Aplastic anemia: Pathogenesis, clinical

manifestations, and diagnosis

Author: Timothy S Olson, MD, PhD
Section Editor: William C Mentzer, MD
Deputy Editor: Alan G Rosmarin, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Jan 2022. | This topic last updated: Dec 03, 2021.

INTRODUCTION

Aplastic anemia (AA) is a life-threatening form of bone marrow failure which,

if untreated, is associated with very high mortality. AA refers to pancytopenia
in association with bone marrow hypoplasia/aplasia, most often due to
immune injury to multipotent hematopoietic stem cells. The term "aplastic
anemia" is a misnomer because the disorder is characterized by pancytopenia
rather than anemia alone.

This topic will review the epidemiology, pathogenesis, clinical manifestations,

evaluation, diagnosis, and differential diagnosis of AA. Our approach to the
evaluation and diagnosis of AA is consistent with published guidelines [1,2].

The following topics are discussed separately:

●(See "Approach to the adult with pancytopenia".)

●(See "Treatment of aplastic anemia in adults".)
●(See "Inherited aplastic anemia in children and adolescents".)
DEFINITIONS

AA refers to pancytopenia in association with bone marrow

hypoplasia/aplasia, and has diverse underlying causes (table 1) [3]. Criteria
for the diagnosis of AA are described below. (See 'Diagnostic criteria' below.)

Bone marrow failure is a broader term, in which pancytopenia may be caused

by bone marrow replacement (eg, by tumor or fibrosis) or myelodysplastic
syndromes (table 2), in addition to other various causes of AA.

EPIDEMIOLOGY

AA is a rare disorder. In Western countries the incidence is approximately two

per million per year and the incidence is estimated to be two- to threefold
higher in Asia [4-8]. The sex ratio of AA is close to 1:1 in almost all population-
based studies. Half of cases of AA occur in the first three decades of life.

PATHOPHYSIOLOGY

Loss of hematopoietic stem cells (HSC) is a defining feature of AA.

Hematopoietic stem cells — HSCs in the bone marrow are the source of all
mature cells in the peripheral blood and tissues. HSCs are multipotent (ie, can
give rise to diverse cellular lineages) and generally quiescent. HSCs have the
capacity for self-renewal (thereby sustaining a lifelong store of HSCs) and give
rise to committed progenitor cells, which have reduced lineage potential but
high proliferative capacity. Through successive mitotic divisions, progenitor
cells ultimately produce fully mature blood cells.

HSCs are not morphologically identifiable (they resemble lymphoid cells), but
they can be recognized and isolated based on their characteristic
immunophenotype. HSCs constitute a small population within the
CD34+/CD38– fraction of bone marrow cells. HSCs can also be detected in the
peripheral blood, from which they can be isolated for use in hematopoietic
cell transplantation.

Pathogenic mechanisms — AA is associated with loss of HSCs and the

resultant decrease in mature blood cells. When the HSC pool falls below a
critical mass, the conflicting demands of self-renewal and differentiation can
lead to pancytopenia.

Pathophysiologic processes that lead to loss of HSCs and cause AA include [9]:

●Autoimmune mechanisms
●Direct injury to HSCs (eg, by drugs, chemicals, irradiation)
●Viral infection
●Clonal and genetic disorders
Autoimmune damage to HSCs causes or contributes to most cases of AA,
whether another underlying cause is identified or not. It is hypothesized that
drugs, chemicals, viruses, or mutations alter the immunologic appearance of
HSCs and lead to autoimmune destruction/suppression. This hypothesis is
supported by clinical observations, laboratory correlative studies, animal
models, and the responsiveness of AA to immune suppression [10-14].

Cytotoxic lymphocytes and type I cytokines appear to be proximate effectors

of autoimmune aplasia in AA, but there is also evidence of deficient quantity
and/or function of T-regulatory cells [15,16]. Interferon gamma (IFN gamma),
other cytokines (eg, IL-17), natural killer cells, and autoantibodies have also
been implicated in immune destruction of HSCs in AA [17-23].

IFN gamma initiates a cytokine cascade and induces the Fas receptor, and
both are implicated in increased apoptotic death of HSCs in AA [17,18,24-30].
IFN gamma is detected in the bone marrow of patients with acquired AA, and
disappears in response to immunosuppression [31]. In one report, 96 percent
of patients with circulating IFN gamma-containing T cells subsequently
responded to immunosuppressive therapy, while only 32 percent who lacked
IFN gamma-containing lymphocytes improved; 12 of 13 subjects in whom IFN
gamma was present during relapse responded to reinstitution of
immunosuppressive agents [32].

AA is occasionally associated with certain conditions in which the mechanism

of HSC loss is poorly understood. Examples include anorexia nervosa (often
associated with gelatinous degeneration and serous fat atrophy of bone
marrow), pregnancy, and as a complication of orthotopic liver transplantation
(especially in the context of fulminant hepatic failure). (See "Anorexia nervosa
in adults and adolescents: Medical complications and their management",
section on 'Hematologic'.)

Clonal evolution — AA may coexist with or evolve into another hematologic

disorder (eg, paroxysmal nocturnal hemoglobinuria [PNH], myelodysplastic
syndromes [MDS], acute myeloid leukemia [AML]).

There is controversy about whether specific treatments of AA foster clonal

evolution. A meta-analysis and a randomized trial did not detect an
association between the development of PNH, MDS, or AML and treatment
with immunosuppression plus growth factors [33,34]. Earlier observational
studies that reported such a link could not distinguish association from
causality [35-40].

Clonal evolution in AA may be detected by the acquisition of mutations or

cytogenetic abnormalities. Examples include:

●The most commonly mutated genes include DMNT3A, ASXL1, BCOR,

BCORL1, and PIGA [41]. Some of the mutations are the same as those
seen in hematopoietic cells of healthy older individuals without a
hematologic disorder (ie, clonal hematopoiesis of indeterminate potential
 [CHIP]) [42]. (See "Clonal hematopoiesis of indeterminate potential (CHIP)
and related disorders of clonal hematopoiesis", section on 'Clonal
hematopoiesis of indeterminate potential (CHIP)'.)

●The most common karyotypic abnormality is 6pUPD (acquired

uniparental disomy with loss of heterozygosity in the short arm of
chromosome 6); others include abnormalities of chromosomes 7 and/or
13 [41].

CAUSES

AA is a specific disease entity reflecting a deficiency of hematopoietic stem

cells (HSC) that results in peripheral pancytopenia and bone marrow aplasia (
table 1). Most patients have no identified underlying cause and are classified
as idiopathic, but the majority of patients with AA appear to have a
component of autoimmune destruction of HSCs.

Drugs, radiation, toxins — Exposure to large doses of cytotoxic medications

and/or ionizing radiation causes predictable, dose-dependent damage to
HSCs and acute hematopoietic failure [4,43]. Such predictable, transient bone
marrow suppression is not considered AA.

Drugs — Drugs can cause bone marrow aplasia either as a dose-dependent

effect (eg, cytotoxic chemotherapy) or as an idiosyncratic reaction (table 1).

The extent and timing of bone marrow suppression to chemotherapy and

other cytotoxic drugs is generally predictable and is not considered AA.
Peripheral blood cell counts may reach a nadir 7 to 10 days after drug
administration and recover to near baseline values within 14 to 28 days.

Other drugs that reduce blood cell production as a predictable effect include
certain immunosuppressive agents (eg, azathioprine), anti-inflammatory
medications (eg, phenylbutazone, gold), and certain antibiotics (eg,
chloramphenicol; see below).

In contrast, idiosyncratic reactions to drugs are associated with less

predictable patterns of bone marrow aplasia. In some cases cytopenias arise
while the patient is still taking the medication. In other cases the effects are
not recognized until days or weeks after exposure. The unpredictable
response in such idiosyncratic reactions can make it challenging to indict a
particular drug as the cause of AA.

Many drugs, including sulfonamides, antiseizure medications (eg, felbamate,

carbamazepine, valproic acid, phenytoin), and nifedipine have been
associated with AA (table 1) [4,5,44-47]. The vast majority of patients exposed
to these drugs do not develop AA, and the reason for idiosyncratic reactions
is unknown. The only potential predisposing factors that have been identified
are mutations in genes encoding cellular efflux pumps (eg, P-glycoprotein 1)
or drug metabolizing enzymes (eg, glutathione-S-transferase) [48-53].

Chloramphenicol is associated with both idiosyncratic and predictable bone

marrow suppression. An idiosyncratic reaction to chloramphenicol causes
irreversible bone marrow aplasia in approximately 1 of every 20,000 patients,
with a sudden onset several months after therapy [5]. Chloramphenicol is also
associated with predictable, reversible dose-related bone marrow
suppression in virtually all patients due to a direct toxic effect on bone
marrow erythroid precursors; this is manifest as a ring of vacuoles around the
proerythroblast nucleus and is associated with increased serum iron, because
iron is inefficiently utilized for hemoglobin synthesis.

Ionizing radiation — Ionizing radiation has a predictable, dose-dependent

bone marrow suppressive effect, which is discussed in more detail separately.
(See "Clinical manifestations, evaluation, and diagnosis of acute radiation
exposure", section on 'Biologic effects of radiation'.)
Toxins — Solvents/Degreasing agents, industrial chemicals, insecticides (eg,
lindane), and pesticides are considered significant risk factors for
development of severe AA, based on case-control and other population-based
studies [6,54-57]. Prolonged exposure to benzene is particularly notorious in
this regard, but benzene and pesticides account for only a small number of
AA cases [6,7].

Viral infection — Certain viruses are associated with AA. In some cases, viral
infection is thought to alter antigens on bone marrow cells and activate a
cytotoxic T cell clone or initiate T cell release of cytokines.

Hepatitis viruses and human immunodeficiency virus (HIV) can cause severe
bone marrow aplasia [58,59]. The mechanism may involve T cell activation
with release of cytokines [60], or activation of a cytotoxic T cell clone that
recognizes similar target antigens on both liver and bone marrow cells [61].

Hepatitis-associated AA generally develops two to three months after an

episode of acute hepatitis and most often affects boys and young men
[59,62]. Hepatitis may account for 5 to 10 percent of cases of AA, but the
responsible virus has not been identified; hepatitis A, B, C, and G appear not
to be involved [59,62,63]. (See "Treatment of acquired aplastic anemia in
children and adolescents".)

Acquired clonal abnormalities — Development of clonal abnormalities in

blood cells during the course of an individual's life (ie, from mutations that
are not transmitted in the germline) are associated with some cases of AA.

AA may coexist with or evolve into other disorders, such as paroxysmal

nocturnal hemoglobinuria (PNH), myelodysplastic syndromes (MDS), or acute
myeloid leukemia (AML). In some cases, immune destruction of the aberrant
HSCs contributes to the cytopenias. (See 'Clonal evolution' above.)
Paroxysmal nocturnal hemoglobinuria — There is a close relationship
between AA and PNH, a clonal disorder in which acquired mutations of the
PIG-A gene can lead to global absence of certain proteins (eg, CD59) on the
surface of blood cells, thereby altering their immune appearance and
reducing their ability to resist destruction by complement. (See "Pathogenesis
of paroxysmal nocturnal hemoglobinuria".)

This association may become evident when hemolysis or thrombosis

suggestive of PNH is seen in a patient with AA, or when PNH evolves into
bone marrow hypoplasia characteristic of AA.

Expanded populations of blood cells with the PNH defect have been detected
by flow cytometry in approximately half of patients with AA [64]. The
abnormal blood cells are thought to initiate an immune response that
damages HSCs and other hematopoietic precursors [65-70]. In one
prospective study in adults, flow cytometry detected a population of PNH-
type cells (range: 0.005 to 23 percent) in 68 percent of 122 patients with newly
diagnosed AA [70].

Myelodysplastic syndromes — Chromosomal abnormalities that are

characteristic of MDS are observed in a minority of patients with AA
(estimated at 5 to 15 percent) [41]. Dysplastic HSCs of MDS may be subject to
immune destruction/suppression by T lymphocytes and lead to bone marrow
hypoplasia that is characteristic of AA.

A subset of patients with MDS have hypoplastic bone marrow, which shares
some features with AA/PNH. This entity and its management are discussed
separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)",
section on 'Hypoplastic MDS or PNH+'.)

Inherited genetic abnormalities — Some inherited genetic disorders that

cause AA have characteristic somatic phenotypes and are easily recognized.
Others are identified only after genetic studies find a diagnostic mutation.
Fanconi anemia — The most common form of inherited AA is Fanconi
anemia (FA), a condition characterized by pancytopenia, predisposition to
malignancy, and physical abnormalities (eg, short stature, microcephaly,
developmental delay, café-au-lait skin lesions, other characteristic
malformations). Diagnosis is usually made in childhood but, because of
variable disease manifestations, some individuals may not be diagnosed with
FA until adulthood [71]. (See "Clinical manifestations and diagnosis of Fanconi
anemia", section on 'Clinical features'.)

Defining FA as the cause of AA has important implications for management.

Individuals with FA should undergo special surveillance for both hematologic
and non-hematologic malignancies and require reduced doses of
chemotherapy for cancer treatment and/or conditioning therapy for
hematopoietic cell transplantation (HCT). Siblings with FA must be excluded
as potential HCT donors. (See "Inherited aplastic anemia in children and
adolescents", section on 'Fanconi anemia'.)

Shwachman-Diamond syndrome — Shwachman-Diamond syndrome (SDS)

usually presents in infancy with bone marrow failure, exocrine pancreatic
dysfunction, and skeletal anomalies. AA is seen in patients with SDS, although
intermittent neutropenia is the most common hematologic manifestation.

The clinical manifestations, genetic basis, and treatment of SDS are discussed
separately. (See "Shwachman-Diamond syndrome".)

Abnormal thrombopoietin or its receptor — AA is associated with

inherited conditions that may manifest as congenital amegakaryocytic
thrombocytopenia (CAMT). Examples include mutations of thrombopoietin
(THPO) [72] or the thrombopoietin receptor (MPL) [73]. These conditions are
discussed in greater detail separately. (See "Inherited aplastic anemia in
children and adolescents", section on 'Amegakaryocytic thrombocytopenia'.)
Dyskeratosis congenita and other telomere abnormalities — Blood cells
of patients with AA frequently have short telomeres [74]. Inherited and
acquired forms of telomere abnormalities that are associated with AA include:

●Dyskeratosis congenita – Dyskeratosis congenita (DC) is an inherited

cause of AA that is associated with characteristic skin and nail findings (
picture 1), pulmonary fibrosis, cancer predisposition, and additional
somatic abnormalities (table 3). The age of onset of DC is variable, and
some clinical presentations are subtle.

●TERT or TERC mutations – Acquired mutations in TERT and other genes

in the telomere repair pathway appear to be genetic risk factors for the
development of bone marrow failure, possibly by making bone marrow
vulnerable to environmental insults (eg, drugs, viruses) and/or altering
their immunologic appearance thereby making them susceptible to
autoimmune destruction.

DC and related disorders are discussed separately. (See "Dyskeratosis

congenita and other telomere biology disorders".)

CLINICAL MANIFESTATIONS

Symptoms and signs — The patient with AA most commonly presents with

recurrent infections due to neutropenia, mucosal hemorrhage or
menorrhagia due to thrombocytopenia, or fatigue and cardiopulmonary
findings associated with progressive anemia. Infections are typically bacterial,
including sepsis, pneumonia, and urinary tract infection; invasive fungal
infection is a common cause of death, especially in subjects with prolonged
and severe neutropenia [75].

Some patients present with hemolytic anemia or thrombosis that may

suggest co-existent paroxysmal nocturnal hemoglobinuria (PNH). (See
'Acquired clonal abnormalities' above.)

Other patients (mostly children) have somatic manifestations associated with

specific inherited syndromes (eg, short stature, microcephaly, developmental
delay, skin and nail lesions). However, some adults with AA may also manifest
characteristic somatic abnormalities (eg, fingernail dystrophy associated with
dyskeratosis congenita) due to a previously unrecognized inherited disorder.
(See 'Inherited genetic abnormalities' above.)

Other patients are asymptomatic and present with abnormal blood counts.

Complete blood count — The complete blood count reveals pancytopenia

(ie, neutropenia, thrombocytopenia, and anemia) along with
reticulocytopenia. The peripheral blood smear typically reveals normocytic
red blood cells, but they may be macrocytic (ie, mean cell volume >100 fL).
Abnormal cells (eg, myeloblasts, atypical lymphoid cells) are not present
unless there is an associated hematologic disorder. (See "Diagnostic approach
to anemia in adults" and 'Clonal evolution' above.)

EVALUATION

Evaluation of a patient with a complete blood count suggestive of AA should

establish the diagnosis of AA, seek to identify an underlying cause, and
distinguish it from other categories of pancytopenia. Bone marrow biopsy is
required to establish the diagnosis of AA.

Urgency of evaluation — The urgency of clinical evaluation and bone

marrow biopsy is guided by the depth of cytopenias and the patient's clinical
status.

●If critical cytopenias and/or potentially life-threatening complications (eg,

infection, bleeding, cardiorespiratory compromise) are present (table 4),
the patient should undergo immediate hematology consultation
 (including bone marrow biopsy) and hospitalization. Further discussion of
assessment and management of such conditions is provided separately.
(See "Approach to the adult with pancytopenia", section on
'Emergencies'.)

●For patients with milder cytopenias and no clinical complications, it may

not be essential to immediately hospitalize, obtain hematology
consultation, and/or perform bone marrow examination. In such a
setting, close observation and monitoring of blood counts (eg, over days
to a few weeks) may reveal a reversible cause of cytopenias (eg, due to
recent viral infection). However, evaluation should proceed promptly if no
improvement is observed and/or complications of cytopenias arise.

History, examination, laboratory studies — The history may provide clues

to an underlying etiology (eg, exposure to drugs/chemicals, viral infection).
Family history (in both children and adults) may reveal other family members
with cytopenias and/or somatic findings suggestive of an inherited disorder.

Physical findings are generally consistent with pancytopenia, especially pallor

and petechiae. The liver, spleen, and lymph nodes are not typically enlarged
in AA; such findings suggest an alternative diagnosis. There may be overt or
subtle manifestations of inherited disorders (eg, cutaneous/nail findings,
short stature, skeletal or genitourinary abnormalities, eye/ear findings).
Physical examination should also evaluate and assess potential complications
of the cytopenias (eg, cardiovascular system, evidence of infections). (See
"Clinical manifestations and diagnosis of Fanconi anemia", section on 'Clinical
features' and "Dyskeratosis congenita and other telomere biology disorders",
section on 'Clinical features'.)

Serum chemistries, including electrolytes, liver function tests (including

lactate dehydrogenase [LDH]), and renal function tests should be performed
to identify associated conditions and complications (eg, hemolysis), and help
to distinguish AA from other causes of pancytopenia. Serum vitamin B12 and
red blood cell folate levels should be performed to exclude those causes of
megaloblastic anemia. (See "Approach to the adult with pancytopenia".)

Bone marrow examination — Bone marrow aspiration and biopsy is

required to establish the diagnosis of AA and exclude other causes of
pancytopenia. The biopsy should be performed at a site that has not suffered
prior direct damage (eg, radiation, trauma, infection). (See "Bone marrow
aspiration and biopsy: Indications and technique", section on 'Choice of
aspiration or biopsy site' and "Evaluation of bone marrow aspirate smears",
section on 'Sample preparation'.)

Diagnostic findings from bone marrow examination include:

●The bone marrow is profoundly hypocellular with a decrease in all

elements; the marrow space is composed mostly of fat cells and marrow
stroma (picture 2).

●Residual hematopoietic cells are morphologically normal and

hematopoiesis is not megaloblastic.

●Infiltration of the bone marrow with malignant cells or fibrosis is not

present.

Bone marrow specimens should undergo cytogenetic, molecular, and other

specialized testing, as described below.

Diagnostic criteria — AA is defined as pancytopenia with a hypocellular

bone marrow in the absence of an abnormal infiltrate or marrow fibrosis.

There is no required duration of cytopenias to establish a diagnosis of AA.

However, if a specific cause of cytopenias is identified (eg, cytotoxic
chemotherapy, viral infection), the blood counts may be monitored for days
to several weeks to permit recovery and determine if the insult is reversible.
For purposes of risk stratification and selection of therapy, AA is classified
according to the following criteria:

Severe AA — Diagnosis of severe aplastic anemia (SAA) requires both of the

following criteria [76]:

●Bone marrow cellularity <25 percent (or 25 to 50 percent if <30 percent of

residual cells are hematopoietic)

●At least two of the following:

•Peripheral blood absolute neutrophil count (ANC) <500/microL (<0.5 X
109/L)

•Peripheral blood platelet count <20,000/microL

•Peripheral blood reticulocyte count <20,000/microL
Very severe AA — Diagnosis of very severe aplastic anemia (vSAA) include
the criteria for SAA (above) and ANC is <200/microL (calculator 1).

Non-severe AA — Criteria for non-severe AA are:

●Hypocellular bone marrow (as described for SAA)

●Peripheral blood cytopenias not fulfilling criteria for SAA or vSAA (see
above)

Specialized testing — The decision to perform specialized testing is

influenced by the clinical setting (eg, adult versus child, findings consistent
with an inherited syndrome).

In all adults with AA, the following specialized testing should be performed
to detect coexistent disorders, such as paroxysmal nocturnal hemoglobinuria,
myelodysplastic syndrome, or acute leukemia:
 ●Flow cytometry for assessment of cell surface CD59 on peripheral blood
red blood cells or neutrophils. (See "Clinical manifestations and diagnosis
of paroxysmal nocturnal hemoglobinuria".)

●Cytogenetic and molecular testing of bone marrow. (See "Genetic

abnormalities in hematologic and lymphoid malignancies".)

In all children with AA we suggest genetic testing (eg, Genetic Testing

Registry) to identify inherited genetic abnormalities. Descriptions of inherited
syndromes associated with AA and diagnostic testing are discussed in greater
detail separately. (See 'Inherited genetic abnormalities' above and "Clinical
manifestations and diagnosis of Fanconi anemia", section on 'Diagnostic
testing' and "Dyskeratosis congenita and other telomere biology disorders",
section on 'Laboratory testing and bone marrow'.)

In some adults with AA we suggest genetic testing, because cytopenias may

be the first manifestation of an inherited disorder. The diagnosis may be
straightforward in adult patients with characteristic abnormalities (eg, short
stature, skeletal abnormalities, skin/nail lesions), but only subtle
nonhematologic abnormalities may be seen in others. Testing should be
performed when there is such suspicion. (See "Clinical manifestations and
diagnosis of Fanconi anemia", section on 'Clinical features' and "Dyskeratosis
congenita and other telomere biology disorders", section on 'Clinical
features'.)

Testing for an inherited disorder should also be considered in adults with AA

who fail to respond to treatment with anti-thymocyte globulin (ATG). (See
"Treatment of aplastic anemia in adults", section on 'Pretreatment
evaluation'.)

DIFFERENTIAL DIAGNOSIS
The differential diagnosis of AA includes other causes of pancytopenia, such
as megaloblastic anemia, bone marrow infiltration (eg, myelofibrosis, various
cancers), sequestration/redistribution (eg, hypersplenism), and certain
myeloid malignancies (eg, myelodysplastic syndrome [MDS], acute myeloid
leukemia [AML]). The evaluation of pancytopenia due to these other causes is
discussed separately. (See "Approach to the adult with pancytopenia".)

Physical examination, review of the peripheral blood smear, and bone

marrow aspirate/biopsy can distinguish some of these disorders from AA, but
more specialized testing (eg, cytogenetic or molecular diagnostics) is often
required.

●Megaloblastic anemia – Megaloblastic anemia (eg, pernicious anemia,

malnutrition) can cause profound pancytopenia and bone marrow
hypoplasia, most commonly due to deficiencies of vitamin B12 and/or
folate. Megaloblastic anemia is characterized by the presence of
hypersegmented neutrophils and macro-ovalocytes on the peripheral
blood smear and megaloblastic changes in the bone marrow
examination; serum levels of vitamin B12 and/or folate can confirm these
diagnoses. (See "Clinical manifestations and diagnosis of vitamin B12 and
folate deficiency".)

●Infiltrative disorders – Infiltration of the bone marrow by fibrosis (eg,

myeloproliferative neoplasms such as primary myelofibrosis),
malignancies (eg, MDS, AML, lymphoma, multiple myeloma, carcinoma),
or infectious agents (eg, tuberculosis, fungi) may cause pancytopenia by
bone marrow replacement and/or sequestration/redistribution of blood
cells. These disorders can usually be distinguished from AA by the
presence of myelophthisic changes on the peripheral blood smear (eg,
schistocytes, nucleated red blood cells) and morphologic, cytogenetic,
and/or molecular abnormalities of the bone marrow. (See "Clinical
manifestations and diagnosis of primary myelofibrosis".)
●Reversible bone marrow suppression – Predictable, dose-dependent
effects of cytotoxic chemotherapy or radiation therapy, overwhelming
sepsis, or acute viral infection can cause transient, reversible
pancytopenia with hypoplastic bone marrow. Such diagnoses are
established by history and laboratory studies (eg, microbiologic and
serologic testing), and serial examinations of blood counts should
demonstrate improvements in days to weeks. If a bone marrow
aspirate/biopsy is planned, it is important to perform it away from sites
of prior radiation treatment or other bone marrow injury.

●Hypersplenism – Hypersplenism refers to cytopenias due to

splenomegaly and may be caused by liver cirrhosis, portal vein
thrombosis, and bone marrow infiltrative disorders. Splenomegaly alone
rarely causes the degree of cytopenias seen with infiltrative bone marrow
disorders or AA. These diagnoses can be assessed by clinical evaluation
and imaging studies; bone marrow examination is expected to reveal
adequate (or increased) hematopoietic activity. (See "Approach to the
adult with pancytopenia".)

●Hypoplastic MDS – The hypocellular variant of MDS can be very difficult

to distinguish from AA. The diagnosis is established by demonstration of
dysplastic changes in bone marrow and/or cytogenetic or molecular
abnormalities that are characteristic of MDS. There is clinical overlap
between hypoplastic MDS and AA, and many cases of the former will
respond to immunosuppressive therapies that are used for treatment of
AA. (See "Clinical manifestations and diagnosis of myelodysplastic
syndromes (MDS)".)

●Large granular lymphocyte leukemia – Large granular lymphocyte

(LGL) leukemia is a clonal disease characterized by cytopenias,
splenomegaly, and infiltration of peripheral blood and bone marrow by
LGLs. The malignant lymphocytes have characteristic azurophilic granules
 (picture 3), and their presence can be confirmed by flow cytometry and
molecular testing. AA and LGL leukemia can coexist, but the presence of
substantial numbers of clonal LGL cells will confirm the latter diagnosis.
(See "Clinical manifestations, pathologic features, and diagnosis of T cell
large granular lymphocyte leukemia".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected

countries and regions around the world are provided separately. (See "Society
guideline links: Bone marrow failure syndromes".)

INFORMATION FOR PATIENTS

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Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
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"patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Aplastic anemia (The Basics)")

SUMMARY AND RECOMMENDATIONS
●Aplastic anemia (AA) refers to pancytopenia in association with bone
marrow hypoplasia/aplasia. AA is a rare disorder (two to four per million
per year) that affects men and women equally, and it is life-threatening if
untreated. (See 'Epidemiology' above.)

●AA is associated with loss of hematopoietic stem cells (HSC) due to direct
stem cell injury, viral suppression, autoimmune mechanisms, and
inherited or acquired clonal/genetic abnormalities. Autoimmune damage
to HSCs is an important contributor to most cases of AA in which no
underlying cause is clearly identifiable (idiopathic AA). (See
'Pathophysiology' above.)

●AA has diverse causes (table 1), including (see 'Causes' above):
•Drugs, chemicals, irradiation, and other sources of HSC injury
•Viral infection
•Autoimmune injury
•Inherited or acquired clonal/genetic abnormalities
Predictable bone marrow suppression (eg, from cytotoxic drugs or
radiation) is generally reversible in days to weeks, and is not considered
AA.

●Patients typically present with clinical findings of pancytopenia (eg,

bleeding/bruising, anemia, infection) and may manifest somatic findings
suggestive of an inherited genetic syndrome. (See 'Symptoms and signs'
above.)
 Complete blood count reveals pancytopenia, and the peripheral blood
smear reveals normocytic or macrocytic red cells with reticulocytopenia,
decreased neutrophils and platelets, and the absence of abnormal
circulating white blood cell forms. (See 'Complete blood count' above.)

●Urgency of clinical evaluation and bone marrow biopsy is guided by the

depth of cytopenias and the patient's clinical status (see 'Urgency of
evaluation' above):

•If critical cytopenias and/or potentially life-threatening complications (

table 4) are present, immediate hematology consultation (including
bone marrow biopsy) and hospitalization are warranted.

•If a reversible cause of cytopenias is identified and no life-threatening

complications are present, close clinical observation, without an
immediate bone marrow biopsy, may be sufficient.

●The diagnosis of AA is based on a profoundly hypocellular/aplastic bone

marrow biopsy, morphologically normal residual hematopoietic cells, and
no infiltration with malignant cells or fibrosis; the marrow space is
composed mostly of fat cells and marrow stroma (picture 2). (See 'Bone
marrow examination' above.)

●AA should be distinguished by clinical evaluation, laboratory studies,

bone marrow examination, and specialized testing from other causes of
bone marrow failure (table 2), including (see 'Differential diagnosis'
above):

•Megaloblastic anemia
•Bone marrow failure from infiltrative disorders (eg, fibrosis, cancer)
with or without associated splenomegaly

•Transient bone marrow suppression (eg, cytotoxic drugs, radiation)

 •Hypoplastic myelodysplastic syndrome (MDS)
•Large granular lymphocyte leukemia
ACKNOWLEDGMENT

The editors of UpToDate acknowledge the contributions of Stanley L Schrier,

MD as author on this topic, his tenure as the founding Editor-in-Chief for
UpToDate in Hematology, and his dedicated and longstanding involvement
with the UpToDate program.

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