Anemia, Aplastic

Essentials of Diagnosis

• Pancytopenia

• No abnormal hematopoietic cells seen in blood or bone marrow

• Hypocellular bone marrow

General Considerations

• In aplastic anemia, bone marrow failure arises from suppression of or injury to the hematopoietic stem cell

• Bone marrow becomes hypoplastic, fails to produce mature blood cells, and pancytopenia develops

Causes of aplastic anemia

• "Idiopathic" (probably autoimmune)

• In some cases of "idiopathic" aplastic anemia, defects have been identified in maintenance of the hematopoietic stem cell telomere length (dyskeratosis congenita) or in DNA repair pathways (ie, Fanconi anemia)

  • Likely linked to initiation of marrow failure

  • May be associated with progression to myelodysplasia, paroxysmal nocturnal hemoglobinuria (PNH), or acute myeloid leukemia

• Complex detrimental immune response to viruses

• Drugs

  • Chloramphenicol

  • Phenylbutazone

  • Gold salts

  • Sulfonamides

  • Phenytoin

  • Carbamazepine

  • Quinacrine

  • Tolbutamide

• Chemotherapy, radiotherapy

• Systemic lupus erythematosus

• Toxins: benzene, toluene, insecticides

• Posthepatitis

• Pregnancy

• Paroxysmal nocturnal hemoglobinuria

• Congenital (rare)

Symptoms and Signs

• Weakness, pallor and fatigue from anemia

• Vulnerability to bacterial or fungal infections from neutropenia

• Mucosal and skin bleeding (petechiae and purpura) from thrombocytopenia

• Hepatosplenomegaly, lymphadenopathy, or bone tenderness should not be present

Differential Diagnosis

• Acute leukemia

• Hairy cell leukemia

• Hypocellular forms of myelodysplasia

• Bone marrow infiltrative process (eg, tumor, infection, granulomatous disease)

• Hypersplenism

• Systemic lupus erythematosus

• Nutritional deficiency (eg, vitamin B₁₂ or folate)

• Immune thrombocytopenia

Laboratory Tests

• Pancytopenia, although in early disease only one or two cell lines may be reduced

• Anemia may be severe

• Reticulocytopenia is always present

• Red blood cell morphology is unremarkable, but there may be mild macrocytosis (increased MCV)

• Neutrophils and platelets reduced in number, no immature or abnormal forms seen

• Severe aplastic anemia defined by neutrophils < 500/mcL, platelets < 20,000/mcL, reticulocytes < 1%, and bone marrow cellularity < 20%

Diagnostic Procedures

• Bone marrow aspirate and bone marrow biopsy appear hypocellular, with scant amounts of morphologically normal hematopoietic progenitors

Medications

• Antibiotics to treat infections

• Immunosuppression with equine antithymocyte globulin (ATG) plus cyclosporine for severe aplastic anemia in adults aged > 40 or those without HLA-matched siblings

• Useful regimen is equine ATG, 40 mg/kg/day intravenously for 4 days, in combination with cyclosporine, 6 mg/kg orally twice daily, given in hospital in conjunction with corticosteroids, and transfusion and antibiotic support

• Corticosteroids are given with ATG (prednisone or methylprednisolone, 1–2 mg/kg/day orally for 1 week followed by taper over 2 weeks) to avoid ATG infusion reactions and serum sickness

• Equine ATG is superior to rabbit ATG

• Androgens (such as fluoxymesterone, 10–20 mg/day orally in divided doses)

  • Used widely used in the past, with a low response rate

  • May be considered in mild cases

  • Appear to partially correct telomere length maintenance defects

  • Appear to increase the production of endogenous erythropoietin

• Eltrombopag

  • A thrombopoietin mimetic

  • In combination with ATG plus cyclosporine, tri-lineage hematologic responses are as high as 90%

Therapeutic Procedures

• Supportive care, including erythropoietic (epoetin or darbepoetin) or myeloid (filgrastim or sargramostim) growth factors, only for mild cases

• Allogeneic bone marrow transplantation is treatment of choice for severe aplastic anemia in adults aged < 40 with HLA-matched siblings

• Allogeneic transplantation using unrelated donor if immunosuppression is not effective

• Red blood cell and platelet transfusions as necessary

Complications

• Bacterial infections

• Bleeding

Prognosis

• Patients with severe aplastic anemia have a rapidly fatal illness if left untreated

• Allogeneic bone marrow transplantation from an HLA-matched sibling donor produces a survival rate over 80% in recipients under 20 years of age and about 65–70% in those 20–50 years of age

• Respective survival rates drop 10–15% when the donor is HLA-matched but unrelated

• Equine ATG-cyclosporine immunosuppressive treatment leads to a response in approximately 70% of patients, including those with hepatitis virus–associated aplastic anemia

• Up to one-third of patients will relapse with aplastic anemia after ATG-based therapy

• Factors that predict response to ATG-cyclosporine therapy

  • Age

  • Reticulocyte count

  • Lymphocyte count

  • Age-adjusted telomere length of leukocytes at the time of diagnosis

• PNH, acute myeloid leukemia, or myelodysplasia develop in as many as 25% of patients treated with immunosuppressive therapy after 10 years of follow-up

When to Refer

• All patients should be referred to hematologist

When to Admit

• Treatment of neutropenic infection

• Administration of ATG

• Allogeneic bone marrow transplantation