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com/article/198759-overview
Aplastic Anemia
Updated: Mar 09, 2017
Author: Sameer Bakhshi, MD; Chief Editor: Emmanuel C Besa, MD more...
OVERVIEW
Practice Essentials
Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral
pancytopenia and marrow hypoplasia. Although the anemia is often normocytic, mild
macrocytosis can also be observed in association with stress erythropoiesis and elevated fetal
hemoglobin levels.
The clinical presentation of patients with aplastic anemia includes symptoms related to the
decrease in bone marrow production of hematopoietic cells (see the image below). The onset is
insidious, and the initial symptom is frequently related to anemia or bleeding, although fever or
infections may be noted at presentation.
Low power, H and E showing a hypocellular bone marrow with increased adipose tissue and decreased
hematopoietic cells in the marrow space.
View Media Gallery
Pallor
Headache
Palpitations, dyspnea
Fatigue
Foot swelling
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A subset of patients with aplastic anemia present with jaundice and evidence of clinical
hepatitis. [1, 2]
Diagnosis
Testing
Procedures
Bone marrow biopsy is performed in addition to aspiration to assess cellularity qualitatively and
quantitatively. Bone marrow culture may be useful in diagnosing mycobacterial and viral
infections; however, the yield is generally low.
Management
Severe or very severe aplastic anemia is a hematologic emergency, and care should be
instituted promptly. Clinicians must stress the need for patient compliance with therapy. The
specific medications administered depend on the choice of therapy and whether it is supportive
care only, immunosuppressive therapy, or hematopoietic cell transplantation. [3]
Pharmacotherapy
Nonpharmacotherapy
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Supportive care
Blood transfusions with blood products that have undergone leukocyte reduction and
irradiation
Hematopoietic cell transplantation
Surgical option
Central venous catheter placement is required before the administration of hematopoietic cell
transplantation.
Background
Paul Ehrlich introduced the concept of aplastic anemia in 1888 when he reported the case of a
pregnant woman who died of bone marrow failure. However, it was not until 1904 that Anatole
Chauffard named this disorder aplastic anemia. (See Etiology.)
The British Society for Standards in Haematology has issued guidelines on diagnosis and
management of aplastic anemia in adults. [5] The Pediatric Haemato-Oncology Italian
Association has issued guidelines on diagnosis and management of acquired aplastic anemia
in childhood. [6]
Anemia
Chronic Anemia
Megaloblastic Anemia
Myelophthisic Anemia
Hemolytic Anemia
Sideroblastic Anemias
Etiology
The theoretical basis for marrow failure includes primary defects in or damage to the stem cell
or the marrow microenvironment. [7, 8, 9] The distinction between acquired and inherited disease
may present a clinical challenge, but more than 80% of cases are acquired. Clinical and
laboratory observations suggest that acquired aplastic anemia is an autoimmune disease.
On morphologic evaluation, the hematopoietic elements in the bone marrow are less than 25%,
and they are largely replaced with fat cells. Flow cytometry shows that the CD34 cell
population, which contains the stem cells and the early committed progenitors, is substantially
reduced. [8, 10] Data from in vitro colony-culture assays suggest profound functional loss of the
hematopoietic progenitors, so much so that they are unresponsive even to high levels of
hematopoietic growth factors.
Previously, it had been hypothesized that aplastic anemia may be due to a defect at various
levels, such as an intrinsic defect of hematopoietic cells; external injury to hematopoietic cells;
and defective stroma, which is critical for normal proliferation and functioning of hematopoietic
cells. Theoretically, all of these mechanisms could be responsible for aplastic anemia. This
theory was the basis of many in vitro stem cell culture experiments using a crossover design in
which stem cells from patients with aplastic anemia were cultured with normal stroma and vice
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versa. The conclusions from these studies led to the understanding that stem cell defect is the
central mechanism in the majority of patients with aplastic anemia. [11, 12]
In patients with severe aplastic anemia, stromal cells have normal function, including growth
factor production. Adequate stromal function is implicit in the success of hematopoietic cell
transplantation (HCT) in aplastic anemia, because the stromal elements are almost entirely
(frequently) of host origin.
The role of an immune dysfunction was suggested in 1970, when autologous recovery was
documented in a patient with aplastic anemia who failed to engraft after HCT. Mathe proposed
that the immunosuppressive regimen used for conditioning promoted the return of normal
marrow function. Since then, numerous studies have shown that, in approximately 70% of
patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function.
[9, 13, 14, 15, 16]
Immunity is genetically regulated (by immune response genes), and it is also influenced by
environment (eg, nutrition, aging, previous exposure). [17, 18] Although the inciting antigens that
breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte
antigen (HLA)-DR2 is overrepresented among European and United States patients with
aplastic anemia, and its presence is predictive of a better response to cyclosporine.
In addition, such cytokines induce nitric oxide synthase and nitric oxide production by marrow
cells, which contributes to immune-mediated cytotoxicity and the elimination of hematopoietic
cells. Hirano et al reported that CD8+ cytotoxic T cells raised against kinectin-derived peptides
suppress colony forming units (CFUs) in an HLA class Irestricted fashion, findings that
suggest kinectin may be a candidate autoantigen in the pathophysiology of aplastic anemia. [19]
Constitutive expression of Tbet, a transcriptional regulator that is critical to type 1 T helper cell
(Th1) polarization, occurs in a majority of aplastic anemia patients. [13] Perforin is a cytolytic
protein expressed mainly in activated cytotoxic lymphocytes and natural-killer cells. Mutations
in the perforin gene are responsible for some cases of familial hemophagocytosis [20] ;
mutations in SAP, a gene encoding for a small modulator protein that inhibits undefined-
interferon production, underlie X-linked lymphoproliferation, a fatal illness associated with an
aberrant immune response to herpesviruses and aplastic anemia. Perforin and SAP protein
levels are markedly diminished in some cases of acquired aplastic anemia.
The transcription factors FOXP3 and NFAT1 have key roles in regulatory T-cell (Treg)
development and function, and Tregs play a role in autoimmunity. Tregs are decreased at
presentation in almost all patients with aplastic anemia; FOXP3 protein and mRNA levels also
are significantly lower in patients with this condition, whereas NFAT1 protein levels are
decreased or absent. [21]
Variations in telomere length have been reported in severe aplastic anemia, but their clinical
significance is unknown. However, although telomere length was unrelated to response, it was
associated with the risk of relapse, clonal evolution, and overall survival in patients with severe
aplastic anemia. [22]
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Congenital or inherited causes of aplastic anemia are responsible for at least 25% of children
with this condition and for perhaps up to 10% of adults. [23] Patients may have dysmorphic
features or physical stigmata, but marrow failure may be the initial presenting feature. Several
loci have been identified that are associated not only with increased susceptibility to aplastic
anemia but also with other physical findings.
Fanconi anemia
Dyskeratosis congenita
Dyskeratosis congenita is characterized by the diagnostic physical triad of dysplastic nails, lacy
reticular pigmentation of the upper torso, and oral leukoplakia. However, over the past decade,
it has been increasingly recognized that patients may have dyskeratosis congenita without the
triad. The following are also features of this condition:
This is an isolated aplastic anemia. Mutations have been found in the TERC and TERT genes
and are thought to confer a susceptibility to aplastic anemia. These genes encode proteins that
are part of the telomerase apparatus that restores repeated regions in the telomere. [24]
Cartilage-hair hypoplasia
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Pearson syndrome
Pearson syndrome causes sideroblastic anemia and exocrine pancreatic dysfunction. This
condition results from mitochondrial deoxyribonucleic acid (DNA) deletions.
Shwachman-Diamond syndrome
Dubowitz syndrome
Diamond-Blackfan anemia
Acquired causes
Idiopathic factors
Infectious causes, such as hepatitis viruses, Epstein-Barr virus (EBV), human
immunodeficiency virus (HIV), parvovirus, and mycobacteria
Exposure to ionizing radiation
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Drugs and elements (eg, chloramphenicol, phenylbutazone, gold) may cause aplasia of the
marrow. The immune mechanism does not account for the marrow failure in idiosyncratic drug
reactions. In such cases, direct toxicity may occur, perhaps due to genetically determined
differences in metabolic detoxification pathways. For example, the null phenotype of certain
glutathione transferases is overrepresented among patients with aplastic anemia.
PNH is caused by an acquired genetic defect affecting the PIGA gene and limited to the stem
cell compartment. Mutations in the PIGA gene render cells of hematopoietic origin sensitive to
increased complement lysis. Approximately one third of patients with aplastic anemia have
evidence of PNH at presentation, as detected by means of flow cytometry. [28] Furthermore,
patients whose disease responds after immunosuppressive therapy may recover with clonal
hematopoiesis and PNH.
Epidemiology
United States statistics
No accurate prospective data are available regarding the incidence of aplastic anemia in the
United States. Findings from several retrospective studies usually overlap those from Europe
and suggest that the incidence is 0.6-6.1 cases per million population; this rate is largely based
on data from retrospective reviews of death registries.
International statistics
The annual incidence of aplastic anemia in Europe, as detailed in large, formal epidemiologic
studies, is 2 cases per million population. [29] Aplastic anemia is thought to be more common in
Asia than in the West. The incidence was accurately determined to be 4 cases per million
population in Bangkok, [30] but based on prospective studies, it may actually be closer to 6
cases per million population in the rural areas of Thailand. This increased incidence may be
related to environmental factors, such as increased exposure to toxic chemicals, rather than to
genetic factors, because this increase is not observed in people of Asian ancestry who are
living in the United States.
Although no racial predisposition for aplastic anemia is reported in the United States, the
prevalence is increased in the Far East. The male-to-female ratio for acquired aplastic anemia
is approximately 1:1, although there are data to suggest that a male preponderance may be
observed in the Far East.
Although aplastic anemia occurs in all age groups, a small peak in the incidence is observed in
childhood because of the inclusion of inherited marrow-failure syndromes. A second peak is
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Prognosis
The outcome of patients with aplastic anemia has substantially improved because of improved
supportive care. The natural history of aplastic anemia suggests that a small number of
patients may spontaneously recover with supportive care [31] ; however, observational and/or
supportive care therapy alone is rarely indicated.
The estimated 10-year survival rate for the typical patient receiving immunosuppression is 68%,
compared with 73% for hematopoietic cell transplantation (HCT). [32] However, there is a
significantly improved outcome for HCT over time, for matched sibling and alternative donors,
and with younger age. [32] In cases of immunosuppression, relapse and late clonal disease are
risks.
Mortality/morbidity
The major causes of morbidity and mortality from aplastic anemia include infection and
bleeding. Patients who undergo HCT have additional issues related to acute and chronic
toxicity from the conditioning regimen and graft versus host disease (GVHD), as well as a
potential for graft failure. [18, 33, 34, 35, 36, 37] In approximately 25-30% of patients with aplastic
anemia, the condition does not respond to immunosuppression. In cases with a treatment
response, relapse and late-onset clonal disease, such as paroxysmal nocturnal hemoglobinuria
(PNH), myelodysplastic syndrome (MDS), and leukemia, are risksregardless of the treatment
response or degree of response. [14, 38, 39, 40, 41]
Kulasekararaj and colleagues reported that the presence of somatic mutations (including
ASXL1, DNMT3A, and BCOR) in patients with aplastic anemia for more than 6 months was
associated with 40% risk of transformation to MDS. Nearly a fifth of patients with aplastic
anemia have mutations in genes typically seen in myeloid malignancies that predicted for later
transformation to MDS. [42]
In a Japanese study of 427 patients (16-72 years old) with aplastic anemia who underwent
unrelated-donor bone marrow transplantation, outcome was significantly inferior in patients
whose donors were 40 years of age or older than in those with younger donors. In the older
donor group, overall survival was significantly inferior (adjusted hazard ratio, 1.64), the
incidence of fatal infection was significantly higher (13.7% vs. 7.5%), and primary engraftment
failure and acute GVHD occurred significantly more often (9.7% vs. 5.0% and 27.1% vs. 19.7%,
respectively). [43]
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Clinical Presentation
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Acknowledgements
Roy Baynes, MB, BCh, PhD, FACP Charles Martin Professor of Cancer Research,
Department of Internal Medicine, Division of Hematology and Oncology, Karmanos Cancer
Institute, Wayne State University
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