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Aplastic anemiais a syndrome ofbone marrow failurecharacterized 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 thatAnatole
Chauardnamed this disorder aplastic anemia.
For excellent patient education resources, visiteMedicinesBlood and Lymphatic System Center. Also, see
eMedicines patient education articleAnemia.
Pathophysiology
The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or the marrow
microenvironment.1,2,3The 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.2,4Data from in vitro colonyculture 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 ofbone 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 therapyimproves marrow function.3,5,6,7,8Immunity is
genetically regulated (by immune response genes), and it is also inuenced by environment (eg, nutrition,
aging, previous exposure).9,10Although the inciting antigens that breach immune tolerance with subsequent
autoimmunity are unknown, human leukocyte antigen (HLA)DR2 is overrepresented among European
andUnited Statespatients 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 andHLADR+, which are
detectable in both the blood and bone marrow of patients
with aplastic anemia. These cells produce inhibitory
cytokines, such as gammainterferon and tumor necrosis
factor, which can suppress 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 aecting the mitotic cycle and cell
killing by inducing Fasmediated apoptosis. In addition,
these cytokines induce nitric oxide synthase and nitric
oxide production by marrow cells, which contributes to immunemediated 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.5Perforin is a cytolytic protein expressed mainly in activated cytotoxic
lymphocytes and naturalkiller cells. Mutations in perforin gene are responsible for some cases offamilial
hemophagocytosis11; mutations inSAP, a gene encoding for a small modulator protein that inhibits
undenedinterferon production, underlie Xlinked 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 0.66.1 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 itmay 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 andgraft versus
host disease (GVHD).10,12,13,14,15,16With immunosuppression, aplastic anemia in approximately one third
of patients does not respond. For the responders, relapse and lateonset clonal disease, such asparoxysmal
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 maletofemale 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 marrowfailure
syndromes.
The incidence of aplastic anemia peaks in people aged
2025 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
stemcell failure unrelated to aplastic anemia. These
syndromes must be considered in the dierential
diagnosis of any marrowfailure 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
toanemiaor 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.
Neutropeniamay 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 marrowfailure
syndrome is subtle, and a thorough family history may rst suggest the condition.
With regard to environmental agents, the time course of aplastic anemia and exposure to the oending agent
varies greatly, and only rarely is an environmental etiology identied.
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 clinicalhepatitis.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 marrowfailure 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 ofdyskeratosis congenita. Oral
leukoplakia is shown in the image below.
Fanconi anemia
Dyskeratosis congenita
Cartilagehair hypoplasia
Pearson syndrome
Amegakaryocytic thrombocytopenia (thrombocytopeniaabsent radius [TAR]syndrome)
ShwachmanDiamond syndrome
Dubowitz syndrome
DiamondBlackfan syndrome
Familial aplastic anemia
Acquired causes of aplastic anemia (80%):
Idiopathic factors
Infectious causes, such as hepatitis viruses,EpsteinBarr virus (EBV), human immunodeciency virus
(HIV),parvovirus, and mycobacteria
Toxic exposure to radiation and chemicals, such as benzene
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 dierences in
metabolic detoxication 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 limited to the stemcell compartment aecting
thePIGAgene. Mutations in thePIGAgene 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 ow cytometry. Furthermore, patients whose disease responds
after immunosuppressive therapy frequently recover with clonal hematopiesis and PNH.
Transfusional GVHD
Orthotopic liver transplantation for fulminant hepatitis
Pregnancy
Eosinophilic fasciitis
Dierential Diagnoses
Acute Lymphoblastic Leukemia Myelodysplastic Syndrome
Acute Myelogenous Leukemia Myelophthisic Anemia
Agnogenic Myeloid Metaplasia With Myelobrosis Osteopetrosis
Human Herpesvirus Type 6 Systemic Lupus Erythematosus
Lymphoma, NonHodgkin
Megaloblastic Anemia
Multiple Myeloma
Imaging Studies
Radiologic studies are generally not needed to establish a diagnosis of aplastic anemia.
A skeletal survey is especially useful for the inherited marrowfailure syndromes, many of which cause
skeletal abnormalities.
Procedures
Procedures include review of peripheral smears andbone marrow aspiration and biopsy, as described below.
hematopoietic precursors and progeny. Islands of immature cells or abnormal localization of immature
progenitors (ALIP) indicate MDS. These patients may have megakaryocytic abnormalities
(micromegakaryocytes, megakaryocytes with dyskaryorrhexis), >5% ring sideroblasts (observed only on iron
stains), and granulocytic abnormalities (pseudo PelgerHut cells, hypogranulation, excess of blasts) On
occasion, marrow brosis may be observed.
Leukemia and metastatic cancers may be diagnosed with bone marrow examination.
Chromosomal rearrangements are considered diagnostic of MDS, with trisomies of 8 and 21 and deletions of
5, 7, and 20 being the most common. However, the conventional karyotype technique reveals abnormalities
in only about 50% of patients with MDS. In hypoplastic marrows, obtaining sucient sample for karyotyping
is often dicult.
The issue of malignant versus nonmalignant clonality in aplastic anemia can sometimes be resolved by using
uorescent in situ hybridization (FISH) to visualize chromosomal abnormalities in interphase cells.
Bone marrow culture is useful in diagnosing mycobacterial and viral infections. However, the yield is generally
low.
Histologic Findings
Histologic ndings of aplastic anemia include hypocellular bone marrow with fatty replacement and relatively
increased nonhematopoietic elements, such as plasma cells and mast cells. Perform careful examination to
exclude metastatic tumor foci on biopsy.
Staging
Staging of aplastic anemia is based on the criteria of the International Aplastic Anemia Study Group, as
follows :
Blood
Neutrophils Less than 0.5 X 109/L
Platelets Less than 20 X 109/L
Reticulocytes Less than 1% corrected (percentage of actual hematocrit [Hct] to normal Hct)
Marrow
Severe hypocellularity
Moderate hypocellularity, with hematopoietic cells representing less than 30% of residual cells
Severe aplasia is dened as including any 2 or 3 peripheral blood criteria and either marrow criterion.
A further subclassication developed after the recognition that individuals with neutrophil counts lower
than 0.2 X 109/L had very SAA (VSAA). This group is less likely than others to respond to
immunosuppressive therapy.
Treatment of infections
Infections are a major cause of mortality.
Risk factors include prolonged neutropenia and the indwelling catheters used for specic therapy. Fungal
infections, especially those due toAspergillusspecies pose a major risk.
Empirical antibiotic therapy should be broad based, with gramnegative and staphylococcal coverage based
on local microbial sensitivities. Especially consider including antipseudomonal coverage at the start of
treatment for patients with febrile neutropenia, and consider early introduction of antifungal agents for those
with persistent fever.
Cytokine support with granulocyte colonystimulating factor (GCSF) and granulocytemacrophage colony
stimulating factor (GMCSF) may be considered in refractory infections, although this therapy should be
weighed against cost and ecacy.2,26,27,28
Donor/recipient HLA matching was 6 of 6 (n = 1), 5 of 6 (n = 2), and 4 of 6 (n = 6). The median nucleated
cell dose infused was 5.7 x 107cells/kg (range 3.520 x 107cells/kg). Six patients were engrafted after the
rst unrelateddonor BMT, and 2 of the 3 patients without hematopoietic reconstitution were engrafted after
a second transfusion. All children who received 120 mg/kg of cyclophosphamide in the preparative
regimen were engrafted. The median time to myeloid engraftment was 25 (1759 days)days.12
Two patients developed acute GVHD, and 5 developed chronic GVHD. Five patients developed EBV viremia
post transplant (lymphoproliferative disorder in 3 patients). At a median followup of 34 months, 7 patients
were alive and transfusionindependent.12
Immunosuppressive therapy
Immune suppression is especially useful if a matched sibling donor for BMT is not available or if the patient is
older than 60 years.
Options include combination therapy, including ATG, CSA, and methylprednisolone, with or without cytokine
support. ATG and CSA alone may also produce a response in aplastic anemia, but the combination improves
the likelihood of a response.
In one study, response rates to CSA alone were 45% overall, 16% for VSSA, 47% for SAA, and 85% for moderate
aplasticanemia.29Therefore, the only predictor of response to CSA was an absolute neutrophil count (ANC)
of 200/mm3does not produce any additional advantage in reducing the infection rate or in increasing
survival or therapeutic responses.
The response in aplastic anemia, unlike other autoimmune diseases, is slow. At least 412 weeks is usually
needed to observe early improvement, and the patient continues to improve only slowly thereafter. About
50% patients respond by 3 months after ATG administration, and about 75% respond by 6 months. Most
patients improve and become transfusion independent, but many still have evidence of a hypoproliferative
bone marrow.
Although the initial response rate is good, relapses are common, and continued immune suppression is often
needed. Approximately one third of patients have a relapse, most of whom have a relapse at the time of CSA
taper. About one third of responders are CSA dependent. Of patients whose conditions have no response or
who relapse, 4050% respond to a second course of immunosuppressive therapy.
In rare cases, full hematologic recovery is observed, but most patients improve to a functional hematologic
recovery that obviates further transfusion support. Furthermore, the risk of some form of clonal disease other
than PNH is 1530% and may be due to the inability of these therapies to completely correct bone marrow
function, due to a missed diagnosis of MDS, or due to the fact that the stem cells under proliferative stress
may be more prone than other cells to mutation.
Preliminary data suggested that highdose cyclophosphamide may result in durable remissions in some
patients with aplastic anemia. However, some of these patients develop PNH and cytogenetic abnormalities
on followup. At present, the use of highdose cyclophosphamide should be limited to clinical trials.
Surgical Care
A central venous catheter placement is required before the administration ofimmunosuppressive therapy or
BMT.
Consultations
Consult a hematologist and/or BMT specialist.
Diet
The diet for the patient with aplastic anemia who has neutropenia or who is receiving immunosuppressive
therapy should be tailored carefully to exclude raw meats, dairy products, or fruits and vegetables that are
likely to be colonized with bacteria, fungus, or molds. Furthermore, a saltlimited diet is recommended
during therapy with steroids or CSA.
Activity
The patient should avoid any activity that increases the risk of trauma during periods of thrombocytopenia.
The risk of communityacquired infections increases during periods of neutropenia.
Medication
The goals of pharmacotherapy in cases of aplastic anemia are to reduce morbidity, prevent complications,
and eradicate malignancy.
Immunosuppressive Agents
The merits of additional immunosuppression versus the increased risk and cost should be considered. Data
from a randomized prospective study indicated that an increased proportion of patients responded to the
addition of CSA to ATG, but this did not translate into a longterm survival advantage.
For patients who cannot tolerate equinebased products, use of the commercially available rabbitbased ATG
product (Thymoglobulin) may be considered. This product is currentlyapproved in the United States and has
been used for the treatment of aplastic anemia in Europe (although note the dierent dose schedule).
Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cellmediated immune
reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft
vs host disease) for a variety of organs.
For children and adults, base the dosing on the ideal body weight. Frequent monitoring of drug levels is
needed. To convert to the PO dose, use a IVtoPO correction factor of 1:4. Dosage and duration of therapy
may vary with dierent protocols.
Dosing
Interactions
Contraindications
Precautions
Adult
1.52 mg/kg IV q12h, adjust to trough level of 500800 ng/mL in mo 1 or so; then adjust to trough level of
200 ng/mL
Pediatric
Administer as in adults.
Adult
5 mg/kg IV on days 18; then tapered by using PO 1 mg/kg on days 914; further tapering over days 1529;
stop after 1 mo except with evidence of serum sickness
Pediatric
Administer as in adults.
Adult
100200 mg/kg IV total dose over variable number of days based on dierent protocols
Pediatric
Administer as in adults.
Cyclophosphamide (Cytoxan)
Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active
metabolites may involve crosslinking of DNA, which may interfere with the growth of normal and neoplastic
cells. Monitor carefully; used only on an investigational basis.
Dosing
Interactions
Contraindications
Precautions
Adult
45 mg/kg/d IV for 4 d
Pediatric
Administer as in adults
Contraindications
Precautions
Adult
1.5 mg/kg IV qd for 714 d; up to 3.5 mg/kg for 5 d also used
Pediatric
Not established
Cytokines
Several preliminary studies have demonstrated that the addition of cytokines (eg, GCSF, GMCSF) may
hasten the neutrophil recovery and thatthese agentsmay improve the response rate and survival, although
longterm use may increase the risk of clonal evolution.
Filgrastim (Neupogen)
GCSF that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils.
Dosing
Interactions
Contraindications
Precautions
Adult
Fludarabine (Fludara)
Contains udarabine phosphate, a uorinated nucleotide analogue of the antiviral agent vidarabine, 9bD
arabinofuranosyladenine (araA) that enters the cell and is phosphorylated to form active metabolite 2
uoroaraATP, which inhibits DNA synthesis. Inhibits DNA polymerase, DNA primase, DNA ligase, and
ribonucleotide reductase. This inhibits RNA function, RNA processing, and mRNA translation. Also activates
apoptosis.
Dosing
Interactions
Contraindications
Precautions
Adult
30 mg/m2/dose for 46 d as IV infusion over 30 min2 h
Pediatric
Administer as in adults
Followup
Further Inpatient Care
Inpatient care for patients with aplastic anemia may be needed during periods of infection and for specic
therapies, such as ATG or BMT.
Transfer
Patients with aplastic anemia should be treated by physicians who are experts in the care of
immunocompromised patients and in consultation with a BMT physician for patients younger than 65 years.
Complications
Complications of aplastic anemia include infections and bleeding.
Complications of BMT include GVHD and graft failure.
Prognosis
The outcome of patients with aplastic anemia has substantially improved because of improved supportive
care. The natural history of aplastic anemia suggests that as many as one fth of patients may spontaneously
recover with supportive care; however, observational and/or supportive care therapy alone is rarely indicated.
The estimated 5year survival rate for the typical patient receiving immunosuppression is 75%. The rate for
those receiving a BMT from a matched sibling donor is greater than 90%. However, in case 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. In a
multivariate analysis, however, telomere length was associated with risk of relapse, clonal evolution, and
overall survival. Additional studies are needed to validate these ndings and to determine how this
information might be incorporated into treatmentalgorithms.37
Patient Education
Patients should maintain hygiene to reduce the risks of infection.
Clinicians must stress the need for compliance with therapy.
Miscellaneous
Medicolegal Pitfalls
Failure to correctly diagnose aplastic anemia and initiate appropriate treatment is a pitfall.
Aplastic anemia has a >70% mortality rate with supportive care alone. It is a hematologic emergency, and
care should be instituted promptly.