplastic anemia nation revealed a fatty marrow with essentially no hematopoiesis. The
includes a hypoplastic marrow that can accompany paroxysmal nocturnal name aplastic anemia was subsequently applied to this disease by Chauf-
hemoglobinuria or hypoplastic oligoblastic (myelodysplastic syndrome) or fard, a French hematologist, in 1904, and although an anachronistic
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polyblastic myelogenous leukemia. Allogeneic hematopoietic stem cell trans- term because the morbidity is the result of pancytopenia, especially
plantation is curative in approximately 80 percent of younger patients with neutropenia and thrombocytopenia, the designation is entrenched in
high-resolution human leukocyte antigen–matched sibling donors, although medical usage. For the next 40 years, many conditions that caused pan-
the posttransplant period may be complicated by severe graft-versus-host cytopenia were confused with aplastic anemia based on incomplete or
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disease. The disease may be significantly ameliorated or occasionally cured by inadequate histologic study of the patient’s marrow. The development of
improved instruments for percutaneous marrow biopsy in the last half
immunotherapy, especially a regimen coupling antithymocyte globulin with of the 20th century improved diagnostic precision. In 1972, Thomas and
cyclosporine. However, after successful treatment with immunosuppressive his colleagues established that marrow transplantation from a histocom-
agents, the disease may relapse or evolve into a clonal myeloid disorder, such patible sibling donor could cure the disease. The disease initially was
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as paroxysmal nocturnal hemoglobinuria, a clonal cytopenia, or oligoblastic thought to result from an atrophy or chemical injury of primitive mar-
row hematopoietic cells. The unexpected recovery of marrow recipients
who were given immunosuppressive conditioning therapy but who did
not engraft with donor stem cells raised the possibility that the disease
may not be intrinsic to primitive hematopoietic cells but the result of
Acronyms and Abbreviations: A, adenine; ALG, antilymphocyte globu- a suppression of hematopoietic cells by immune cells, notably T lym-
lin; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; phocytes. The requirement to treat the recipient of a marrow transplant
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ATG, antithymocyte globulin; ATR, ataxia-telangiectasia mutated and from an identical twin with immunosuppressive conditioning therapy
rad3-related kinase; BFU-E, erythroid burst-forming units; CD, cluster of for optimal results of transplant, buttressed this concept. This suppo-
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differentiation; CFU-GM, colony-forming unit–granulocyte-macrophage; sition was confirmed by a clinical trial that established antilymphocyte
CMV, cytomegalovirus; EBV, Epstein-Barr virus; G, guanine; G-CSF, granu- globulin (ALG) capable of ameliorating the disease in the majority of
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locyte colony-stimulating factor; HHV, human herpes virus; HLA, human patients. Since that time, compelling evidence for a cellular autoimmune
leukocyte antigen; IL, interleukin; MRI, magnetic resonance imaging; PCP, mechanism has accumulated (see “Etiology and Pathogenesis” below).
pentachlorophenol; PNH, paroxysmal nocturnal hemoglobinuria; SCF, stem
cell factor; T, thymine; TERC, telomerase RNA component; TERT, telomerase EPIDEMIOLOGY
reverse transcriptase; TNF, tumor necrosis factor; TNT, trinitrotoluene; TPO, The International Aplastic Anemia and Agranulocytosis Study and
thrombopoietin. a French study found the incidence of acquired aplastic anemia to be
approximately 2 per 1,000,000 persons per year. This annual incidence
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