Aplastic Anemia

Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Specifically known acquired causes and associations of AAs include medications, chemicals, high doses of whole-body radiation, viral infections, immune diseases, and pregnancy. Inherited or constitutional syndromes associated with AA include Fanconi anemia, dyskeratosis congenita, and Down syndrome. Therapies include transfusion support, immunosuppression, and bone marrow transplantation.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Epidemiology and Etiology


  • Varying incidence worldwide 
    • Incidence in Europe: 2.35 per 1 million 
    • Incidence in Asia: 7 per 1 million 
  • No sex preference
  • Acquired aplastic anemia (AA): biphasic age distribution → major peak in the teens to twenties; 2nd peak in the elderly


Inherited conditions: 

  • Intrinsic defect(s) in hematopoietic stem cells
  • Fanconi anemia: 
    • Autosomal recessive inheritance
    • Inability to repair certain types of damage to the DNA
    • Cell damage occurs in multiple cell types, including hematopoietic stem cells.
  • Dyskeratosis congenita: a telomere biology syndrome with different inheritance patterns involving multiple differing genes
  • Shwachman-Diamond syndrome: gene mutations affecting ribosome biogenesis and mitosis
  • Diamond-Blackfan anemia: gene mutations affecting ribosome synthesis
  • Trisomy 21/Down syndrome: can lead to multiple hematologic disorders (AA less often than myeloproliferative diseases or leukemia)

Acquired AA: 

  • Autoimmune or other types of damage to hematopoietic stem cells
  • Idiopathic: 
    • Most cases (80%–85%)
    • Immune-mediated: increased numbers of activated cytotoxic T cell clones
  • Medications and other agents: 
    • Allopurinol 
    • Antihistamines
    • Antithyroid agents
    • Antiprotozoals
    • Anticonvulsants
    • Cytotoxic chemotherapeutic drugs
    • Chloramphenicol
    • D-penicillamine
    • NSAIDs 
    • Sulfonamides
    • Other agents
      • Benzene
      • Estrogens 
      • Heavy metals: gold, arsenic, bismuth, mercury
  • Radiation to the whole body: 
    • Nuclear accidents → direct damage to DNA
    • AA is an acute sequela.
    • Myelodysplasia and leukemia are late effects.
  • Viruses may alter antigens on stem cells activating a cytotoxic T cell clone, or initiating T cell release of cytokines:
    • EBV
    • CMV
    • Human immunodeficiency virus (HIV)-1, AIDS
    • Parvovirus B19 (transient AA, more commonly causes pure red cell aplasia)
    • Seronegative hepatitis (most likely due to a yet-unknown virus)
  • Immune diseases (e.g., eosinophilic fasciitis, thymoma)
  • Clonal evolution (AA may be associated with another hematologic disorder):
    • Paroxysmal nocturnal hemoglobinuria (PNH):
      • Approximately 50% of patients with AA show an expanded clonal population with the PNH defect by flow cytometry. 
      • Approximately 15% of patients with PNH develop pancytopenia at 8 years. 
    • Myelodysplastic syndrome
    • AML
  • Pregnancy


Normal hematopoiesis

  • At birth: Hematopoiesis is present throughout the entire skeleton, with islands of residual hematopoiesis remaining in the liver for 1 month.
  • After puberty: Hematopoiesis ceases in distal bones and becomes restricted to the axial skeleton (skull, sternum, ribs, vertebrae, head of humerus and femur, and pelvis).
    • In normal adults, only about half of the marrow space is hematopoietically active (red marrow); the inactive marrow is fatty (yellow marrow).
    • Bone marrow cellularity decreases 10% every decade.
Renal myelolipoma

Normal hematopoiesis (all 3 cell lines present) with a megakaryocyte near the center of the field (H&E, 200x)

Image: “Histologic findings” by Department of Pathology, Ibn Sina University Hospital, Rabat, Morocco. License: CC BY 2.0

Aplastic anemia

  • Peripheral blood: 
    • Decrease in all 3 cell lines, e.g., WBCs, RBCs, and platelets (= pancytopenia)
    • No abnormal (e.g., dysplastic or leukemic) cells present and no evidence of hemolysis
  • Bone marrow: hypocellular for age; no abnormal cells or marrow fibrosis
  • Various degrees of severity

Clinical Presentation

  • Anemia: pallor, headache, palpitations, dyspnea, fatigue
  • Thrombocytopenia: mucosal and gingival bleeding or petechial rashes
  • Neutropenia: overt infections, recurrent infections, fever, oropharyngeal ulcers
  • May see congenital malformations in the associated inherited disorders
Features of aplastic anemia

Fanconi anemia malformation:
A: Fanconi facies with tapering jaw
B: Polydactyly
C: Chromosomal breaks in lymphocytes in peripheral blood

Image: “Figure 1” by Shabneez Hussain, Salman Naseem Adil. License: CC BY 2.0


History and physical exam

  • Check for exposure to drugs or chemicals.
  • Check for viral infection.
  • Family history: cytopenias and/or somatic findings suggestive of an inherited disorder 
  • Physical findings:
    • Associated with pancytopenia, especially pallor and petechiae
    • Complications of the cytopenias (e.g., cardiovascular system, infections)
    • Manifestations of inherited disorders (e.g., cutaneous/nail findings, short stature, skeletal or genitourinary abnormalities, eye/ear findings)
    • Enlargement of liver, spleen, or lymph nodes suggests negative for AA.

Bone marrow biopsy

Pancytopenia with a hypocellular bone marrow showing:

  • No abnormal infiltrates (no leukemic blasts or evidence of megaloblastic anemia)
  • No marrow fibrosis (as seen in myeloproliferative disorders)
  • No myeloid dysplasia (as seen in myelodysplastic syndrome)
  • Only 1 cell line may be suppressed before profound pancytopenia arrives!

Laboratory studies

  • Electrolytes, liver function tests, lactate dehydrogenase, renal function tests
  • Serum vitamin B12 and RBC folate level to exclude megaloblastic anemia
  • Flow cytometry to detect PNH (absence of CD59 and CD55 on blood cells) 
  • Cytogenetic and molecular testing of bone marrow to exclude certain inherited disorders

Categories of severity

  • Moderate AA (= nonsevere AA):
    • Bone marrow cellularity < 25% 
    • Peripheral blood cytopenias not fulfilling criteria for severe AA 
  • Severe AA:
    • Bone marrow cellularity < 25%
    • At least 2 of the following in the peripheral blood count: 
      • Absolute neutrophil count < 500/μL 
      • Platelet count < 20,000/μL 
      • Reticulocyte count < 20,000/μL


Moderate aplastic anemia

  • Remove potential causative drugs or agents.
  • Transfusions and antiinfective therapy if needed
  • Wait to treat since spontaneous remission may occur (if caused by a virus or a drug).
  • Treat if AA transforms to a more severe form or becomes transfusion-dependent.

Severe aplastic anemia

  • Remove potential causative drugs or agents.
  • Transfusions and antiinfective therapy if needed
  • If under 50 years old and medically fit:
    • Triple therapy: includes 2 immunosuppressants + 1 bone marrow stimulant
      • Horse anti-thymocyte globulin
      • Cyclosporine 
      • Eltrombopag (thrombopoietin receptor agonist)
    • Allogeneic hematopoietic cell transplantation (HCT)
  • If > 50 years old, or if not medically fit: only triple therapy

Differential Diagnosis

  • Reversible bone marrow suppression: predictable, dose-dependent effects of cytotoxic chemotherapy, accidental radiation therapy, severe sepsis, or acute viral infection. Diagnosis is made by history, microbiological testing, and serology testing. Blood counts are expected to improve over days to weeks.
  • Megaloblastic anemia: due to deficiencies of vitamin B12 (pernicious anemia) and/or folate (malnutrition). Peripheral blood smear shows hypersegmented neutrophils and macro-ovalocytes; bone marrow shows megaloblasts. Low serum levels of vitamin B12 (or methylmalonic acid) and/or folate can confirm the diagnosis. The patient is managed with vitamin supplementation.
  • Infiltrative disorders of the bone marrow: can be due to fibrosis (e.g., myelofibrosis), malignancies, or infectious agents (e.g., tuberculosis, fungi). Peripheral blood smear often shows abnormally shaped cells (poikilocytes), tear-drop cells, and leukoerythroblastic changes (i.e., both immature WBCs and immature/nucleated RBCs). Bone marrow is usually diagnostic of infectious cases, or abnormalities seen in malignancies.
  • Hypersplenism: Cytopenias due to sequestration associated with splenomegaly may be caused by liver cirrhosis, portal vein thrombosis, and bone marrow infiltrative disorders. The cytopenia is not as severe as seen in AA or other disorders. Bone marrow exam reveals normal or increased hematopoietic activity.
  • Myelodysplastic syndrome: usually shows a full marrow with peripheral cytopenia. Bone marrow shows cellular dysplastic changes and/or characteristic myelodysplastic syndrome cytogenetic or molecular abnormalities. Myelodysplastic syndrome may respond to the same triple therapy used for AA.
  • Large granular lymphocyte leukemia: a leukemia characterized by cytopenias, splenomegaly, and infiltration of peripheral blood and bone marrow by large granular lymphocytes, which may coexist with AA. Diagnosis is possible with flow cytometry and molecular testing.


  1. Montané, E., Ibáñez, L., Vidal, X., Ballarín, E., Puig, R., García, N., Laporte, J. R., & Catalan Group for Study of Agranulocytosis and Aplastic Anemia (2008). Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica, 93(4), 518–523. https://doi.org/10.3324/haematol.12020
  2. Olson, T.S. (2019). Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis. Uptodate. Retrieved November 23, 2020, from https://www.uptodate.com/contents/aplastic-anemia-pathogenesis-clinical-manifestations-and-diagnosis
  3. Young, N.S. (2018). Bone marrow failure syndromes including aplastic anemia and myelodysplasia. In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. Vol 1, pp. 723–728. 
  4. Red Blood Cell and Bleeding Disorders (2020). In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.). Robbins & Cotran Pathologic Basis of Disease, 10th ed. pp. 659–660.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.