APLASTIC ANEMIA

Background

Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral

pancytopenia and marrow hypoplasia, and mild macrocytosis is observed in association with
stress erythropoiesis and an elevated fetal hemoglobin levels. Paul Ehrlich introduced the
concept of aplastic anemia in 1888 when he studied 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.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System
Center. Also, see eMedicine's patient education article Anemia.

Pathophysiology

The theoretical basis for marrow failure includes primary defects in or damage to the stem
cell or the marrow microenvironment.1,2,3 The distinction between acquired and inherited
disease may present a clinical challenge, but more than 80% of cases are acquired. In
acquired aplastic anemia, clinical and laboratory observations suggest that this is an
autoimmune disease.

On morphologic evaluation, the bone marrow is devoid of hematopoietic elements, showing

largely fat cells. Flow cytometry shows that the CD34 cell population, which contains the
stem cells and the early committed progenitors, is substantially reduced. 2,4 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.

Little evidence points to a defective microenvironment as a cause of aplastic anemia. In

patients with severe aplastic anemia (SAA), stromal cells have normal function, including
growth factor production. Adequate stromal function is implicit in the success of bone
marrow transplantation (BMT) in aplastic anemia because the stromal elements are
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 in whom engrafting failed after BMT. 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.3,5,6,7,8
 
Immunity is genetically regulated (by immune response genes), and it is also influenced by
environment (eg, nutrition, aging, previous exposure).9,10 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, suggesting a role for antigen recognition, and its presence is predictive of a
better response to cyclosporine.

Suppression of hematopoiesis is likely mediated by an expanded population of the following

cytotoxic T lymphocytes (CTLs): CD8 and HLA-DR+, which are detectable in both 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 suppressing progenitor cell
growth. Polymorphisms in these cytokine genes, associated with an increased immune
response, are more prevalent in patients with aplastic anemia. These cytokines suppress
hematopoiesis by affecting the mitotic cycle and cell killing by inducing Fas-mediated
apoptosis. In addition, these cytokines induce nitric oxide synthase and nitric oxide
production by marrow cells, which contributes to immune-mediated cytotoxicity and the
elimination of hematopoietic cells.

Constitutive expression of Tbet, a transcriptional regulator that is critical to Th1 polarization,

occurs in a majority of aplastic anemia patients.5 Perforin is a cytolytic protein expressed
mainly in activated cytotoxic lymphocytes and natural-killer cells. Mutations in perforin gene
are responsible for some cases of familial hemophagocytosis11 ; 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 a majority of acquired aplastic anemia cases.

Frequency

United States

No accurate prospective data are available regarding the incidence of aplastic anemia in the
United States. Findings from several retrospective studies suggest that the incidence is 0.6-
6.1 cases per million population; this rate was largely based on data from retrospective
reviews of death registries.

International

The annual incidence of aplastic anemia in Europe, as detailed in large, formal epidemiologic
studies, is similar to that in the United States, with 2 cases per million population. 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, but it may be closer
to 6 cases per million population in the rural areas of Thailand and as high as 14 cases per
million population in Japan, based on prospective studies. 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
presently living in the United States.

Mortality/Morbidity

The major causes of morbidity and mortality from aplastic anemia include infection and
bleeding. Patients who undergo BMT have additional issues related to toxicity from the
conditioning regimen and graft versus host disease (GVHD).10,12,13,14,15,16 With
immunosuppression, aplastic anemia in approximately one third of patients does not
respond. For the responders, relapse and late-onset clonal disease, such as paroxysmal
nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and leukemia, are
risks.6,17,18,19,20

Race
No racial predisposition is reported in the United States. However, the prevalence is
increased in the Far East.

Sex

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.

Age

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.
 The incidence of aplastic anemia peaks in people aged 20-25 years, and a
subsequent peak is observed in people older than 60 years. The latter peak may be
due to the inclusion of MDSs, which are syndromes of stem-cell failure unrelated to
aplastic anemia. These syndromes must be considered in the differential diagnosis of
any marrow-failure syndrome.

Clinical

History

The clinical presentation of patients with aplastic anemia includes symptoms related to the
decrease in bone-marrow production of hematopoietic cells. The onset is insidious, and the
initial symptom is related to anemia or bleeding, although fever or infections are also often
noted at presentation.

 Anemia may manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot

swelling.
 Thrombocytopenia may result in mucosal and gingival bleeding or petechial rashes.
 Neutropenia may manifest as overt infections, recurrent infections, or mouth and
pharyngeal ulcerations.
 Although the search for an etiologic agent is often unproductive, an appropriately
detailed work history, with emphasis on solvent and radiation exposure should be
obtained, as should a family, environmental, travel, and infectious disease history.
 In the absence of obvious phenotypic features, the presentation of a patient with an
inherited marrow-failure syndrome is subtle, and a thorough family history may first
suggest the condition.
 With regard to environmental agents, the time course of aplastic anemia and
exposure to the offending agent varies greatly, and only rarely is an environmental
etiology identified.

Physical

Physical examination may show signs of anemia, such as pallor and tachycardia, and signs
of thrombocytopenia, such as petechiae, purpura, or ecchymoses. Overt signs of infection
are usually not apparent at diagnosis.
  A subset of patients with aplastic anemia present with jaundice and evidence of
clinical hepatitis.21,22
 Findings of adenopathy or organomegaly should suggest an alternative diagnosis
(eg, hepatosplenomegaly and supraclavicular adenopathy are observed more
frequently in cases of leukemia and lymphoma than in cases of aplastic anemia).
 In any case of aplastic anemia, look for physical stigmata of inherited marrow-failure
syndromes, such as skin pigmentation, short stature, microcephaly, hypogonadism,
mental retardation, and skeletal anomalies. The oral pharynx, hands, and nail beds
should be carefully examined for clues of dyskeratosis congenita. Oral leukoplakia is
shown in the image below.
o

Oral leukoplakia in dyskeratosis congenita.

Causes

 Congenital or inherited causes of aplastic anemia (20%)

o Patients usually have dysmorphic features or physical stigmata. On occasion,
marrow failure may be the initial presenting feature.
o Fanconi anemia
o Dyskeratosis congenita
o Cartilage-hair hypoplasia
o Pearson syndrome
o Amegakaryocytic thrombocytopenia (thrombocytopenia-absent radius [TAR]
syndrome)
o Shwachman-Diamond syndrome
o Dubowitz syndrome
o Diamond-Blackfan syndrome
o Familial aplastic anemia
 Acquired causes of aplastic anemia (80%)
o Idiopathic factors
o Infectious causes, such as hepatitis viruses, Epstein-Barr virus (EBV), human
immunodeficiency virus (HIV), parvovirus, and mycobacteria
o Toxic exposure to radiation and chemicals, such as benzene
o Drugs and elements, such as chloramphenicol, phenylbutazone, and 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.
o PNH is caused by an acquired genetic defect limited to the stem-cell
compartment affecting the PIGA gene. Mutations in the PIGA gene render
cells of hematopoietic origin sensitive to increased complement lysis.
Approximately 20% of patients with aplastic anemia have evidence of PNH at
presentation, as detected by means of flow cytometry. Furthermore, patients
whose disease responds after immunosuppressive therapy frequently recover
with clonal hematopiesis and PNH.
o Transfusional GVHD
o Orthotopic liver transplantation for fulminant hepatitis
o Pregnancy
o Eosinophilic fasciitis