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518 Part VI: The Erythrocyte Chapter 35: Aplastic Anemia: Acquired and Inherited 519

Trinitrotoluene (TNT), an explosive used extensively during World cell 93,94 directed against hematopoietic progenitor cells. Patients have
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Wars I and II, is absorbed readily by inhalation and through the skin. recovered after plasmapheresis, glucocorticoids, or cyclophosphamide
Fatal cases of aplastic anemia were observed in munitions workers therapy, 93,95 which is compatible with an immune etiology.
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exposed to TNT in Great Britain from 1940 to 1946. In most cases, Eosinophilic fasciitis, an uncommon connective tissue disorder
these conclusions have not been derived from specific studies but from with painful swelling and induration of the skin and subcutaneous tis-
accumulation of case reports or from patient histories, making conclu- sue, has been associated with aplastic anemia. 96,97 Although it may be
sions provisional, although the argument for minimizing exposures to antibody-mediated in some cases, it has been largely unresponsive to
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potential toxins is logical in any case. therapy. Nevertheless, (1) stem cell transplantation, (2) immunosup-
pressive therapy using cyclosporine, (3) immunosuppressive therapy
Viruses using antithymocyte globulin (ATG), or (4) immunosuppressive ther-
Non-A, -B, -C, -D, -E, -G Hepatitis Virus A relationship between hepati- apy with ATG and cyclosporine has cured or significantly ameliorated
tis and the subsequent development of aplastic anemia has been the sub- the disease in a few patients. 96,97
ject of a number of case reports, and this association was emphasized by Severe aplastic anemia also has been reported coincident with
two major reviews in the 1970s. 72,73 In the aggregate, these reports sum- immune thyroid disease (Graves disease) 98–102 and the aplasia has been
marized findings in more than 200 cases. In many instances, the hepa- reversed with treatment of the hyperthyroidism. Aplastic anemia has
titis was improving or had resolved when the aplastic anemia was noted occurred in association with thymoma. 102–108 Autoimmune renal disease
4 to 12 weeks later. Approximately 10 percent of cases occurred more and aplastic anemia have occurred concurrently. The underlying rela-
than 1 year after the initial diagnosis of hepatitis. Most patients were tionship may be the role of cytotoxic T lymphocytes in the pathogenesis
young (ages 18 to 20 years); two-thirds were male, and their survival was of several autoimmune diseases and in aplastic anemia. 109
short (10 weeks). Although hepatitides A and B have been implicated in
aplastic anemia in a small number of cases, most cases are related to Pregnancy
non-A, non-B, non-C hepatitis. 74–76 Severe aplastic anemia developed in There are a number of reports of pregnancy-associated aplastic anemia,
9 of 31 patients who underwent liver transplantation for non-A, non- but the relationship between the two conditions is not always clear. 110–115
B, non-C hepatitis, but in none of 1463 patients transplanted for other In some patients, preexisting aplastic anemia is exacerbated with preg-
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indications. Several lines of evidence indicate there is no causal asso- nancy, only to improve following termination of the pregnancy. 110,111 In
ciation with hepatitis C virus, suggesting that an unknown viral agent other cases, the aplasia develops during pregnancy with recurrences dur-
is involved. 16,78,79 Hepatitis virus B or C can be a secondary infection, ing subsequent pregnancies. 111,112 Termination of pregnancy or delivery
if carefully screened blood products are not used for transfusion. In may improve the marrow function, but the disease may progress to a fatal
15 patients with posthepatitic aplastic anemia, no evidence was found outcome even after delivery. 110–112 Therapy may include elective termina-
for hepatitis A, B, C, D, E, or G, transfusion-transmitted virus, or par- tion of early pregnancy, supportive care, immunosuppressive therapy, or
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vovirus B19. Several reports suggest a relationship of parvovirus B19 marrow transplantation after delivery. Pregnancy in women previously
to aplastic anemia, 81,82 whereas others have not. This relationship has treated with immunosuppression for aplastic anemia can result in the
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not been established (Chap. 36). The effect of seronegative hepatitis may birth of a normal newborn. In this latter study of 36 pregnancies,
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be mediated through an autoimmune T-cell effect because of evidence 22 were uncomplicated, 7 were complicated by a relapse of the marrow
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of T-cell activation and cytokine elaboration. These patients also have aplasia, and 5 without marrow aplasia required red cell transfusion during
a similar response to combined immunotherapy as do those with idio- delivery. One death occurred from cerebral thrombosis in a patient
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pathic aplastic anemia 83,84 (see “Treatment: Combination Immunother- with paroxysmal nocturnal hemoglobinuria (PNH) and marrow aplasia.
apy” below).
Epstein-Barr Virus Epstein-Barr virus (EBV) has been implicated Iatrogenic Causes
in the pathogenesis of aplastic anemia. 85,86 The onset usually occurs Although marrow toxicity from cytotoxic chemotherapy or radiation
within 4 to 6 weeks of infection. In some cases, infectious mononucle- produces direct damage to stem cells and more mature cells, resulting
osis is subclinical, with a finding of reactive lymphocytes in the blood in marrow aplasia, most patients with acquired aplastic anemia cannot
film and serologic results consistent with a recent infection (Chap. 82). relate an exposure that would be responsible for marrow damage.
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EBV has been detected in marrow cells, but it is uncertain whether Chronic exposure to low doses of radiation or use of spinal radi-
marrow aplasia results from a direct effect or an immunologic response ation for ankylosing spondylitis is associated with an increased, but
by the host. Patients have recovered following therapy with antithymo- delayed, risk of developing aplastic anemia and acute leukemia. 116,117
cyte globulin. 86 Patients who were given thorium dioxide (Thorotrast) as an intrave-
Other Viruses HIV infection frequently is associated with varying nous contrast medium suffered numerous late complications, including
degrees of cytopenia. The marrow is often cellular, but occasional cases of malignant liver tumors, acute leukemia, and aplastic anemia. Chronic
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aplastic anemia have been noted. 87–89 Marrow hypoplasia may result from radium poisoning with osteitis of the jaw, osteogenic sarcoma, and
viral suppression and from the drugs used to control viral replication in aplastic anemia was seen in workers who painted watch dials with lumi-
this disorder. Human herpes virus (HHV)-6 has caused severe marrow nous paint when they moistened the brushes orally. 119
aplasia subsequent to marrow transplantation for other disorders. 90 Acute exposures to large doses of radiation are associated with the
development of marrow aplasia and a gastrointestinal syndrome. 120,121
Autoimmune Diseases Total-body exposure to between 1 and 2.5 Gy leads to gastrointesti-
The incidence of severe aplastic anemia was sevenfold greater than nal symptoms and depression of leukocyte counts, but most patients
expected in patients with rheumatoid arthritis. It is uncertain whether recover. A dose of 4.5 Gy leads to death in half the individuals (LD )
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the aplastic anemia is related directly to rheumatoid arthritis or to the owing to marrow failure. Higher doses in the range of 10 Gy are univer-
various drugs used to treat the condition (gold salts, d-penicillamine, sally fatal unless the patient receives extensive supportive care followed
and nonsteroidal antiinflammatory agents). Occasional cases of aplastic by marrow transplantation. Aplastic anemia associated with nuclear
anemia are seen in conjunction with systemic lupus erythematosus. In accidents was seen after the disaster that occurred at the Chernobyl
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vitro studies found either the presence of an antibody or suppressor nuclear power station in the Ukraine in 1986. 122
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