Acquired Aplastic Anemia

Clinical Laboratory Science, Summer 2004 by Keohane, Elaine M

Acquired aplastic anemia (AA) is a disorder characterized by a profound deficit of hematopoietic stem and progenitor cells, bone marrow hypocellularity, and peripheral blood pancytopenia. It primarily affects children, young adults, and those over 60 years of age. The majority of cases are idiopathic; however, idiosyncratic reactions to some drugs, chemicals, and viruses have been implicated in its etiology. An autoimmune T-cell reaction likely causes the stem cell depletion, but the precise mechanism, as well as the eliciting and target antigens, is unknown. Symptoms vary from severe life-threatening cytopenias to moderate or non-severe disease that does not require transfusion support. The peripheral blood typically exhibits pancytopenia, reticulocytopenia, and normocytic or macrocytic erythrocytes. The bone marrow is hypocellular and may exhibit dysplasia of the erythrocyte precursors. First line treatment for severe AA consists of hematopoietic stem cell transplantation in young patients with HLA identical siblings, while immunosuppression therapy is used for older patients and for those of any age who lack a HLA matched donor. Patients with AA have an increased risk of developing paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or acute leukemia. Further elucidation of the pathophysiology of this disease will result in a better understanding of the interrelationship among AA, PNH, and MDS, and may lead to novel targeted therapies.

ABBREVIATIONS: AA = acquired aplastic anemia; IST = immunosuppression therapy; PNH = paroxysmal nocturnal hemoglobinuria; MDS = myelodysplastic syndrome.

INDEX TERMS: acquired aplastic anemia; myelodysplastic syndrome; paroxysmal nocturnal hemoglobinuria.

Acquired aplastic anemia (AA) is a bone marrow failure disorder characterized by a marked reduction in the number of hematopoietic stem cells, hypocellular bone marrow, and peripheral blood pancytopenia. The resulting decreased levels of circulating platelets, erythrocytes, and granulocytes can cause life-threatening symptoms of bleeding, anemia, and later in the course of disease, infection. Acquired AA is rare, with an incidence of two per million in Europe and North America, but a two to three-fold greater incidence in East Asia.1,2 There are no significant gender differences, and the peak age distribution is bimodal at 10 to 25 years and over 60 years of age.2

ETIOLOGY

Cytotoxic drugs and radiation therapy cause bone marrow hypoplasia and cytopenia that is anticipated, usually predictable, and dose dependent.1 The bone marrow and blood cell counts recover upon discontinuation. In contrast, acquired AA is bone marrow failure in which the cause is largely idiopathic or unknown. Approximately 15% to 25% of acquired AA may occur as idiosyncratic reactions to various drugs, or after exposure to certain chemicals or viruses.1,2 Idiosyncratic reactions are rare, unexpected, and unpredictable, and the bone marrow does not usually recover after the agent is withdrawn. Table 1 lists some agents associated with acquired AA.1,2,3,4 The incidence of AA as a complication of drug therapy is rare. A genetic predisposition to idiosyncratic reactions may exist due to individual differences in metabolic or immune response pathways. Sutton and others found a higher than expected frequency of glutathione S-transferase (GST) gene deletions in AA. GSTT1 null and GSTM1/GSTT1 double null genotypes were found in 30% and 22% of Caucasians with AA, respectively.5 GST deficiency may hinder the biometabolism of some chemical toxins and increase the risk of development of AA.5

AA may occur as a rare complication in pregnancy, autoimmune disease, and in some viral infections, such as Epstein-Barr virus and human immunodeficiency virus.1,2 As many as 2% to 10% of patients have a history of acute hepatitis one to three months prior to presentation with severe AA; however, tests for hepatitis A, B, and C are negative.6 It is important to recognize hepatitis-associated AA syndrome for its poor prognosis and high mortality rate.

Quantitative and qualitative deficiency of hematopoietic stem and progenitor cells cause the peripheral blood pancytopenia and hypocellular bone marrow in acquired AA.7,8 In aplasia following cytotoxic chemotherapy and radiation, as well as in benzene toxicity, there is direct damage to the DNA or proteins of hematopoietic stem cells and progenitor cells, resulting in cell death.1 However, in idiopathic AA, viral associations, and idiosyncratic reactions to drugs or chemicals, bone marrow failure is thought to be the result of a T-cell-mediated autoimmune attack against hematopoietic stem and progenitor cells.9 It is likely that the offending antigen in this autoimmune reaction is expressed on stem and early progenitor cells, but the precise mechanism for this reaction, as well as the identity of the inciting and target antigens, remains unknown.

PATHOPHYSIOLOGY

Hematopoietic stem cells are severely decreased in the bone marrow of AA patients as evidenced by a greater than ten-fold reduction in CD34 cells detected by flow cytometry (mean of 557/mL in AA compared to 5,867/mL in normal controls), and diminished colony formation and growth of long-term culture initiating cells in vitro.7,8 Stem cell numbers remain low despite elevated serum growth factors.10 Stromal cells in AA produce normal or increased growth factors and support the growth of normal CD34 cells in culture.10,11,12 Further evidence of a functional stroma is demonstrated clinically by the successful engraftment of bone marrow transplants in AA patients.