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Aplastic Anemia:
Review of Etiology and Treatment
Nabiel AlKhouri, MD
Solveig G. Ericson, MD, PhD
plastic anemia is defined as the failure of United States. Anticonvulsant medications, in particular
Rheumatic diseases. Connective tissue disorders such Table 1. Etiologic Classification of Aplastic Anemia
as rheumatoid arthritis and systemic lupus erythematosus
have been associated with aplastic anemia. However, it Acquired aplastic anemia
is not certain whether the drugs used to treat these dis- Idiopathic
orders (NSAIDs, gold salts, allopurinol, D-penicillamine) Secondary
cause the anemia or whether the activated immune sys- Chemicals
tem, which is a feature of these diseases, is the responsi-
Benzene
ble factor.
Pregnancy. Many cases of aplastic anemia have also Insecticides
been found in association with pregnancy. However, Glue
because these cases showed variable clinical courses, Solvents
the relationship between pregnancy and aplastic ane- Drugs
mia is yet to be defined. Cytotoxic agents
PATHOPHYSIOLOGY Antibiotics
The pancytopenia in aplastic anemia reflects failure of Nonsteroidal anti-inflammatory drugs
the hematopoietic process manifested as a severe de- Anticonvulsive agents
crease in the numbers of all hematopoietic progenitor Gold salts
cells. Two mechanisms have been suggested for bone Radiation
marrow failure. The first mechanism is direct hematopoi- Viruses
etic injury by chemicals (eg, benzene), drugs, or radia-
Epstein-Barr virus
tion to both proliferating and quiescent hematopoietic
cells. The second mechanism, supported by clinical Non-A, non-B, non-C hepatitis viral agent (?)
observations and laboratory studies, is immune-mediated Human immunodeficiency virus
suppression of marrow cells;7 examples of this mecha- Immune and rheumatologic diseases
nism are bone marrow failure after graft-versus-host- Graft-versus-host disease
disease (GVHD), eosinophilic fasciitis, and hepatitis. The Rheumatoid arthritis
mechanism for idiopathic, pregnancy-associated, and
Systemic lupus erythematosus
some cases of drug-associated aplastic anemia is not clear
but may involve immunologic processes as well. Cytotoxic Paroxysmal nocturnal hemoglobinuria
T cells are thought to mediate the suppressive effect Pregnancy
on hematopoietic cells through the production of
Inherited aplastic anemia
hematopoiesis-inhibiting cytokines such as interferon-γ
and tumor necrosis factor-α.8 An immune-mediated sup- Fanconi’s anemia
pressive effect on hematopoiesis may explain why most Dyskeratosis congenita
patients with acquired aplastic anemia respond to treat- Schwachman syndrome
ment with immunosuppressive therapy.
At presentation, patients with aplastic anemia usually
do not have more than 10% of the normal number of
stem cells. However, laboratory studies show that stro- tation and suppression of a destructive immunologic
mal cells from patients with aplastic anemia can support process.
growth and development of normal hematopoietic
stem cells and can also produce normal or increased CLINICAL PRESENTATION
quantities of hematopoietic growth factors. Although The signs and symptoms of patients presenting with
the success of bone marrow transplantation depends aplastic anemia are typically related to the decrease or
on adequately functioning stromal elements, clinical absence of peripheral blood cellular components.9
and in vitro data do not support the use of hematopoi- The clinical presentation ranges from insidious to dra-
etic growth factors alone in the treatment of aplastic matic. Because platelets are depleted early in the
anemia. process of the disease, dependent petechiae, bruising,
The pathophysiology of aplastic anemia, therefore, gum bleeding, buccal hemorrhage, epistaxis, or retinal
suggests two major approaches for treatment: replace- hemorrhage may be among the first presentations.
ment of deficient stem cells by bone marrow transplan- Because of anemia, patients may complain of shortness
Table 2. Diagnostic Criteria for Severe Aplastic Anemia* acquired disorder that is characterized by anemia
caused by intravascular hemolysis and manifested by
At least two of the following: transient episodes of hemoglobinuria and life-threaten-
Absolute neutrophil count <0.5 x 109/L ing venous thromboses.12 A deficiency of CD59, an ery-
Platelet count < 20 x 109/L throcyte surface antigen that inhibits reactive lysis, is
Anemia with corrected reticulocyte count < 1 %
largely responsible for the hemolysis.13 Approximately
10% to 30% of patients with aplastic anemia develop
—AND—
PNH later in the clinical course.14 It is possible that
One of the following: the majority of patients with PNH have an underlying
Bone marrow cellularity < 25 % aplastic process.15 The diagnosis of PNH is currently
Bone marrow cellularity < 50 % with fewer than made by demonstrating decreased expression of the
30% hematopoietic cells cell surface antigen CD59 by flow cytometry, replacing
previously used screening tests such as the sucrose
*According to the International Aplastic Anemia Study Group
hemolysis test and examination of the urine for hemo-
Data from Camitta et al: A prospective study of androgens and bone siderin.16
marrow transplantation for treatment of severe aplastic anemia. Blood Myelodysplastic syndromes. The MDSs are a group
1979;53:504.
of clonal hematopoietic stem cell disorders that are
characterized by abnormal bone marrow differentia-
tion and maturation, which leads to bone marrow fail-
of breath, fatigue, or chest pain. Neutropenia or leuko- ure with peripheral cytopenias, dysfunctional blood
penia may result in fever, chills, or infections. Hepa- elements, and probability of leukemic conversion. The
tosplenomegaly, lymphadenopathy, or bone pain are bone marrow in MDS is typically hypercellular or nor-
less common in patients with aplastic anemia, but mocellular, although hypocellularity may also be de-
these findings should alert the physician to other diag- tected. It is important to distinguish hypocellular MDS
noses, such as infection, leukemia, or lymphoma. from aplastic anemia because the diagnosis dictates
clinical management and prognosis. A critical feature
DIAGNOSIS that identifies hypocellular MDS is an associated clonal
Differential Diagnosis cytogenetic abnormality (such as deletions in chromo-
Pancytopenia is a common feature of many illness- some arms 5q and 7q).17
es. Although the medical history, physical examination, Idiopathic myelofibrosis. The two major features of
and basic laboratory studies can often exclude aplastic idiopathic myelofibrosis are extramedullary hema-
anemia, the distinction is more difficult in certain topoiesis (in spleen, liver, and other organs) and bone
hematologic diseases, and further testing is required. marrow fibrosis. The extramedullary hematopoiesis
Causes of pancytopenia that need to be considered causes hepatosplenomegaly in the majority of patients.
in the differential diagnosis include Fanconi’s anemia, Bone marrow biopsy specimens show varying degrees
paroxysmal nocturnal hemoglobinuria (PNH), myelo- of reticulin or collagen fibrosis, with prominent mega-
dysplastic syndrome (MDS), myelofibrosis, aleukemic karyocytes.
leukemia, agranulocytosis, and pure red cell aplasia. Aleukemic leukemia. Aleukemic leukemia, a rare
Each of these conditions is briefly reviewed in the fol- condition characterized by the absence of blast cells in
lowing discussion. the peripheral blood of patients with leukemia, occurs
Fanconi’s anemia. This congenital form of aplastic in fewer than 10% of all leukemic patients and is gen-
anemia is an autosomal recessive inherited condition in erally seen in very young children or in elderly pa-
which 10% of patients present beyond childhood.10,11 tients. Bone marrow aspirate and biopsy demonstrate
Typical physical stigmata include short stature, skin the blast cells.
hyperpigmentation, microcephaly, thumb or radius Pure red cell aplasia. This rare disorder that in-
hypoplasia, urogenital abnormalities, and mental retar- volves only erythrocyte production is characterized by
dation. Fanconi’s anemia is confirmed by cytogenetic severe anemia, a reticulocyte count of less than 1%,
analysis of peripheral blood lymphocytes, which show and a normocellular bone marrow containing less than
chromosome breaks after culture with substances that 0.5 % mature erythroblasts.
promote chromosome stress (eg, diepoxybutane or mi- Agranulocytosis. Agranulocytosis is an immune dis-
tomycin C). order that affects the production of blood granulocytes
Paroxysmal nocturnal hemoglobinuria. PNH is an but not that of platelets or erythrocytes.
A B
Figure 1. Bone marrow biopsy specimens from A) a healthy patient and B) a patient with aplastic anemia.
Diagnostic Evaluation tient are, in general, the two major considerations that
The hallmark of aplastic anemia is pancytopenia and guide treatment.18 As an initial treatment strategy, all un-
a hypocellular bone marrow.2 A complete blood count is necessary medications that could be suppressing bone
the initial diagnostic study, and this study reveals varying marrow function should be discontinued. Occasionally,
degrees of anemia, thrombocytopenia, and leukopenia. patients with mild to moderate aplastic anemia respond
Because of the hypoproliferative marrow, the reticulo- to treatment with androgens, which act by stimulating
cyte response is low or absent despite the anemia. erythropoiesis.19
Aplastic anemia is classified as mild, moderate, or Some patients with aplastic anemia may have de-
severe on the basis of the severity of the pancytopenia. creased production of cytokines that are required in he-
Criteria for classifying aplastic anemia as severe are listed matopoiesis. Administration of hematopoietic growth
in Table 2. The most important prognostic factor is the factors (such as granulocyte colony-stimulating factor
absolute neutrophil count (ANC). Patients with an ANC and granulocyte-macrophage colony-stimulating factor)
less than 0.5 x 109/L have a high risk of developing as the sole treatment for aplastic anemia, however, has
infection and patients with an ANC less than 0.2 x 109/L not been very successful.18 Growth factor administration
have a poor prognosis. as an adjunct to immunosuppressive treatment or after
Bone marrow aspiration and biopsy must be per- bone marrow transplantation has been useful in de-
formed to rule out other possible causes for pancytope- creasing periods of absolute neutropenia.
nia, such as MDS or leukemia. In normal bone mar- While diagnostic testing for aplastic anemia is being
row, 40% to 60% of the marrow space is typically undertaken and treatment options are being contem-
occupied with hematopoietic cells (depending on the plated, patients may require transfusions of blood
age of the person) (Figure 1A); by contrast, the bone products. It is important that patients, particularly po-
marrow in patients with aplastic anemia typically con- tential candidates for bone marrow transplantation,
tains very few hematopoietic cells and consists primari- receive as few blood products as possible in order to
ly of fatty space and stromal cells (Figure 1B). decrease the risk of sensitization. Also, blood donations
Human leukocyte antigen (HLA) typing should be from a family member should be avoided during this
performed on all patients as soon as the diagnosis of time period. Younger patients may tolerate hemoglo-
aplastic anemia is entertained. Tests for exposure to bin levels of 7 to 8 g/dL; older patients or patients with
viruses, especially cytomegalovirus, should also be per- a history of coronary artery disease may require hemo-
formed early because these tests assist in the choice of globin levels to be maintained at more than 8 g/dL.
blood products for transfusion. Platelet transfusions should be given when the patient
Table 3 lists the relevant diagnostic studies that must has an active bleeding episode or when the platelet
be undertaken in patients with aplastic anemia. count is severely depressed (less than 10 x 109/L).
Blood transfusion guidelines for patients with aplastic
TREATMENT anemia are presented in Table 4.
Treatment Considerations and Supportive Care Precautions for neutropenia should be followed in
The severity of aplastic anemia and the age of the pa- patients with aplastic anemia. These patients should
Table 3. Diagnostic Studies and Additional Laboratory Table 4. Blood Transfusion Guidelines for Patients with
Tests for Aplastic Anemia Aplastic Anemia
Yes No
result from a search for an unrelated donor because ministration of ATG and cyclosporine has resulted in
this process typically takes approximately 6 months. hematologic recovery in 70% to 80% of patients.22,23 In a
series of 51 patients, 67% of patients showed a response
Immunosuppressive Therapy to treatment within 3 months, and this number in-
The risk of morbidity and mortality after BMT in- creased to 78% by 1 year.22 A patient was considered a
creases with age. Hence, immunosuppressive treatment responder if the patient’s peripheral blood count no
is considered first-line treatment for older patients and longer met the criteria for severe disease. In a series of
for younger patients for whom a matched sibling donor 227 patients with severe aplastic anemia who were treat-
is not available. ed with immunosuppressive therapy at a single center
Immunosuppressive therapy, which typically consists over a period of 23 years (1978 to 1991), 78 patients
of ATG, cyclosporine, and corticosteroids, is aimed at (34%) achieved a complete or partial response, 23 pa-
suppressing T-cell subsets that might exert a suppres- tients (10%) had a minimal response, 122 patients
sive effect on bone marrow function. ATG, which is (54%) did not respond, and four patients (2%) were
prepared from horse serum, can lead to allergic reac- not evaluable. Of the 122 nonresponders, 29 died within
tions or serum sickness, with patients developing fever, 3 months of the start of treatment.24
arthralgia, and skin rash.22 Steroid treatment can
reduce or eliminate many of these symptoms. Cyclo- PROGNOSIS
sporine inhibits interleukin-2 (IL-2) production by Before the advent of BMT and intensive immuno-
T cells and also inhibits proliferation of T cells in suppressive therapy, the prognosis for patients with
response to IL-2.19 Patients treated with cyclosporine severe aplastic anemia was dismal—more than 25% of
require close monitoring because the drug may cause patients died within 4 months of diagnosis and 50%
renal dysfunction or hypertension and also leads to died within 1 year.19 In previously untransfused patients,
interactions with other drugs. BMT has a cure rate of 75% to 85%; in patients who
Intense immunosuppression with simultaneous ad- receive multiple transfusions before BMT, the cure
rates are 55% to 65%.19 However, 20% to 30% of all exposures to clinical features and outcome. Eur J
patients undergoing BMT may suffer from severe Haematol Suppl 1996;60:47–52.
10. Liu JM, Buchwald M, Walsh CE, Young NS: Fanconi ane-
GVHD. Approximately 15% of patients suffer a relapse
mia and novel strategies for therapy. Blood 1994;
of aplastic anemia. Older immunosuppressive regimens 84:3995–4007.
led to a significant improvement in blood counts in 11. Auerbach AD, Rogatko A, Traute M, Schroeder-Kurth
50% of patients,19 but with the recent intensive regi- TM: International Fanconi Anemia Registry: relation of
mens, response rates as high as 78% by 1 year have clinical symptoms to diepoxybutane sensitivity. Blood
been reported.22 Although 36% of the patients res- 1989;73:391–396.
ponding to intense immunosuppressive treatment had 12. Rotoli B, Luzatto L: Paroxysmal nocturnal hemoglobin-
a risk of relapse at 2 years, most of these patients res- uria. Baillieres Clin Haematol 1989;2:113–138.
ponded to additional courses of immunosuppression.22 13. Yamashina M, Ueda E, Kinoshita T, et al: Inherited com-
As many as 40% of patients who initially respond to plete deficiency of 20-kilodalton homologous restriction
factor (CD59) as a cause of paroxysmal nocturnal hemo-
immunosuppressive agents progress over a 10-year peri-
globinuria. N Engl J Med 1990;323:1184–1189.
od to PNH, acute myeloid leukemia, or MDS because 14. Tichelli A, Gratwohl A, Wursch A, et al: Late haemato-
of the underlying stem cell disorder.19 logical complications in severe aplastic anemia. Br J
Haematol 1988;69:413–418.
SUMMARY 15. Hillmen P, Lewis SM, Bessler M, et al: Natural history of
Severe aplastic anemia is a rare disease, but this dis- paroxysmal nocturnal hemoglobinuria. N Engl J Med
ease must be included in the differential diagnosis of pa- 1995;333:1253–1258.
tients presenting with pancytopenia. With prompt diag- 16. Hartmann RC, Jenkins DEJ: The "sugar-water" test for
nostic evaluation and appropriate initial supportive care, paroxysmal nocturnal hemoglobinuria. N Engl J Med
the majority of patients respond to aggressive treatment 1965;275:155–157.
17. Kampmeier P, Anastasi J, Vardiman JW: Issues in the
with immunosuppressive agents or to BMT. HP
pathology of the myelodysplastic syndromes. Hematol
Oncol Clin North Am 1992;6:501–522.
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