Etiology and Epidemiology

Drugs, chemicals, toxins, infectious agents, radiation, and immune disorders can result in pancytopenia by direct destruction of hematopoietic progenitors, disruption of the marrow microenvironment, or immune-mediated suppression of marrow elements (Table 463-1). A careful history of exposure to known risk factors should be obtained for every child presenting with pancytopenia. Even in the absence of the classic associated physical findings, the possibility of a genetic predisposition to bone marrow failure should always be considered (Chapter 462). The majority of cases of acquired marrow failure in childhood are “idiopathic,” in that no causative agent is identified. These are probably immune-mediated through activated T lymphocytes and cytokine destruction of marrow progenitor cells. The overall incidence of acquired aplastic anemia is relatively low, with an approximate incidence in both children and adults in the USA and Europe of 2-6 cases/million/yr. The incidence is higher in Asia, with as many as 14 cases/million/yr in Japan.

Severe bone marrow suppression can develop after exposure to many different drugs and chemicals, including certain chemotherapeutic agents, insecticides, antibiotics, anticonvulsants, nonsteroidal anti-inflammatory agents, and recreational drugs. Some of the most notable agents are benzene, chloramphenicol, gold, and, most recently, 3,4,-methylenedioxymethamphetamine (Ecstasy).

A number of viruses can either directly or indirectly result in bone marrow failure. Parvovirus B19 is classically associated with isolated red blood cell (RBC) aplasia, but in patients with sickle cell disease or immunodeficiency, it can result in transient pancytopenia (Chapters 243 and 462). Prolonged pancytopenia can occur after infection with many of the hepatitis viruses, herpes viruses, Epstein-Barr virus (Chapter 246), cytomegalovirus (Chapter 247), and HIV (Chapter 268).

Patients with evidence of bone marrow failure should also be evaluated for paroxysmal nocturnal hemoglobinuria (PNH; Chapter 458) and collagen vascular diseases, although these are uncommon causes of pancytopenia in childhood. Pancytopenia without peripheral blasts may be caused by bone marrow replacement by leukemic blasts or neuroblastoma cells.

Pathology and Pathogenesis

The hallmark of aplastic anemia is peripheral pancytopenia, coupled with hypoplastic or aplastic bone marrow. The severity of the clinical course is related to the degree of myelosuppression. Severe aplastic anemia is defined as a condition in which 2 or more cell components have become seriously compromised (absolute neutrophil count [ANC] <500/mm³, platelet count <20,000/mm³, reticulocyte count <1% after correction for hematocrit) in a patient whose bone marrow biopsy material is moderately or severely hypocellular. Approximately 65% of patients who first present with moderate aplastic anemia (ANC 500-1,500/mm³

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