Aplastic Anemia

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    Aplastic Anemia


    Key Points

    • Acquired aplastic anemia is an impairment of hematopoiesis that appears to have an immunologic basis in the majority of cases; may be idiopathic or may be triggered by drugs, other toxic agents, or disease states (eg, viruses) that may trigger an immune response
    • Characterized by hypocellular bone marrow and significantly decreased counts in all peripheral blood cell lines
    • Nonsevere aplastic anemia may be treated with supportive care, but severe aplastic anemia requires either immunosuppressive treatment or hematopoietic stem cell transplant, depending on patient age and overall condition
    • While matched sibling bone marrow transplant has been the most desirable treatment for children and young adults, excellent results can now be achieved with alternative donors r1r2
    • When relapses occur or initial immunosuppressive therapy fails, there are multiple options for rescue therapies, and prognosis for aplastic anemia has improved to the extent that most patients have an excellent chance of survival

    Urgent Action

    • Urgently obtain evaluation by a hematologist, including a bone marrow biopsy, to make a prompt diagnosis in any patient with pancytopenia
    • Immediately remove any potential offending agent (medication or toxic agent) r3
    • Promptly evaluate symptoms or signs of bleeding or infection


    • Distinction between genetic syndromes associated with bone marrow failure and acquired aplastic anemia is important because these entities may respond differently to therapies
    • If a patient is a candidate for hematopoietic stem cell transplant, it is important not to transfuse unnecessarily, as higher transfusion burden may increase the risk for graft-versus-host disease, although this risk is expected to be lower with administration of irradiated blood
    • Conversely, transfusion may be lifesaving and should not be withheld if it is necessary


    Clinical Clarification

    • Aplastic anemia is peripheral blood pancytopenia and hypocellular bone marrow with autoimmune destruction of hematopoietic stem cells, in the absence of major dysplastic signs and marrow fibrosis r3r4
      • At least 2 cell lines must be affected and 2 of following criteria need to be met to diagnose aplastic anemia: r3
        • Hemoglobin level less than 10 g/dL
        • Neutrophil count less than 1.5 × 10⁹/L
        • Platelet count less than 50 × 10⁹/L
      • Either acquired or inherited, but disease manifestations are the same


    • By cause
      • Idiopathic (60% of cases) r4
        • Immune-mediated, via abnormal T-cell response leading to overproduction of bone marrow–inhibiting cytokines;r5r6 genetic predisposition is suspected
        • No trigger can be found
        • Slowly progressive course
      • Secondary r4
        • Drug, virus, or other toxic agent triggers T-cell mediated immune response to hematopoietic stem cells
        • Onset is more abrupt than idiopathic aplastic anemia
    • By severity, as defined by the modified Camitta criteria r3r7
      • Nonsevere aplastic anemia r3
        • Decreased bone marrow cellularity and peripheral blood cytopenia (for age)
        • Does not fulfill criteria for severe aplastic anemia
      • Severe aplastic anemia r3
        • Bone marrow cellularity less than 25% of reference range
        • Meets at least 2 of the following criteria:
          • Neutrophil count less than 0.5 × 10⁹/L
          • Platelet count less than 20 × 10⁹/L
          • Absolute reticulocyte count less than 20 × 10⁹/L
      • Very severe aplastic anemia r3
        • Meets criteria of severe aplastic anemia, plus
        • Neutrophil count less than 0.2 × 10⁹/L


    Clinical Presentation


    • Can be an incidental finding if severity is mild
    • Most commonly, patients present with complaints related to bleeding or anemia; presentation with complaints of fever or infection are less common r4r8
      • Easy bruising c1
      • Bleeding gums c2
      • Menorrhagia c3
      • Episodic epistaxis c4
      • Petechiae over the extremities c5
      • Fatigue c6
      • Dyspnea c7
      • Angina pectoris, if anemia is severe c8
    • Systemic symptoms such as weight loss, pain, and loss of appetite are not generally associated with aplastic anemia and suggest an alternative diagnosis r4c9c10
    • A recent infection, new medication, or possible toxic exposure may be reported c11c12c13
      • If associated with drug exposure or viral infection, latent period of 6 to 8 weeks is common r4
      • Idiopathic aplastic anemia has a more gradual onset of several months r4
    • Suggestive personal or family history of physical anomalies, or a history of chronic multilineage low blood counts since childhood, suggests an inherited syndrome (of which aplastic anemia is a component) rather than idiopathic aplastic anemia r4
      • Fanconi syndrome c14c15
      • Dyskeratosis congenita and related short-telomere syndromes c16c17
      • Shwachman-Diamond syndrome r4c18c19

    Physical examination

    • Typically patients do not appear severely ill, but they can appear toxic depending on severity of illness c20
    • Depending on the severity of cytopenias, physical findings include:
      • Signs of thrombocytopenia
        • Ecchymoses (most often unexplained by the patient) c21
        • Petechiae on pretibial surface of lower legs, dorsal forearms, wrists, and in oropharynx c22c23
        • Nose or gum bleeding may be witnessed, although this is an uncommon presentation c24c25
        • Heme positive stool c26
        • Retinal hemorrhages may be seen in patients with severe thrombocytopenia c27
      • Signs of anemia
        • Pallor c28
        • Tachypnea and tachycardia, if anemia is severe or has developed rapidly c29c30
      • Signs of leukopenia
        • If there is infection, fever c31c32
    • Usually do not see cachexia, splenomegaly, or lymphadenopathy; these suggest an alternative diagnosis c33c34c35
    • If the pancytopenia occurs in the setting of an inherited bone marrow failure syndrome, a variety of physical findings can assist in the diagnosis; these syndromes may have different treatments and prognoses c36
      • Fanconi syndrome r9
        • Thumb and radial malformations c37c38
        • Café au lait spots c39
        • Short stature c40
      • Telomere diseases (dyskeratosis congenita and related syndromes) r10
        • Nail dysplasia c41
        • Leukoplakia c42
        • Skin hypopigmentation c43
        • Premature graying of hair c44
      • Shwachman-Diamond syndrome
        • Growth retardation with short stature c45

    Causes and Risk Factors


    • Idiopathic r4c46
      • Immune-mediated destruction of hematopoietic cells
    • Secondary
      • Injury to stem cells from drug or toxic exposure r4
        • Agents that predictably depress bone marrow in commonly used doses/exposures
          • Benzene and benzene-containing chemicals (benzene binds to bone marrow DNA, inhibits synthesis, and introduces DNA breaks, acting as a mitotic poison); negligible risk in most countries now but remains a risk in China c47
          • Cytotoxic cancer chemotherapeutic agents result in direct marrow toxicity and short-term bone marrow failure, but this is not generally considered aplastic anemia, as it resolves within weeks c48c49c50
        • Agents associated with aplastic anemia, but with lower probability (idiosyncratic drug reaction)
          • Chloramphenicol (withdrawn from US market owing to aplastic anemia risk) c51
          • Some anticonvulsants (hydantoins, carbamazepine, phenacemide, ethosuximide) c52c53c54c55
          • NSAIDs (phenylbutazone, indomethacin, ibuprofen, diclofenac, naproxen, sulindac, fenoprofen, piroxicam, aspirin) c56c57c58c59c60c61c62c63c64
          • Gold salts and heavy metals (arsenic, bismuth, mercury) c65c66c67
          • Antithyroid drugs (methimazole, methylthiouracil, propylthiouracil) c68c69c70
          • Sulfonamides c71
          • Antiprotozoals (chloroquine, quinacrine) c72c73
          • Drugs treating diabetes (tolbutamide, chlorpropamide, carbutamide) c74c75c76
          • Carbonic anhydrase inhibitors (acetazolamide, mesalazine, methazolamide) c77c78c79
          • Insecticides (chlordane, lindane) c80c81
      • Injury to stem cells from radiation exposure r6r11r12c82
        • Primarily occurs in victims of radiation accidents or atomic bombs
        • Aplastic anemia has not been found in unexpected numbers in patients receiving radiation therapy for cancer or in people working at or living near nuclear power plants
      • Autoimmune hepatitis c83

    Risk factors and/or associations

    • Inherited bone marrow failure syndromes (ie, Fanconi syndrome, dyskeratosis congenita, Shwachman-Diamond syndrome) have clinical overlap with aplastic anemia, but these are separate disease entities with additional clinical features r13c89
      • Loss-of-function germline mutations result in physical anomalies and bone marrow failure, which classically manifest in childhood
    • Aplastic anemia not associated with 1 of these syndromes is an acquired disorder; however, somatic clonal mutations may be present
      • Up to one-half of patients with aplastic anemia have a small clonal population of cells deficient in GPI (glycosylphosphatidylinositol)-linked proteins that characterize paroxysmal nocturnal hemoglobinuria; this is caused by a mutation in the PIGA gene c90
        • Only a small percentage of patients develop classic paroxysmal nocturnal hemoglobinuria
        • In patients with only aplastic anemia (but not clinical paroxysmal nocturnal hemoglobinuria) with a PIGA mutation, a mutant hematopoietic stem cell clone has not expanded; however, in patients with both aplastic anemia and paroxysmal nocturnal hemoglobinuria, it has r13
    • Highest incidence is reported in Asia r14c91
    Other risk factors/associations
    • Generally, aplastic anemia is a rare disease; however, differences in prevalence may be explained by environmental factors r4
      • 2 per 1 million people in Europe and North America
      • 4 to 5.6 per 1 million people in Asia
    • Paroxysmal nocturnal hemoglobinuria r15r16c92
      • 20% to 30% of patients will go on to develop aplastic anemia r15
    • Hepatitis r17c93c94
      • Uncommon but distinct association, usually in young boys r17
      • Sometimes associated with hepatitis A or B, but most cases are associated with seronegative, autoimmune hepatitis r18r19c95c96c97
      • Pancytopenia with hypocellular marrow develops 2 to 3 months after acute hepatitis r17
    • Epstein-Barr virus or cytomegalovirus infection r4r17r20r21c98c99
      • Rare but distinct association
      • Pancytopenia develops soon after clinical symptoms of infection
      • Believed to be immune mechanism
    • Autoimmune connective tissue disease r4
      • Aplastic anemia can be part of eosinophilic fasciitis, an autoimmune infiltration of macrophages and lymphocytes into skin and muscle, sometimes responsive to corticosteroids or other immunosuppressive therapy c100c101
      • Aplastic anemia can also complicate scleroderma, systemic lupus erythematosus, or rheumatoid arthritis, but it is unclear if medication used to treat disease is a confounding factor
    • Posttransfusion graft-versus-host disease r4
      • Caused by transfusion of competent lymphocytes into immunodeficient hosts c102
      • Resistant to immunosuppressive therapy and usually fatal
    • Pregnancy r22c103
      • While pregnancy does appear to present a rare risk of developing aplastic anemia, the mechanism is poorly understood
      • While it is believed to be autoimmune, immunosuppressive therapy is not an option because of fetal toxicity
      • Stem cell transplant is also not an option; therefore, only supportive care is available during pregnancy

    Diagnostic Procedures

    Primary diagnostic tools

    • Suspect diagnosis based on signs or symptoms suggesting anemia, thrombocytopenia, or leukopenia c104
    • Obtain CBC to confirm at least 2 of the 3 following findings: r3c105c106
      • Hemoglobin level less than 10 g/dL
      • Neutrophil count less than 1.5 × 10⁹/L
      • Platelet count less than 50 × 10⁹/L
    • Obtain routine laboratory studies to further evaluate pancytopenia, including absolute reticulocyte count, vitamin B₁₂ and folate levels, liver function tests, and viral serologies (if there is a suggestive history) c107c108c109
    • Definitive diagnosis requires bone marrow aspiration and trephine biopsy c110
      • Aplastic anemia is characterized by hypocellular, fatty marrow with cellularity less than 30% of reference range, in the absence of major dysplastic signs and marrow fibrosis r4
    • Complete certainty of acquired aplastic anemia, rather than aplastic anemia as a component of an inherited or clonal syndrome, requires additional testing in consultation with a hematologist in inherited bone marrow failure syndromes
      • Chromosomal breakage testing on peripheral blood to screen for Fanconi syndrome r23
      • Flow cytometry testing of peripheral blood to identify patients with paroxysmal nocturnal hemoglobinuria clones r23c111
      • Cytogenetics and molecular testing of bone marrow c112
        • Testing for known genes associated with Fanconi syndrome (to confirm a positive chromosomal breakage test result) and dyskeratosis congenita is reasonable in adult patients with moderate, chronic pancytopenia, and in children and adolescents r6
          • Some patients may lack physical anomalies, and genetic syndrome may be otherwise unrecognized
          • However, in severe cases with no family history, genetic test results are likely to be negative r6
    • HLA typing for future treatment purposes is recommended at time of diagnosis, and is usually accomplished by urgent referral (especially for children and younger adults) to transplant specialist center r3c113


    • CBC c114
      • Pancytopenia (or cytopenia of least 2 cell lines)
        • Isolated thrombocytopenia may occur in early stage
      • Relative lymphocytosis is common
    • Peripheral blood smear r4c115
      • Usually demonstrates paucity of all cell lines
      • RBC macrocytosis and anisopoikilocytosis r23
      • May show toxic granulations in neutrophils
    • Absolute reticulocyte count c116
      • Reference range: 50 to 100 × 10⁹/L
      • Count will be low, owing to decreased hematopoiesis
      • Used along with CBC results and bone marrow examination to determine if disease falls into severe category (Camitta criteria) r3
        • Severe aplastic anemia
          • Bone marrow cellularity less than 25% of reference range
          • At least 2 of the following:
            • Neutrophil count less than 0.5 × 10⁹/L c117
            • Platelet count less than 20 × 10⁹/L c118
            • Absolute reticulocyte count less than 20 × 10⁹/L
        • Very severe aplastic anemia
          • Fulfills criteria of severe aplastic anemia, plus
          • Neutrophil count less than 0.2 × 10⁹/L
    • Vitamin B₁₂ and folate levels r23c119c120
      • Deficiencies must be documented (and corrected) before diagnosis of aplastic anemia can be confirmed, although bone marrow aplasia from this cause is rare
    • Liver function tests and viral serologies c121c122
      • Liver function tests detect recent or ongoing hepatitis
      • Viral serologies (if liver function test results or history suggest current or antecedent infection)
        • Some experts recommend routine hepatitis serologies in all patients in whom disease appears to be idiopathic r4
          • Majority of cases are associated with infection not stemming from hepatitis A, B, or C r19
          • Posthepatitis aplastic anemia has worse prognosis r18
        • Epstein-Barr virus, cytomegalovirus, HIV, and parvovirus B19 are rare causes of aplastic anemia
    • Flow cytometry c123
      • Identifies paroxysmal nocturnal hemoglobinuria clones
      • Uses monoclonal antibodies, most commonly anti-CD59 (because it is expressed on all cell lineages), to detect deficiency of GPI (glycosylphosphatidylinositol) anchor proteins, which are consistent with a paroxysmal nocturnal hemoglobinuria clone r15
    • Peripheral blood leukocyte telomere length r23c124
      • Screening test for telomere-maintenance gene mutations associated with dyskeratosis congenita
      • Telomere length analysis is performed
      • Test methods include flow cytometric fluorescence in situ hybridization or multiplex quantitative polymerase chain reaction
    • HLA typing r18c125
      • Because of time delay in finding an HLA-suitable donor for those patients who will be treated with bone marrow transplant, typing is usually obtained as part of initial evaluation after diagnosis


    Bone marrow aspiration and trephine (core) biopsy c126c127
    General explanation
    • Under local anesthesia, a small incision is made over the posterior iliac crest (anterior may be used if posterior is unavailable because of injury or obesity) under sterile conditions r24
    • Aspiration: a hollow needle is inserted through bone into the marrow; using a syringe attached to the needle, a sample of the liquid bone marrow is withdrawn
    • Trephine biopsy: a small amount of the spongy bone marrow is removed r24c128
    • All patients with pancytopenia r24
    • No absolute contraindications r24r25
    • Thrombocytopenia is not a contraindication in itself, although many favor performing the procedure when platelet count is greater than 10 × 10⁹/L or during a platelet transfusion r24r25
    • Significant hypocoagulability should be corrected before bone marrow aspiration and/or biopsy if possible r24
    • Serious adverse events are rare and have been reported in less than 0.05% of procedures r25
    • Adverse events r25
      • Bleeding (occurs primarily in patients with coagulation defects)
      • Infection
      • Persistent pain at biopsy site
    Interpretation of results
    • Trephine biopsy specimen will show: r3
      • Hematopoietic hypocellularity
        • Bone marrow hypocellularity less than 30% in children or young adults
          • Older adults may show more hypocellularity on basis of age alone; this cut-off may not be applicable
        • Remaining cells are morphologically normal
      • Fatty marrow without fibrosis or infiltration with malignant cells
    • Evaluate aspirate r3
      • Check cellular morphology
        • Often shows signs of dyserythropoiesis, but dysplasia of megakaryocytes and granulocytes should not be present
      • Perform cytogenic and molecular analysis
        • To rule out inherited genetic syndrome, myelodysplastic syndrome, or other malignancy
    • Send bone marrow sample for cytogenic and molecular testing
      • Next-generation sequencing and gene panels are performed to identify/confirm: r18r23
        • Inherited bone marrow failure syndromes
        • Acquired somatic mutations typical of myeloid malignancies and myelodysplastic syndrome

    Differential Diagnosis

    Most common

    • Myelodysplastic syndrome c129
      • Group of bone marrow failure syndromes usually characterized by hypercellular bone marrow with ineffective hematopoiesis, with variable risk for progression to leukemia r26
        • Some forms of myelodysplastic syndrome have hypocellular bone marrow with excessive cell death accounting for cytopenias; this makes differentiation from aplastic anemia more difficult
        • Diagnostic criteria include meaningful cytopenia (hemoglobin level less than 11 g/dL; absolute neutrophil count less than 1500/mm³; or platelet count less than 100,000/mm³) plus at least 1 of the following:
          • Greater than 5% blasts in bone marrow
          • Greater than 10% of cells in any given hematopoietic lineage that appear dysplastic
          • Abnormal bone marrow karyotype
          • Other evidence of clonal hematopoiesis
        • On physical examination, splenomegaly is usually present in myelodysplastic syndrome but absent in aplastic anemia
        • Maintain a high degree of suspicion of a myelodysplastic syndrome when an elderly patient presents with pancytopenia
      • Differentiate from aplastic anemia by morphologic and cytogenetic analysis of bone marrow cells r26
    • Acute myelogenous leukemia c130d1
      • Replacement of bone marrow by neoplastic cells can result in pancytopenia
      • Although uncommon, hypoplastic anemia may precede onset of acute leukemia by several months
      • Differentiate from aplastic anemia by morphologic and cytogenetic analysis of bone marrow cells
    • Primary myelofibrosis c131
      • Clonal stem cell disorder characterized by myeloproliferation, atypical megakaryocytic hyperplasia, bone marrow fibrosis, and extramedullary hematopoiesis r27
      • Clinically manifests with anemia but usually not other cytopenias r26
      • Splenomegaly and hypercatabolic symptoms may be seen in primary myelofibrosis but not in aplastic anemia r27
      • Differentiate from aplastic anemia with examination of bone marrow (often not aspirable), which shows fibrosis not fatty marrow, as in aplastic anemia r27
    • Inherited bone marrow failure syndromes, of which aplastic anemia is a component
      • Important for therapeutic implications
      • Acquired and inherited forms of aplastic anemia look identical under the microscope, and are differentiated by history, physical findings, and genetic studies
        • Fanconi syndrome r3r4r9c132
          • Recessive genetic disorder (up to 0.5% of population are heterozygous) with diverse congenital malformations, progressive pancytopenia, and predisposition to hematologic malignancies and solid tumors r9
          • Like acquired aplastic anemia, presentation may include progressive pancytopenia
          • Two-thirds of patients with Fanconi syndrome have major congenital abnormalities, with wide phenotypic variability, involving any organ system r9
          • One-third of patients with Fanconi syndrome have only subtle growth or endocrine abnormalities that go unrecognized; these include abnormalities of growth parameters (eg, decreased height, weight, or head circumference) r9
            • In these patients, Fanconi syndrome may not be suspected and pancytopenia may erroneously be attributed to acquired aplastic anemia
          • Differentiate from acquired aplastic anemia with chromosomal fragility testing (quantification of chromosomal breakage with exposure to DNA cross-linking agents), which will show excessive chromosomal breakage with Fanconi syndrome; can be confirmed with cytogenetic testing r9
        • Dyskeratosis congenita r10c133
          • Inherited bone marrow failure syndrome characterized by abnormal nail appearance, reticular skin pigmentation, and oral leukoplakia
          • Patients may develop bone marrow aplasia, myelodysplasia, leukemia, or solid tumors; sometimes presents with aplastic anemia as initial manifestation
          • Telomeres in germline cells are very short; one-half of patients have been found to have mutations in genes encoding proteins that maintain function of telomeres
          • Important to distinguish from acquired aplastic anemia, as these patients do not respond to immunotherapy as patients with aplastic anemia do, and they may not do well with stem cell transplantation
          • Differentiate from acquired aplastic anemia with telomere length analysis r23
        • Shwachman-Diamond syndrome r28c134
          • Autosomal recessive disease characterized by pancreatic insufficiency, skeletal abnormalities, and bone marrow dysfunction
          • May lead to bone marrow failure, myelodysplasia, or leukemia
          • Bone marrow failure in Shwachman-Diamond syndrome does not respond to immunosuppressive treatment, but can be treated with hematopoietic stem cell transplant
          • Differentiate from acquired aplastic anemia with genetic testing, which shows mutation on chromosome 7 in the gene coding for the SBDS protein, which is expressed in multiple organ systems



    • Improve hematopoiesis and blood counts; avoid transfusion dependency


    Admission criteria

    Bleeding complications or severe anemia requiring inpatient treatment or monitoring

    Infection requiring IV antibiotics or inpatient monitoring

    Criteria for ICU admission
    • Severe bleeding requiring ICU-level monitoring and treatment
    • Hypotension or other unstable vital signs
    • Sepsis

    Recommendations for specialist referral

    • Aplastic anemia should be treated by a hematologist-oncologist with experience treating bone marrow failure

    Treatment Options

    Management for all patients diagnosed with aplastic anemia

    • Discontinuation of potential offending drugs or other toxic agents r3
      • Be aware that removal of triggering toxic agent does not reverse aplastic anemia r4
      • Treatment should proceed promptly regardless of possible trigger removal r4
    • Transfusions, if needed to improve quality of life r23
      • To reduce risk of alloimmunization and later graft rejection after hematopoietic stem cell transplant: r4
        • Blood products should be irradiated (or physically leukocyte-depleted) and should not be from a potential later bone marrow donor
        • Although large numbers of transfusions do increase the risk of graft rejection, small numbers of transfusions do not have a major adverse effect on survival; irradiation should reduce this risk
        • Transfusions should not be withheld when clearly necessary
      • Manage symptomatic anemia with packed RBC transfusions
        • No specific guidance for threshold to transfuse; individualize based on comorbidities r23
          • Children may tolerate a hemoglobin level as low as 6 g/dL r18
          • Physically fit adults are usually asymptomatic at hemoglobin levels as low as 7 g/dL r4
          • Older adults and those with cardiopulmonary disease may need target hemoglobin level over 9 g/dL to avoid symptoms r4
          • If repeated RBC transfusions are required, monitor for iron overload; consider chelation therapy when the serum ferritin is greater than 1000 μg/L r29
      • Manage bleeding risk with platelet transfusions if necessary
        • In absence of bleeding, platelets are commonly given only when counts decline to 10 × 10⁹/L or lower r18
          • Some experts will not transfuse platelets in the absence of bleeding until counts decrease to 5 × 10⁹/L or lower r4
        • If there is active bleeding, threshold to transfuse platelets is generally set at 20 × 10⁹/L or higher r18
    • Avoidance of other bleeding risk
      • Hormonal suppression of menses in females r18
        • Continuous oral contraceptives
        • Gonadotropin-releasing hormone agonists
      • Avoidance of contact sports and activities with high risk for falls or injuries
    • Infection prevention and management
      • Good hand hygiene and avoidance of sick contacts is prudent for all patients, and imperative for patients with severe aplastic anemia
      • There is no current standard for infection prophylaxis; treatment is individualized because of the long-term nature of neutropenia r8
        • May include antibiotic, antifungal, and antiviral prophylaxis r29
      • Fever in the setting of a neutrophil count less than 0.5 × 10⁹/L is treated as a medical emergency with hospital admission, obtaining cultures, and administration of broad-spectrum parenteral antibiotics r4

    Further treatment will depend on severity of illness, patient age, and need for transfusion

    • Determine severity by modified Camitta criteria
      • Nonsevere aplastic anemia r3
        • Decreased bone marrow cellularity and peripheral blood cytopenia
        • Does not fulfill criteria for severe aplastic anemia
      • Severe aplastic anemia r3
        • Bone marrow cellularity less than 25% of reference range
        • At least 2 of the following criteria:
          • Neutrophil count less than 0.5 × 10⁹/L
          • Platelet count less than 20 × 10⁹/L
          • Reticulocyte count less than 20 × 10⁹/L
      • Very severe aplastic anemia r3
        • Fulfills criteria of severe aplastic anemia, plus
        • Neutrophil count less than 0.2 × 10⁹/L
        • Treated with same approach as severe aplastic anemia
    • Nonsevere aplastic anemia r3r4r30
      • Determine if transfusion-dependent
        • Definition is somewhat controversial, but RBC-transfusion dependence has been defined by 1 expert panel of hematologists as requiring an average of 2 units of packed red blood cells per month over a 3-month period r31
      • Observation with monitoring of CBC may be acceptable if patient is not transfusion-dependent r3r32
      • Transfusions, if needed
    • Severe aplastic anemia, very severe aplastic anemia, and transfusion-dependent nonsevere aplastic anemia
      • Matched sibling hematopoietic stem cell transplant, if available r3r4r6
        • First line treatment for children and young adults r1r23
        • Second line for older adults whose condition does not respond to first line immunosuppressive therapy r23
        • In the absence of a matched sibling donor, a matched, unrelated donor hematopoietic stem cell transplant is considered a safe and feasible alternative first line treatment for children and young adults r1r2
      • Immunosuppressive therapy
        • First line treatment for older adults (older than 35-50 years; no strict upper age limit, but mortality increases if patient is older than 60 years) r23
        • Second line for children and young adults (first line in the absence of an appropriate donor for hematopoietic stem cell transplant) r1r23
        • Standard regimen includes:
          • Equine antithymocyte immune globulin on days 1 to 4, plus cyclosporine daily (recommended duration of therapy varies from 6-12 months) r23
          • Prednisone or methylprednisolone in modest dose to ameliorate serum sickness during antithymocyte immune globulin therapy r4
          • This combination is well tolerated, with improvement expected in 3 to 6 months. Response rate is 60% to 70% r4
            • Patients may need to be maintained on cyclosporine after initial treatment
            • Relapse is common but not a sign of poor prognosis
        • Addition of eltrombopag (synthetic thrombopoietin receptor agonist) to standard immunosuppressive regimen increases overall response to 80% r6r33
          • About 50% of patients show trilineage improvements, which last after discontinuation r6
      • Mismatched unrelated donor hematopoietic stem cell transplant
        • Indicated in children who fail to respond to immunosuppressive therapy and have no suitable matched donor r1
      • Options for patients who are refractory to immunosuppressive therapy and have no suitable matched/mismatched donor include r1
        • Clinical trial, if 1 is available
        • Second course of immunosuppressive therapy r1
        • Androgens r1
          • Generally less effective than immunosuppression but may be tried when immunosuppression fails; options include: r4r6
            • Danazol
            • Oxymetholone
            • Nandrolone decanoate
          • Hepatotoxicity may be limiting
          • Most commonly used outside of the United States in medical settings where antithymocyte immune globulin is unavailable
        • Monoclonal antibodies
          • Alemtuzumab r1
            • Monoclonal antibody against CD52
            • Alemtuzumab can been used alone in refractory cases with a response rate of 37% r34
        • Thrombopoietin receptor agonists
          • Eltrombopag
            • Non-peptide thrombopoietin receptor agonist that acts as a bone marrow stimulating agent r35
            • Approved for use alone in patients with refractory severe aplastic anemia r6
            • Some experts avoid using in patients with clonal cytogenetic abnormalities as it may promote expansion of dormant preexisting clones with an aberrant karyotype r36
          • Romiplostim
            • Thrombopoietin agonist that is approved to treat immune thrombocytopenia r37
            • Demonstrated efficacy in patients with refractory aplastic anemia in a phase 3 clinical trial r38
        • Haploidentical or unrelated umbilical cord blood hematopoietic stem cell transplant r1
          • Considered a reasonable and potentially curative option for patients who: r39
            • Are nonresponsive to immunosuppressive therapy
            • Relapsed after immunosuppressive therapy
            • Acquired a secondary clonal disorder (ie, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria) after immunosuppressive therapy
      • Hematopoietic growth factors r40
        • Routine use of traditional hematopoietic growth factors is not recommended
        • While trials of traditional growth factors (eg, erythropoietin, granulocyte colony-stimulating factor) are sometimes used clinically, a meta-analysis of trials showed no effect on mortality, relapse, risk of malignancy, or infection, and no difference in overall hematologic response to other treatments

    Drug therapy

    • Immunosuppressive therapy
      • For severe, very severe, or transfusion-dependent nonsevere aplastic anemia r3r4r6r8r32
        • Equine antithymocyte immune globulin c135c136
          • Anti-Thymocyte Immune Globulin (Equine) Solution for injection; Adults, Adolescents, and Children: 40 mg/kg once daily for 4 days in combination with cyclosporine. r3r32
        • Cyclosporine; duration of treatment varies c137c138
          • Cyclosporine Oral capsule; Adults and Children: 12 mg/kg/day PO in adults or 15 mg/kg/day PO in children and antithymocyte globulin (ATG).
        • Prednisone or methylprednisolone to ameliorate serum sickness c139c140
          • Prednisone Oral tablet; Children, Adolescents, and Adults: 1 mg/kg/day PO in divided doses for 2 weeks.
          • Methylprednisolone; Infants, Children, Adolescents, and Adults: 1 mg/kg/day PO, IV, or IM in 1 to 4 divided doses for 2 weeks.
    • Hematopoietic growth factor
      • Eltrombopag c141
        • For use as an adjunct to immunosuppressive therapy
          • Eltrombopag Oral suspension; Children 2 to 5 years: 2.5 mg/kg/dose PO once daily, initially; for persons of East/Southeast-Asian ancestry, 1.25 mg/kg/dose PO once daily, initially. Treat for 6 months. Reduce dose based on platelet count and hepatic enzyme concentrations; use the lowest effective dose. Do not exceed initial dose.
          • Eltrombopag Oral suspension; Children 6 to 11 years: 75 mg PO once daily initially; for persons of East/Southeast-Asian ancestry, 37.5 mg PO once daily, initially. Treat for 6 months. Reduce dose based on platelet count and hepatic enzyme concentrations; use the lowest effective dose. Do not exceed initial dose.
          • Eltrombopag Olamine Oral tablet; Children and Adolescents 12 to 17 years: 150 mg PO once daily, initially; for persons of East/Southeast-Asian ancestry, 75 mg PO once daily, initially. Treat for 6 months. Reduce dose based on platelet count and hepatic enzyme concentrations; use the lowest effective dose. Do not exceed initial dose.
          • Eltrombopag Olamine Oral tablet; Adults: 150 mg PO once daily, initially; for persons of East/Southeast-Asian ancestry, 75 mg PO once daily, initially. Treat for 6 months. Reduce dose based on platelet count and hepatic enzyme concentrations; use the lowest effective dose. Do not exceed initial dose.
      • For use in adults with refractory severe aplastic anemia
        • Eltrombopag Olamine Oral tablet; Adults: 50 mg PO once daily, initially; for patients of East/Southeast-Asian ancestry, 25 mg PO once daily, initially. Adjust dose by 50 mg/day PO every 2 weeks as necessary to achieve the target platelet count; use the lowest effective dose. Max: 150 mg/day.

    Nondrug and supportive care

    Hematopoietic stem cell transplantation c142
    General explanation
    • Patient is prepared with immunosuppressive conditioning regimen to improve engraftment by eliminating recipient lymphocytes (usually antithymocyte immune globulin and cyclosporine with or without total body irradiation, or a variation of this combination)
    • Bone marrow or peripheral blood is retrieved from donor; obtaining stem cells from bone marrow achieves lower risk of graft-versus-host disease than from peripheral blood stem cells
    • Stem cells are removed from donor tissue and infused into recipient
    Indication r3r4r8r32
    • Severe aplastic anemia
      • First line treatment in children or young adults with matched sibling; a matched unrelated donor is an alternative if matched sibling donor is not available
      • Older adults whose condition does not respond to immunotherapy, regardless of matched donor status; haploidentical donor can be considered
    • Early
      • Graft rejection r41
        • Occurs when immunologically competent host cells destroy transplanted donor cells
        • More common in aplastic anemia than in other indications for stem cell transplant
        • Defined by failure of hematopoietic response by day 100 after hematopoietic stem cell transplant r42
      • Graft-versus-host disease r41
        • Major complication that occurs when donor immune cells from graft becomes sensitized to and attack host tissue
        • Acute disease characterized by rash, jaundice, and diarrhea
        • Chronic disease affects multiple organs and may lead to death
        • About one-half of patients respond to steroids or other immunosuppressive treatment
    • Late r3r4r41r43
      • Impaired gonadal function
        • Primarily in children who received total body irradiation
      • Impaired growth and development
      • Secondary malignancies
        • More common in patients who received total body irradiation
        • Lymphoid malignancies: risk decreases over time
        • Solid tumors: risk continues over time
      • Long-term follow-up of children showed complications of hepatitis C, as original treatment occurred before isolation of virus and ability to screen r43
      • Chronic graft-versus-host disease
    Interpretation of results
    • Peripheral blood counts are used to determine success; response should be seen before 100 days posttransplant r41
      • A small group of patients will see recovery between 3 and 6 months r32
      • Hematologic response is defined as no longer meeting criteria for severe aplastic anemia r32

    Allogeneic stem cell transplantation from an HLA-matched sibling donor is curative in over 90% of children and 80% of adolescents and does not require prior irradiation r6

    Well-matched alternative donor stem cells may achieve a good result but with a higher risk of graft-versus-host disease; prior irradiation decreases risk of graft-versus-host disease r3r44

    • Alternative donors are usually HLA-matched unrelated donors, but haploidentical donors may be an acceptable option for young patients when no matched donor is available
    • Umbilical cord blood transplant is a second line treatment option used mainly in children with no matched sibling donor; there is an increased rate of graft rejection r3


    • Patients responsive to treatment are followed for relapse and clonal evolution
      • There are no clear guidelines, but expert opinion seems to agree on the following:
        • Regular and frequent peripheral blood counts c143
        • Peripheral blood counts should guide management, rather than marrow cellularity r32
        • Bone marrow biopsy at 6 and 12 months, then yearly after treatment to monitor for morphology and karyotype r32c144
        • Marrow is expected to remain hypocellular for long periods r32

    Complications and Prognosis


    • Relapse after immunosuppressive therapy or hematopoietic stem cell transplant r6r32c145
      • Relapse alone is not correlated with decreased survival
      • Initially, treat with immunotherapy
      • Further treatment will be individualized
      • Relapse is most likely to occur in the first 2 to 4 years after treatment
    • Clonal evolution to myelodysplastic syndrome, acute myelogenous leukemia, or paroxysmal nocturnal hemoglobinuria r6r32c146
      • Clonality may be present as an intrinsic feature of aplastic anemia, but increases after immunosuppressive therapy
        • Between 10% and 15% of adult patients will go on to develop clonal evolution after immunosuppressive therapy
          • Children have a lower rate of clonal progression r2
        • Paroxysmal nocturnal hemoglobinuria is the most common clonal hematopoietic disorder arising in patients with aplastic anemia r45
        • Most likely to occur in the first 2 to 4 years after treatment
        • Clonal evolution with the 3-drug immunosuppressive regimen (antithymocyte immune globulin and cyclosporine plus eltrombopag) appears to be similar to that with antithymocyte immune globulin plus cyclosporine alone r46
      • Hematopoietic stem cell transplant may be the only option for patients with clonal evolution
    • Chronic graft-versus-host disease after hematopoietic stem cell transplant r4c147
    • Solid tumors as late complications of hematopoietic stem cell transplant r4


    • Prognosis for acquired aplastic anemia has improved over past decades with better immunosuppressive therapies, deeper knowledge of hematopoietic stem cell transplantation, and novel drug treatment r6
    • Children with matched sibling donors have a cure rate over 90% and studies show excellent long-term quality of life for survivors r47
    • Adolescents have a cure rate of about 80% with a matched sibling donor r48
    • Matched unrelated donor transplantations are now achieving excellent results, particularly in children r49
    • Initial immunotherapy in those who are not candidates for hematopoietic stem cell transplant has a 60% to 70% response rate and, while relapse occurs in approximately 30%,r14 these patients usually respond to further immunosuppression. Addition of eltrombopag significantly increases the response rate r2r32
    • Long-term survival rate among children who respond to first line immunosuppressive therapy is comparable to those who have received an up-front matched sibling donor hematopoietic stem cell transplant r14
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