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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.

Signs and symptoms

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

Signs and symptoms of aplastic anemia may include the following:

Pallor
Headache
Palpitations, dyspnea
Fatigue
Foot swelling

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Gingival bleeding, petechial rashes


Overt and/or recurrent infections
Oropharyngeal ulcerations

A subset of patients with aplastic anemia present with jaundice and evidence of clinical
hepatitis. [1, 2]

See Clinical Presentation for more detail.

Diagnosis

Testing

Laboratory testing for suspected aplastic anemia includes the following:

Complete blood count


Peripheral blood smears
Hemoglobin electrophoresis and blood-group testing
Biochemical profile
Serology for hepatitis and other viral entities
Autoimmune-disease evaluation for evidence of collagen-vascular disease
Fluorescence-activated cell sorter profiling
Fluorescent-labeled inactive toxin aerolysin testing
Diepoxybutane incubation
Histocompatibility testing
Kidney function studies
Liver function studies
Transaminase, bilirubin, and lactate dehydrogenase levels

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.

See Workup for more detail.

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

The following medications are used in patients with aplastic anemia:

Immunosuppressive agents (eg, cyclosporine, methylprednisolone, equine antithymocyte


globulin, rabbit antithymocyte globulin, cyclophosphamide, alemtuzumab)
Hematopoietic growth factors (eg, eltrombopag [4] , sargramostim, filgrastim)
Antimetabolite (purine) antineoplastic agents (eg, fludarabine)
Chelating agents (eg, deferoxamine, deferasirox)

Nonpharmacotherapy

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Nonpharmacologic management of aplastic anemia includes the following:

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.

See Treatment and Medication for more detail.

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]

For more information, see the following Medscape articles:

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.

Suppression of hematopoiesis is likely mediated by an expanded population of CD8+


HLA-DR+, cytotoxic T lymphocytes (CTLs) that are frequently detectable in the blood and bone
marrow of patients with aplastic anemia. These cells produce inhibitory cytokines, such as
gamma-interferon and tumor necrosis factor, which can suppress progenitor cell growth.
Polymorphisms associated with an increased immune response are more prevalent in these
cytokine genes in patients with aplastic anemia. These cytokines suppress hematopoiesis by
affecting the mitotic cycle and cell killing by inducing Fas-mediated apoptosis.

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

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

Fanconi anemia is characterized by the following:

Multiple congenital anomalies (60-75%): Short stature, abnormal skin pigmentation,


malformations of the thumbs with or without dysplastic or absent radii, as well as
microphthalmos and malformations of the heart, kidneys, intestines, and ears
Bone marrow failure: Thrombocytopenia, leukopenia, or aplastic anemia; most patients
with Fanconi anemia have bone marrow failure by adulthood
Cancer: Hematologic malignancies are common with Fanconi anemia and
myelodysplasia, with acute myeloid leukemia (AML) being the most common; solid tumors
such as those in squamous cell head and neck cancer, female genital tumors, and liver
tumors are also seen; Fanconi anemia is associated with increased chromosomal
breakage and abnormal sister chromatid exchange in the presence of agents such as
diepoxybutane or mitomycin C
Predominantly autosomal recessive inheritance pattern: Fifteen genes are now known to
be causative for Fanconi anemia; only 1 of these FANCB (X-lined recessive)is not
inherited in an autosomal recessive manner
Association between bone marrow progression and a complex pattern of recurrent
chromosomal abnormalities: Some chromosomal abnormalities are commonly found in
non-Fanconi anemia myelodysplastic syndrome (MDS) and secondary acute myeloid
leukemia (eg, -7/7q or RUNX1 abnormalities), whereas others are specific for Fanconi
anemia (eg, 1q+ and 3q+)

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:

Some signs of premature aging, such as early graying of the hair


Progressive bone marrow failure at any age, which can cause any combination of
cytopenias, including aplastic anemia
Malignancy: Common; frequently MDS or AML; solid tumors such as head and neck
cancer or genital cancers can also be seen
Pulmonary fibrosis
Autosomal dominant, autosomal recessive, and X-linked inheritance patterns; 6 genes are
known to cause this disorder

Familial aplastic anemia

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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Cartilage-hair hypoplasia, which is caused by mutations in the RMRP gene, is inherited in an


autosomal recessive manner. This condition is characterized by the following:

Short stature with short and bowed limbs


Sparse, lightly pigmented hair
Variably severe immune deficiency
Anemia during childhood
Hematopoietic malignancies, as well as malignancies of the skin, eyes, and liver
Gastrointestinal malformations and malabsorption

Pearson syndrome

Pearson syndrome causes sideroblastic anemia and exocrine pancreatic dysfunction. This
condition results from mitochondrial deoxyribonucleic acid (DNA) deletions.

Thrombocytopenia-absent radius syndrome

Thrombocytopenia-absent radius (TAR) syndrome is characterized by deletions located at


chromosome 1q21.1 (which are typically about 200kb in size). Patients have bilateral absence
of the radii with presence of the thumbs, as well as thrombocytopenia. Other congenital
anomalies can also occur (eg, cardiac disease, skeletal anomalies, urogenital anomalies).

Shwachman-Diamond syndrome

Shwachman-Diamond syndrome is caused by mutations in the SBDS gene and is inherited in


an autosomal recessive manner. This disease is characterized by dysfunction of the exocrine
pancreas with malabsorption and growth failure, as well as cytopenias of single or multiple
lineage. Patients with Shwachman-Diamond syndrome also have an increased risk of MDS and
AML. [25]

Dubowitz syndrome

Dubowitz syndrome is caused by an as-yet unknown gene. This condition is characterized by


intrauterine growth retardation, extremely short stature, and wizened facial appearance.
Patients also have microcephaly and mild developmental delay. Dubowitz syndrome is also
associated with eczema, immune deficiency, and aplastic anemia. Malignancy is more common
with this disorder, particularly lymphoma and neuroblastoma.

Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is characterized by a normochromic macrocytic anemia that


can be isolated, or it can be associated with growth retardation or congenital malformation in
the upper limbs, heart, and genitourinary systems. In a small minority of patients, DBA can
progress to aplastic anemia. Nine genes have been found to be causative for DBA, and they
are inherited in an autosomal dominant manner. [26] Approximately 50% of cases are inherited
from a parent, and about 50% result from de novo mutations.

Acquired causes

Acquired causes of aplastic anemia (80%) include the following:

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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Exposure to toxic chemicals, such as benzene or pesticides [27]


Transfusional graft versus host disease (GVHD)
Orthotopic liver transplantation for fulminant hepatitis
Pregnancy
Eosinophilic fasciitis
Anorexia
Severe nutritional deficiencies (B12, folate)
Paroxysmal nocturnal hemoglobinuria (PNH)
MDS
Acute lymphoblastic leukemia (ALL)(rarely)

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.

Race-, sex-, and age-related demographics

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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observed in people aged 20-25 years.

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.

In a single-institution analysis of 183 patients who received immunosuppressive treatments for


severe aplastic anemia, the telomere length of peripheral blood leukocytes was unrelated to
treatment response. [22] In a multivariate analysis, however, telomere length was associated
with risk of relapse, clonal evolution, and overall survival. [22] Additional studies are needed to
validate these findings and to determine how this information might be incorporated into
treatment algorithms.

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]

An Australian population-based cohort study of adults receiving allogeneic HCT reported an


elevated secondary cancer risk in several patient groups, including those transplanted for
severe aplastic anemia. Overall, in patients alive 2 years after transplantation (n=1463), the
cumulative incidence of late mortality was 22.2% at 10 years and the risk of death relative to the
matched general population was 13.8. [44]

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Clinical Presentation

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Oral leukoplakia in dyskeratosis congenita.


Low power, H and E showing a hypocellular bone marrow with increased adipose tissue
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Contributor Information and Disclosures

Author

Sameer Bakhshi, MD Additional Professor of Pediatric Oncology, Department of Medical


Oncology, Dr BRA Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, India

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic


Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson
Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association


for Cancer Education, American Society of Clinical Oncology, American College of Clinical
Pharmacology, American Federation for Medical Research, American Society of Hematology,

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New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Esteban Abella, MD Consulting Staff, Arizona Pediatric Hematology/Oncology, PLLC

Disclosure: Nothing to disclose.

David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department


of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology,
Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG

David Aboulafia, MD is a member of the following medical societies: American College of


Physicians, American Medical Association, American Medical Directors Association, American
Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska


Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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