Epidemiology

• Aplastic anemia is primarily a disease of children and younger adults. There is another peak in incidence in patients 60 years of age and older, although in these older patients some reported cases of aplastic anemia may represent cases of hypoplastic myelodysplastic syndrome (hMDS).
• Aplastic anemia is rare in Western Europe and the United States (less than 2 cases per million population per year). Aplastic anemia is more common in Asia than in Western countries, and several epidemiologic studies have determined an incidence of 3.9 cases per million in Bangkok, 6 cases per million in rural areas of Thailand, and 14 cases per million in Japan.
  • The higher incidence in Asian countries has been linked to environmental factors, such as exposure to chemicals like insecticides, more than genetic factors.
• Both males and females are equally affected.

• Rarely, acute EBV infection can be complicated by the development of aplastic anemia.

• Unlike agranulocytosis and drug-induced thrombocytopenia, stopping the putative drug does not usually lead to hematopoietic recovery. Most cases of drug-induced aplastic anemia lead to an idiosyncratic immune response directed against hematopoietic progenitor cells and are managed similarly to all patients with idiopathic aplastic anemia with the addition of stopping the offending agent.
• There are no convincing data that B19 parvovirus causes aplastic anemia, but this virus is often linked with aplastic anemia due to the unfortunate term “aplastic crisis” used to describe the transient red cell aplasia and severe anemia that occur in sickle cell anemia patients (or others with chronic hemolytic anemia) who are acutely infected with B19 parvovirus.

Pathophysiology

• Cytotoxic T lymphocytes were found to mediate the destruction of hematopoietic stem cells in aplastic anemia.
  • These cytotoxic T cells are more conspicuous in the bone marrow of aplastic anemia patients than in the peripheral blood, and they overproduce interferon-γ and tumor necrosis factor (TNF).
  • TNF and interferon-γ are direct inhibitors of hematopoiesis and appear to upregulate Fas expression on CD34+ cells.
  • T cells from aplastic anemia patients kill hematopoietic stem cells in an HLA-DR-restricted manner via Fas ligand.
  • A reduction in the number of hematopoietic stem/progenitor cells is a universal laboratory finding in aplastic anemia.
  • The bone marrow shows hypoplasia, with loss of haemopoietic tissue and replacement by fat which comprises over 75% of the marrow. Trephine biopsy may show patchy cellular areas in a hypocellular background. The main cells present are lymphocytes and plasma cells; megakaryocytes in particular are severely reduced or absent.
• At the time of diagnosis, 60% to 70% of aplastic anemia patients are suspected to demonstrate clonality, with many of them developing aggressive MDSs 5 to 10 years after immunosuppressive therapy.
  • Somatic mutations of genes such as PIGA, ASXLI and DNMT3A, presumably arising by selection in a failed marrow, occur in about 50% of cases.
  • Up to 15% of children and adults with aplastic anemia will develop MDS following immunosuppressive therapy, with monosomy 7 being the most common chromosomal abnormality to emerge.
  • Small to moderate PNH clones are found in up to 70% of patients with aplastic anemia. PNH cells may be relatively resistant to an autoimmune attack on the bone marrow, and “second hit” mutations may also give the PNH clone a growth advantage.
  • This clonality is not eliminated post-immunosuppressive therapy (IST) alone and often is the source of relapse and/or progression.
  • The increased survival following immunosuppressive therapy allows time for these underlying clones to develop and expand.

Clinical Presentations

• Aplastic anemia can present abruptly over days or more gradually over weeks to months.
• Mild dyserythropoiesis is common in aplastic anemia, especially in cases with simultaneous small- to moderate-sized PNH populations; however, the presence of a small percentage of myeloid blasts or dysplastic features in the myeloid or megakaryocyte lineages favors a diagnosis of hMDS.

Classification

• VSAA satisfies the above criteria except when the neutrophil count is <200/μL.
• The 2-year mortality rate with supportive care alone for patients with SAA or VSAA approaches 80%, with invasive fungal infections and overwhelming bacterial sepsis being the most frequent causes of death. NSAA is seldom life-threatening and in many instances requires no therapy.

Treatment

• All transfusions in patients with suspected aplastic anemia should be irradiated to prevent transfusion-associated GVHD.
• Levels of measurable hematopoietic growth factors are markedly elevated in aplastic anemia patients in a compensatory attempt to increase blood production.