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C H A P T E R 30

APLASTIC ANEMIA

Neal S. Young and Jaroslaw P. Maciejewski

Aplastic anemia (AA), the paradigm of the bone marrow (BM) failure personal communications, and first-hand observations, AA appears
syndromes, is most simply defined as peripheral blood pancytopenia more prevalent in less developed regions of the world. There are no
and a hypocellular BM (Fig. 30.1). From epidemiologic and clinical major sex or racial differences in the occurrence of AA.
features, pathophysiologic studies, and response to therapy, AA is a AA is a disease of the young (Fig. 30.2). Most patients present
distinctive disease. However, the diagnosis of AA requires excluding between 15 and 25 years of age or older than 60 years of age.
other causes of pancytopenia (Table 30.1). AA can occur as a primary
hematologic disorder, most often idiopathic, or apparently result
from various proximate causes, including obvious physical and Epidemiologic Clues to Causality
chemical toxins but also drugs and viruses that can act indirectly.
Although AA is usually characterized by a severe diminution in BM Population-based studies have investigated possible causal associa-
function that affects all the hematopoietic lineages, granulocyte, tions. Drugs are implicated in only approximately 25% of cases of
platelet, and red blood cell (RBC) levels may not be depressed uni- AA in the West; in Thailand, AA was attributed to drug exposure in
3
formly, and less severe degrees of BM hypoplasia and odd combina- only approximately 15% of cases. There are associations with chemi-
tions of bicytopenias and monocytopenias can occur. AA can be cal exposures, exposures to viruses, hepatitis, and occupation. There
especially difficult to distinguish from hypocellular myelodysplasia, a is evidence that geographic variation in AA might result from envi-
diagnostic dilemma that can rest on real biologic similarities. Even ronmental causes and also genetic predispositions.
typical AA can vary in its clinical course, from a fulminant illness
marked by hemorrhage and infections to an indolent process manage-
able by transfusions. The reader is referred to previous editions of this Genetic Aspects
textbook for references, as well as to the authors’ recent reviews 1
In children and young adults, acquired AA should be distinguished
from the main inherited forms of BM failure, Fanconi anemia (FA)
HISTORY and dyskeratosis congenita (DKC) (Chapter 29). Identification of
constitutional AA has important therapeutic implications. Patients
The study of BM failure dates to 1888, when Paul Ehrlich described with FA and DKC can lack typical physical anomalies, and the
a young woman who died after an explosive short illness marked by pancytopenia can develop long after childhood, mimicking acquired
severe anemia, bleeding, and high fever. As a pathologist, Ehrlich was disease. The distinction between inherited and acquired AA has been
struck by the absence of nucleated RBCs and the fatty quality of the blurred with the identification of mutations in the telomerase genes
femoral BM. Vaquez and Aubertin, in a 1904 case report of “perni- that appear to be risk factors rather than determinants of clinical BM
cious anemia with yellow BM,” named the disease and emphasized a failure (see later). Genomic approaches to the study of AA are likely to
pathophysiology of anhematopoiesis. The etymologic root of the term uncover other genetic contributions to susceptibility to BM failure. 4,5
aplastique is the Greek verb pl¿Jw, to create and give shape to (¿plaztká, A few histocompatibility types have also been associated with AA,
the adjective, unformed). most consistently human leukocyte antigen (HLA)-DR2. HLA-DR
subtypes predicted response to immunosuppressive therapy in a
large cohort of US AA patients, in which HLA-DR15 was associated
CLASSIFICATION with the presence of a paroxysmal nocturnal hemoglobinuria (PNH)
clone and responsiveness to immunosuppression. Genetic predisposi-
AA is a major sequela of irradiation and exposure to cytotoxic che- tion may be responsible for some idiosyncratic reactions to drugs and
motherapy. It has been associated with the use of chemicals and chemicals leading to the development of AA. Polymorphisms in
drugs, viral infections, and other diseases (Table 30.2). Most patients cytokine genes, associated with an increased immune response, are
have an idiopathic form of the disease. Historical associations of also more prevalent in AA. Genome-wide transcriptional analysis of
environmental exposures and causation are interesting but should be T and natural killer cells from AA patients has implicated pathologic
considered with some skepticism because of biases of observation and expression of components of innate immunity, including Toll-like
reporting, and lack of direct evidence in most cases. receptors.

EPIDEMIOLOGY
ETIOLOGY AND PATHOGENESIS
Incidence, Geographic and Age Distribution
Hematopoiesis in Bone Marrow Failure
The International AA and Agranulocytosis Study (IAAAS) was
2
conducted in Europe and Israel from 1980–1984. This study Stem Cells
was performed prospectively and applied strict case definition to
pathologically confirmed cases. Using stringent criteria, the overall A consistent laboratory finding for patients with AA is a very low
annual incidence of AA was 2 cases per 1 million people. In Asia, number of hematopoietic progenitor cells. Deficient colony forma-
similar methodology was applied by Thai investigators to determine tion by BM cells of AA patients is observed, even in the presence
a higher annual incidence, 4.0 cases per 1 million people in Bangkok of high levels of hematopoietic growth factors. The total number of
and 5.6 cases per 1 million people in the northeastern province progenitors in a BM sample is reduced, and the number of colony
+
3
of Khonkaen. In general, from published, hospital-based series, progenitor cells assayed from a purified CD34 cell population is low.
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