• Unknown/idiopathic (50%–75%)
• Hepatitis (and untypable), EBV, CMV, Parvo-virus B19, HIV
• Drugs, e.g., chloramphenicol, oxyphenylbutazone, quinacrine, cimetidine, carbamazepine
• Toxins, e.g., heavy metals, aromatic hydrocarbons (benzenes)
• Radiation
• Autoimmune diseases

• Fanconi anemia
• Dyskeratosis congenita
• Paroxysmal nocturnal hemoglobinuria

• Hematopoietic stem cell has an intrinsic proliferative defect
• Autoimmune reaction against the stem cell
• Abnormal stromal cells of the bone marrow microenvironment
• Genetic predisposition

• Most cases are sporadic
• Several rare disorders are associated with aplastic anemia; of these, Fanconi anemia is a congenital disorder in which most patients are predisposed to develop aplastic anemia within the first decade and is generally associated with multiple congenital anomalies; inheritance is autosomal recessive with variable penetrance and genetic heterogeneity

• Incidence in United States and Europe is 3.5 to 5.4 cases per million per year
• Two major age peaks: 15 to 25 years and above 60 years
• Males and females affected equally
• Increased incidence in Asia presumably related to environmental factors

• Infection: especially fungal (Aspergillus) or gram negative bacteria
• Hemorrhage: intracranial, especially if refractory to platelet transfusions
• Hemosiderosis secondary to long-term red blood cell transfusions, with subsequent organ dysfunction if untreated

• In patients with severe aplastic anemia, 90% fatal within first year if untreated
• Bone marrow transplant (HLA identical matched sibling) group
  • 70% overall survival
  • 80% to 90% survival for the young, uninfected, and minimally transfused group of patients
• Medical immunosuppressive therapy
  • 75% survival
• Factors associated with poor outcome:
  • Bleeding at presentation
  • Acute onset with severe pancytopenia
  • Pancytopenia greater than 1 month
  • Male sex
  • MCV not elevated

• Acute leukemia
• Myelodysplastic syndrome
• Paroxysmal nocturnal hemoglobinuria
• Folate or B₁₂ deficiency
• Acute drug reaction with bone marrow suppression
• Acute infection (viral) with bone marrow suppression, e.g., HIV-1, CMV, Parvovirus B19, Epstein-Barr virus
• Marrow infiltration by malignant tumors, e.g., non-Hogkin lymphoma, neuroblastoma
• Hemophagocytic lymphohistiocytosis (also known as Familial Erythrophagocytic Lymphohistiocytosis)

Question: Lethargy
Significance: Symptom of anemia

Question: Pallor
Significance: Sign of anemia

Question: Bruising
Significance: Due to thrombocytopenia

Question: Bloody stools
Significance: Thrombocytopenia, mucosal ulceration

Question: Nosebleeds
Significance: Thrombocytopenia

Question: Gum bleed
Significance: Thrombocytopenia

Question: Fevers
Significance: Infection associated with neutropenia

• Drug or toxin exposure (although usually not identified)
• History of hepatitis or jaundice

Finding: Skin bruising, petechiae, pallor, jaundice
Significance: Thrombocytopenia

Finding: Fundal exam
Significance: Detects retinal hemorrhages

Finding: Sinus tenderness
Significance: Infection

Finding: Gum bleeds, thrush, petechiae, oral ulcerations
Significance: Neutropenia, candida colonization

Finding: Adenopathy
Significance: Suggests leukemia, cancer

Finding: Liver/spleen enlarged
Significance: Suggests leukemia, cancer

Finding: Perianal ulcerations infection
Significance: Infection and/or neutropenia

Finding: Skeletal anomalies (as seen in Fanconi anemia)
Significance: Seen in Fanconi anemia

Test: CBC with differential and reticulocyte count
Significance:

• Severe (2 of the following):
  • Granulocyte count <500 cells per fL
  • Platelet count <20,000 per fL
  • Reticulocyte count (corrected for hematocrit) <1%
• Mild or moderate (hypoplastic anemia)
  • Mild or moderate cytopenia

Test: Bone marrow aspirate and biopsy
Significance:

• Severe aplastic anemia:
  • Hypocellular
• Mild or moderate aplastic anemia: normal or increased cellularity may be seen

Test: MRI of lumbar/thoracic spine (investigational)
Significance: T₁-weighted images reveal marrow cellularity based on fat content

Test: Bone marrow aspirate and chromosomes for karyotype
Significance: Myelodysplastic syndrome/acute leukemia

Test: Peripheral blood lymphocytes to assess chromosomal breakage
Significance: Fanconi anemia

Test: Ham test
Significance: Paroxysmal nocturnal hemoglobinuria

Test: Folate and B₁₂ levels
Significance: Macrocytic anemia with neutropenia

Test: Chemistry panel with liver function tests, hepatitis serology
Significance: Hepatitis associated with aplastic anemia

• Bone marrow transplantation
  • Therapy of choice for severe aplastic anemia
  • For patients with HLA identical sibling (15%–20% of U.S. population)
• Immunosuppressive therapy
  • Anti-thymocyte globulin and cyclosporine
• Androgens
  • Used for the treatment of aplastic anemia associated with Fanconi anemia
• Supportive therapy
  • Growth factors (G-CSF, GM-CSF, erythropoietin, IL-3, IL-11, stem cell factor, thrombopoietin)
  • Transfusion support: no first degree relatives (could interfere with bone marrow transplantation), CMV negative, irradiated, leukodepleted, try to have a limited donor pool and minimize the number of transfusions
  • Infectious disease support: pan culture and institute broad spectrum antibiotics if febrile and neutropenic, antifungal oral prophylaxis, handwashing, cooked food, nail care, avoid construction sites (often a source of fungus)

• Rate 10%; most are still salvageable
• Salvage therapy: unrelated donor bone marrow transplant (prognosis 30%–40%)

• 5%–10% risk of myelodysplastic syndrome or paroxysmal nocturnal hemoglobinuria

Q: Can family members donate blood for a child with aplastic anemia?
A: This is not recommended as transfusion with blood products from parents or siblings increases the risk of nonengraftment of bone marrow in the setting of bone marrow transplantation.

Q: What activities should a child with aplastic anemia avoid?
A: Patients with low red blood cell counts should avoid excessive exercise or going to high altitudes. Patients with low white blood cell counts are more susceptible to infection with bacteria but not with viruses. Patients should avoid dental work as this may introduce bacteria into the blood stream through the mouth. Patients with low platelet counts should avoid contact sports, including football, hockey, skiing, roller blading, etc.

Q: How does one learn more about experimental therapies for the treatment of aplastic anemia?
A: Inquiries to the National Institute of Health in Bethesda, Maryland, or to the Hematology division of the nearest medical school or NIH designated cancer center should result in information about the availability of experimental therapies.