AA may have diverse causes that allow for clinically useful classification (Table 41.1). While iatrogenic AA is uncommon, it can be easily recognized. The most common is the idiopathic form of AA, and most parts of this chapter deal with this classical AA entity. Congenital bone marrow failure syndromes can evolve to AA; they will not be discussed in detail here.
Drugs and chemicals have been implicated as etiologic agents in AA for many decades. Benzene has served as a model chemical implicated in AA.41-43 Intermittent exposure may be at least or even more toxic than chronic exposure. The mechanism of benzene toxicity is not entirely clear, and several metabolites may be
Classification of aplastic anemia by etiology
Aplastic anemia Acquired aplastic anemia Inherited aplastic anemia
Idiopathic aplastic anemia Pregnancy
Paroxysmal nocturnal hemoglobinuria
Secondary Drugs Iatrogenic/cytotoxic Idiosyncratic Radiation Iatrogenic Accidental Viruses
Fanconi anemia Dyskeratosis congenita Reticular dysgenesis Schwachman anemia Genetic primary non-hematologic syndromes involved. Consequently, genetic polymorphisms of the catabolic pathways may constitute predisposition factors for the development of benzene toxicity. In addition to direct toxicity comparable to that of some cytotoxic agents, other mechanisms, including stro-mal damage or even immune mediated effects, can be involved. Other aromatic hydrocarbons are also cited as causes of AA. Similarly, pesticides and insecticides have often been reported as causes of AA, but the rigorous systematic epidemiologic studies are scarce or showed mixed results. Overall, the proportion or cases attributable to specific pesticides or aromatic hydrocarbons is relatively small, especially given the ubiquitous nature of these chemicals in the modern world.
Medical drugs have been frequently implicated as causes of AA.6 Cytotoxic agents may serve as a prototype, and a patient's medical history should make a diagnosis obvious. Of importance are drugs used for treatment of unrelated disorders. Chloramphenicol and AA as well as aminopyridine and agranulocytosis are the best examples of agents recognized to be associated with an increased risk of disease.44-46 In general, drug reactions can be classified into dose-related effects and idiosyncratic reactions, in which occurrence is rare and not dose dependent. The list of drugs that have been implicated in causing AA is long, but all of them can account only for a fraction of cases (around 15%). The most comprehensive epidemiologic study performed in Europe identified agents that were associated with the occurrence of AA, but for most of the cases the stratified risk estimate was relatively low. The highest risk was found for some nonsteroidal anti-inflammatory drugs (NSAIDs) (piroxicam), gold, antithyroid agents, and allopurinol. Even for chloramphenicol, notoriously implicated in AA (at the peak of its usage 30% of all cases), the increase in the risk is modest (13-fold, or about 1/20,000). In general, agranulocytosis and mild pancytopenia are more common drug reactions than severe AA. The list of commonly implicated agents is provided in Table 41.2.
Table 41.2 Drugs most commonly implicated in aplastic anemia
Dose-dependent marrow cytopenia
Chemotherapy Drug that may cause idiosyncratic association but low probability Chloramphenicol NSAID
Anticonvulsants (e.g., carbamazepine) Antithyroid
Gold, D-penicilinamine Sufonamides
Carbonic anhydrase inhibitors Very rare associations Antibiotics Allopurinol
Psychotropic (e.g., phenothiazines)
Sedatives (e.g., chlorpromazine)
Bone marrow aplasia is a well-known toxicity of ionizing radiation. Myeloablation using 7-radiation is used therapeutically as a conditioning regimen for stem cell transplantation. The bone marrow is affected directly by 7-rays, and secondarily by a- and p-particles. Certain cell types, such as lymphocytes, are very sensitive and are killed directly, while hematopoietic progenitors require cell division for severe damage; thus, mitotically active cells are most sensitive. The onset and severity of pancytopenia is dose dependent. However, the regeneration capacity of the irradiated marrow is remarkable, likely due to the presence of quiescent, more resistant stem cells. While the exact LD50 dose is not precisely known in humans, 1.5-2 Gy of whole body radiation can induce marrow aplasia. The dose of 4.5 Gy (Shields-Warren number) has been estimated to constitute the LD50.1147 The estimation of marrow toxicity is hampered by the toxicity to other organ systems that may limit survival. At doses at LD50, bone marrow toxicity limits survival.
In many respects, clinical and pathophysiologic features of AA suggest a possible infectious etiology. Most commonly, viruses have been implicated. Over the years, many of the suggested agents have been excluded as etiologic factors. The search for AA agents has been extensive. Hepatitis B and A were proven not to be the causative agent for typical AA. Similarly, cytomegalovirus (CMV), although certainly capable of producing bone marrow suppression under certain clinical circumstances, such as following stem cell transplantation, is not responsible for idiopathic AA. Certain serologic CMV types have been implicated in transplantation-refractory AA, but these studies have not found application to explain typical AA.48-50 A series of cases clearly attributable to Epstein-Barr virus (EBV) has been described, but again, EBV is a rare cause of AA.51 The best evidence for a viral etiology exists in a specific hepatitis/AA syndrome, in which severe AA follows with a 3-6 months latency. So far, a specific agent of this non-A, non-B, non-C hepatitis has not been found.52
That AA is an immune-mediated disease has been concluded from the successes of immunosuppressive (IS) therapy. Despite progress in laboratory investigations, most experimental evidence supporting an autoimmune attack in AA remains indirect, and this clinical observation provides the strongest evidence for an autoimmune pathophysiology of this disease. The inciting events for the immune reaction in AA include viral infections that, through molecular mimicry, lead to the breach of tolerance toward antigens residing on hematopoietic stem cells. In addition, cross-reactive antigens could also be generated by chemical modification or conjugation with drugs. Finally, neoantigens created by transcription of mutated fused genes may induce an immune reaction with effector cells that are unable to selectively kill abnormal cells, and mediate depletion of normal elements as well (Figure 41.2).
Experimental evidence supports an immunologic mechanism in AA (for review see8-10) (Figure 41.3). A role for T cells in AA was first suggested by coculture and depletion experiments, in which inhibition of hematopoietic colony formation was associated with this lymphocyte population.5354 Later, an inverted CD4/CD8 ratio,27 activated cytotoxic lymphocytes (CTL) as detected by the expression of HLA-DR55 and CD25,56 and skewing of the variable p-chain (Vp)reper-toire of the T-cell receptor (TCR) were found, consistent with expansion of autoimmune T-cell clones.57-65
The damage to the stem cells can be mediated by a variety of mechanisms, including direct cell-mediated killing by CTL as well as cytokine-transduced inhibition (Figure 41.2). In addition to interferon 7 (IFN7) and tumor necrosis factor a (TNFa), Fas ligand or TNF-ralated inhibitory ligand (TRAIL) appears to play an important role as effector cytokines in the hematopoi-etic inhibition in AA.29 66-68 Such mechanisms may be restricted not only to the original targets, but also may include bystander cells. Ultimately, these factors may result in apoptosis of stem cells.
Several rare congenital syndromes can present as AA or evolve to a clinical picture consistent with AA. Defect in the DNA repair machinery may lead to stem cell damage, but the pathophysiologic mechanism leading to pancytopenia is not clear. In some studies, immune mechanisms such as excessive production of TNFa have been implicated.4142 Fanconi anemia is the most common differential diagnostic consideration that should be excluded in all children and younger
Products of mutated gene m m
Products of mutated gene
Figure 41.2 Immune mechanisms in AA. APC: antigen presenting cell; HSC: hematopoietic stem cells
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