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Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis
Author:
Stanley L Schrier, MD
Section Editor:
William C Mentzer, MD
Deputy Editor:
Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Oct 03, 2017.

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 unexplained 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:

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 [9-13].

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 [14,15]. 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 [16-22].

IFN gamma initiates a cytokine cascade and induces the Fas receptor, and both are implicated in increased apoptotic death of HSCs in AA [16,17,23-29]. IFN gamma is detected in the bone marrow of patients with acquired AA, and disappears in response to immunosuppression [30]. 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 [31].

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 [32,33]. Earlier observational studies that reported such a link could not distinguish association from causality [34-39].

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 [40]. 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]) [41]. (See "Idiopathic cytopenias of undetermined significance (ICUS), clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)", 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 [40].

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 [4,42]. 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) [4,5,43-46]. 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) [47-52].

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 "Biology and clinical features of radiation injury in adults", section on 'Hematopoietic syndrome'.)

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 [6,53-56]. 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 HIV can cause severe bone marrow aplasia [57,58]. The mechanism may involve T cell activation with release of cytokines [59], or activation of a cytotoxic T cell clone that recognizes similar target antigens on both liver and bone marrow cells [60].

Hepatitis-associated AA generally develops two to three months after an episode of acute hepatitis and most often affects boys and young men [58,61]. 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 [58,61,62]. (See "Acquired aplastic anemia in children and adolescents", section on 'Infectious agents'.)

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 [63]. The abnormal blood cells are thought to initiate an immune response that damages HSCs and other hematopoietic precursors [64-69]. 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 [69]

Myelodysplastic syndromes — Chromosomal abnormalities that are characteristic of MDS are observed in a minority of patients with AA (estimated at 5 to 15 percent) [40]. 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 intermediate, low, or very low risk myelodysplastic syndromes", section on 'Hypoplastic MDS'.)

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 [70]. (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 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) [71] or the thrombopoietin receptor (MPL) [72]. 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 [73]. 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 short telomere syndromes".)

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 [74].

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 "Approach to the adult with anemia" 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 unexplained 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 short telomere syndromes", 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 unexplained 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 [75]:

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 short telomere syndromes", 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 short telomere syndromes", 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 'Initial considerations'.)

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 unexplained 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 unexplained 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 the myelodysplastic syndromes".)

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".)

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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 (2 to 4 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 (HSCs) 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

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