c
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The term aplastic anemia describes a clinical syndrome in which there is a deficiency of red cells,
neutrophils, and monocytes, and platelets without morphologic evidence of another marrow disorder.
Marrow examination shows a near absence of hematopoietic precursor cells and fatty replacement. The
disorder can be induced by toxic chemicals (e.g., benzene), specific viruses (e.g., Epstein-Barr virus), or
can be inherited (e.g., Fanconi's anemia). Most cases occur without an evident incitant and are the
result of autoreactive T lymphocytes that suppress or destroy hematopoietic cells. The disease may be
ameliorated or sometimes cured by immunosuppressive therapy, especially antithymocyte globulin. For
those with a suitable donor, allogeneic stem cell therapy is often curative. The disease, even after
successful treatment with immunosuppressive agents, has a propensity to evolve into a clonal
hematopoietic disorder such as paroxysmal nocturnal hemoglobinuria, oligoblastic or acute
myelogenous leukemia.

Acronyms and abbreviations that appear in this chapter include: ALG, antilymphocyte globulin; ALS,
antilymphocyte serum; ATG, antithymocyte globulin; BFUʹE, erythroid burst-forming units; CFU-GM,
granulocyte-macrophage colony-forming units; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV,
human herpes virus; HIV, human immunodeficiency virus; IL, interleukin; NMRI, nuclear magnetic
resonance imaging; PNH, paroxysmal nocturnal hemoglobinuria; SCF, stem cell factor.

DEFINITION AND HISTORY

Aplastic anemia results from a failure of blood cell production in the marrow. This results in a markedly
hypocellular marrow and varying degrees of anemia, granulocytopenia, and thrombocytopenia. Most
cases of aplastic anemia are acquired. The decrease in hematopoiesis may be secondary to toxic effects
of offending agents on marrow stem cells; in many cases, however, the pathogenesis is the suppression
of blood cell progenitor proliferation and maturation by autoreactive lymphocytes. The disease also may
occur as the result of an inherited disorder, especially Fanconi anemia. A close association also exists
between the clonal hemopathy, PNH, and aplastic anemia.

Aplastic anemia was first recognized by Ehrlich in 1888.1 He described a young pregnant woman who
died of severe anemia and neutropenia; autopsy examination revealed a fatty marrow with essentially
no hematopoiesis. The name aplastic anemia was subsequently applied to this disease in 1904.2 Over
the next 30 years many conditions that caused pancytopenia were confused with aplastic anemia based
on incomplete or inadequate histologic study of the patient's marrow. Marrow biopsies are required to
document that a hypocellular marrow aspirate represents hypoplasia or aplasia and to exclude other
conditions that may infiltrate, replace, or suppress normal marrow cells.3

ETIOLOGY AND PATHOGENESIS

It is unclear why some individuals who are exposed repeatedly to potential marrow toxins sustain severe
and often irreversible marrow injury, whereas most have no untoward effects. It has been postulated
that there is a genetic predisposition based on a high incidence of HLA class II antigens DR24 and DPw35
in patients with marrow aplasia. The disease may result from the accumulated effects of multiple
noxious exposures on pluripotential stem cells. Ultimately, all stem cells sustain sufficient damage to
hinder their ability to replicate. Alternatively, such exposures may induce a single abnormal cell to
proliferate in a clonal fashion and to somehow hinder the growth of normal stem cells. The result in the
first case would be aplastic anemia from a polyclonal injury (classical aplastic anemia) to stem cells
and/or very early multipotential progenitor cells and in the latter injury to a single stem cell resulting in
a monoclonal disorder (e.g., paroxysmal nocturnal hemoglobinuriaͶaplastic anemia syndrome).
Although classic aplastic anemia and paroxysmal nocturnal hemoglobinuria are thought to be distinct
clinical entities, studies suggest an overlap in these conditions. As many as 40 percent of patients with
otherwise typical aplastic anemia have evidence of glycosyl-phosphatidylinositol molecule defects in
leukocytes and red cells as judged by flow cytometry, analogous to that seen in PNH.6,7 and 8 Aplastic
anemia, hypoplastic myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria each may
eventually evolve into acute myelogenous leukemia.9,10,11,12 and 13

STEM CELLS, MICROENVIRONMENT, CYTOKINES

Potential mechanisms responsible for acquired marrow cell failure include induced defects in
hematopoietic stem cells, failure of the stromal microenvironment of the marrow, impaired production
or release of hemopoietic growth factors, and cellular or humoral immune suppression of the marrow.
Several pathogenic abnormalities have been found in patients with aplastic anemia14,15,16,17 and 18;
however, it is unclear whether these are inciting events or represent epiphenomena secondary to the
disease. Although it is not possible to assess human totipotential stem cells in culture, their progeny are
easily identified by clonal growth in vitro. The number of CFU-GM and BFUʹE are reduced markedly in
patients with aplastic anemia.19,20,21,22,23,24 and 25 The more immature long-term culture initiating
cells are also reduced to about 1 percent of normal values.26 CD34-positive hematopoietic cells, in
which fraction the hematopoietic stem cells reside, are also correspondingly low.27,28 These findings
suggest that reduced hematopoietic stem cells are the primary defect in the abnormal hematopoiesis.
Stem cell inhibition may, however, occur by a T-cellʹmediated suppressor effect. Early studies showed
inhibition of colony growth by autologous marrow lymphocytes or by blood or marrow mononuclear
cells from patients with aplastic anemia when cocultured with normal marrow.20,23,29,30 and 31 In
many cases the inhibition was thought to result from transfusion sensitization rather than
autoimmunity.32,33 However, culture studies in patients with aplastic anemia prior to transfusion34 or
before and after successful treatment35,36 are highly suggestive of a T-cellʹmediated suppressor cell
phenomenon. Alternatively, injured hemopoietic stem cells may present neoantigens that serve as a
stimulus for secondary T-cellʹmediated suppression, which serves to worsen the aplasia.

Based on studies in rats, a theory of ͞seed͟ (stem cells) versus ͞soil͟ (microenvironment) abnormality
was established.37 Modest doses of irradiation to a limb lead to transient aplasia, with recovery
secondary to ingress of circulating stem cells. With doses of 20 Gy (2000 rad) and greater, there is
similar aplasia and recovery; however, permanent aplasia develops in this limb several months later.
This appears to result from late damage to the marrow microenvironment, which may also occur in
certain cases of aplastic anemia.

Pathogenetic studies have been conducted of the residual marrow damage in mice that receive
busulfan.38,39 Although blood counts are usually normal, both marrow progenitor cells and stem cells
are decreased substantially. Some animals progress to chronic hypoplastic marrow failure, whereas
others retain relatively normal blood counts.38 When treated with chloramphenicol, animals exposed to
busulfan have a marked decrease in progenitor cells, whereas controls are unaffected.39 Perhaps similar
repeated exposures with different agents may be necessary to induce aplastic anemia in humans.

The hematopoietic defects, macrocytic anemia, and mild hypoplasia occur in two strains of mice (WWv
and Sl/Sld). WWv anemia is cured by lethal irradiation and infusion of stem cells from nonaffected litter
mates, whereas the Steel (Sl) defect is not corrected by stem cell transplantation because it is the result
of an abnormal microenvironment.40 WWv cells are deficient in the proto-oncogene kit,41 which
encodes a tyrosine kinase receptor for the hemopoietic growth factor kit ligand42 (see Chap. 14). Sl/Sld
mice do not produce kit ligand, also called stem cell factor (SCF). Similar defects have not been observed
in patients with aplastic anemia. Serum levels of SCF have been either moderately low or normal in
several studies of aplastic anemia.43,44 and 45 Although SCF augments the growth of hemopoietic
colonies from aplastic marrows,46 its use in patients has not led to clinical remissions. Another early
acting growth factor, Flt-3 ligand, is 30- to 100-fold elevated in the serum of patients with aplastic
anemia.47 Short-term clonal assays for marrow stromal cells have shown variable defects in stromal cell
function. Fibroblasts grown from patients with severe aplastic anemia have subnormal cytokine
production. However, serum levels of granulocyte colony-stimulating factor,48 erythropoietin,49 and
thrombopoietin50 are usually high. Synthesis of IL-1, an early stimulator of hemopoiesis, is decreased in
mononuclear cells from patients with aplastic anemia, but it is produced normally by cells from patients
with myelodysplastic syndrome.51 Levels of cytokines with inhibitory effects on hemopoiesis are
increased in most patients with severe aplastic anemia. Increased mononuclear cell production of
interferon-g,52,53 IL-2,54 and tumor necrosis factor-a55,56 has been noted spontaneously or in
response to certain mitogens. Elevated serum levels of interferon-g have been found in 30 percent of
patients with aplastic anemia, and interferon-g expression has been detected in the marrow of most
patients with acquired aplastic anemia.57 Moreover, addition of antibodies to interferon enhances in
vitro colony growth of marrow cells from affected patients.52 This suggests a potential role for
interferon-g in either the initiation or propagation of the defect in aplastic anemia.

Studies of the microenvironment have shown relatively normal stromal cell proliferation and growth
factor production.58,59 and 60 These findings, coupled with the limited response of patients with
aplastic anemia to the known growth factors, suggest that cytokine deficiency is not the etiologic
problem in most cases.

Potential causes for aplastic anemia are shown in Table 31-1. The disorder may follow exposure to
various chemicals, drugs, radiation, or viruses. In addition, connective tissue disorders and pregnancy
may be associated with marrow aplasia. Constitutional forms, particularly Fanconi anemia, develop in
the setting of an underlying genetic defect. As many as 65 percent of cases of aplastic anemia, however,
are idiopathic.

TABLE 31-1 ETIOLOGIC CLASSIFICATION OF APLASTIC ANEMIA

CHEMICALS

Benzene was the first chemical linked to aplastic anemia, based on studies in factory workers before the
twentieth century.61 Despite its known properties as a marrow toxin, benzene is still used widely as a
solvent and is employed in the manufacture of chemicals, drugs, dyes, and explosives. It has been a vital
chemical in the manufacture of rubber and leather goods and has been used widely in the shoe industry,
leading to an increased risk for aplastic anemia and leukemia in workers in all these
industries.62,63,64,65 and 66 In China, where benzene is still used widely in industry, benzene poisoning
was found in 0.5 percent of the workers; aplastic anemia among workers was sixfold higher than in the
general population.67

The U.S. Occupational Safety and Health Administration has lowered the permissible exposure limit to
benzene to 1 ppm,68 after it was shown that exposure to 100 ppm was associated with leukopenia in
about one-third of workers.69 Other hematologic abnormalities have been observed in patients
exposed to benzene, including hemolytic anemia, marrow hyperplasia, myeloid metaplasia, and acute
myelogenous leukemia.62,63,64,65,66 and 67,70

There appears to be a relationship between the use of insecticides related to benzene and aplastic
anemia. Chlorinated hydrocarbons and organophosphate compounds have been implicated in 280 cases
reported in the literature.71 DDT (chlorophenothane), lindane, and chlordane appear to be the most
common insecticides involved. Aplastic anemia was reported following the use of lindane in home
vaporizers for disinfection. This practice continued until the 1970s, when over 30 case reports of aplastic
anemia led to its curtailment.72 Occasional cases still occur following heavy exposure at industrial plants
or after its use as a pesticide.73 Lindane is metabolized in part to pentachlorophenol (PCP), another
toxic chlorinated hydrocarbon that is manufactured for use as a wood preservative. Many cases of
aplastic anemia and related blood disorders have been attributed to PCP over the past 25 years.72,73,74
and 75 Prolonged exposures to petroleum distillates in the form of Stoddard solvent76 and acute
exposure of toluene through the practice of glue sniffing77 have also been reported to cause aplasia.
Trinitrotoluene (TNT), an explosive used extensively during World Wars I and II, is absorbed readily by
inhalation and through the skin. Many fatal cases of aplastic anemia were observed in munitions
workers exposed to TNT in Great Britain from 1940 to 1946.78

DRUGS

Chloramphenicol is a nitrobenzene compound with broad-spectrum antibiotic activity. It was introduced

in 1948 and used widely during the 1950s and 1960s by various routes of administration, often for trivial
indications. Reports of an association with aplastic anemia began early after its introduction.79,80 and
81 Indiscriminant use of the drug continued, however, despite warnings to limit its use to infections
caused by organisms that were resistant to other agents or for which no other drugs were available.82
The risk of developing aplastic anemia in patients treated with chloramphenicol is about 1 in 20,000, or
10 to 50 times that of the general population.83,84 and 85 Unfortunately, reports of fatal aplastic
anemia continue to appear with topical or systemic use of the drug.86,87

Two adverse hematopoietic responses to the drug occur. Suppression of marrow function occurs in
many individuals receiving the drug, with reduced erythroid cell production characterized by a rise in
serum iron, accumulation of iron in the mitochondria, and vacuolization of marrow erythroid precursor
cells.88,89,90 and 91 Reticulocytes decrease and the hematocrit declines as inhibition of red cell
production continues. Mild decreases in circulating neutrophils and platelets are also observed in some
patients. These effects are probably the result of inhibition of mitochondrial protein synthesis and are
reversible after discontinuation of the drug. There appears to be no relationship between this common,
temporary inhibition of hematopoiesis and the rare, but devastating, severe aplastic anemia that ensues
in a small proportion of patients. This latter reaction may occur weeks to months after treatment and
does not appear related to the total drug exposure nor to the route of administration. Based on the
nearly simultaneous development of aplastic anemia in identical twins given this agent,92 it was
postulated that there is a genetic defect that predisposes to this severe reaction to the drug.

With chloramphenicol, the many cases of aplastic anemia strongly established the potential for toxic
effects with this drug. Owing to a lower incidence of aplastic anemia with many other drugs, however, it
has often been difficult to isolate the single offending agent. Perhaps the only drug for which there is
good statistical information is quinacrine (Atabrine).93 This drug was administered to all U.S. troops in
the South Pacific and Asiatic theaters of operations as prophylaxis for malaria during 1943 and 1944. The
incidence of aplastic anemia was compared to army personnel in the United States and Europe who did
not receive quinacrine. The incidence of aplastic anemia was 7 to 28 cases per 1,000,000 personnel per
year in the prophylaxis zones, whereas nontreated soldiers had 1 to 2 cases per 1,000,000 personnel per
year. In contrast to other drugs, the aplasia occurred during administration of the offending agent and
was preceded by a characteristic rash in nearly half the cases.

Many other drugs have been implicated in sporadic cases of aplastic anemia, but owing to limited
reporting of information, it is possible that the spectrum of drug-induced aplastic anemia is not fully
appreciated. A list of drugs that have been implicated is shown in Table 31-2. Antineoplastic drugs such
as alkylating agents, antimetabolites, and certain cytotoxic antibiotics all have the potential for
producing marrow aplasia. In general, this is transient, is an extension of their pharmacologic action, and
resolves within several weeks of completing chemotherapy. Although unusual, severe hypoplasia can
follow use of the alkylating agent busulfan and may persist for extended intervals. Patients may develop
marrow aplasia 2 to 5 years after discontinuation of alkylating agent therapy. These cases often evolve
into hypoplastic myelodysplastic syndromes.

TABLE 31-2 DRUGS ASSOCIATED WITH APLASTIC ANEMIA

Other types of drugs may be associated with occasional cases of aplastic anemia. These include
analgesics as well as antiarthritic and anti-inflammatory agents. The most serious offenders in the latter
group include gold salts, penicillamine, and the butazone compounds. Many nonsteroidal analgesics
have been associated with sporadic cases of marrow aplasia. Anticonvulsant medications, particularly
carbamazepine, are marrow suppressants. The sulfonamides and their derivatives, which include
diuretics and oral hypoglycemic agents, have been associated with cases of aplastic anemia. Many of
these drugs are known to induce selective cytopenias, such as agranulocytosis, which are usually
reversible after discontinuation of the offending agent. These reversible reactions are not correlated
with the risk of aplastic anemia, casting doubt on the effectiveness of routine monitoring of blood
counts as a strategy to avoid aplastic anemia.

Since aplastic anemia remains a rare event, it may occur because of an underlying metabolic
predisposition in susceptible individuals. In the case of phenylbutazone-associated aplasia, there is
delayed oxidation and clearance of a related compound, acetanilide, as compared to either normal
controls or those with aplastic anemia due to other causes.94 This suggests excess accumulation of the
drug as a potential mechanism for the aplasia. In some cases drug interactions or synergy may be
required to induce aplasia. Cimetidine, a histamine H2-receptor antagonist, is occasionally implicated in
cytopenias and in causing aplastic anemia, perhaps owing to a direct effect on hematopoietic stem
cells.95,96 This drug accentuates the marrow-suppressive effects of the chemotherapy drug
carmustine97 and in several instances has been reported as a possible cause of aplasia when given with
chloramphenicol.87
RADIATION

Chronic exposure to low doses of radiation or use of localized radiation for ankylosing spondylitis is
associated with an increased, but delayed, risk of developing aplastic anemia and acute leukemia.98,99
Patients who were given thorium dioxide (Thorotrast) as an intravenous contrast medium suffered
numerous late complications, including malignant liver tumors, acute leukemia, and chronic aplastic
anemia.100 Chronic radium poisoning with osteitis of the jaw, osteogenic sarcoma, and aplastic anemia
was seen in workers who painted watch dials with luminous paint when they moistened the brushes
orally.101

Acute exposures to large doses of radiation are associated with the development of marrow aplasia and
a gastrointestinal syndrome.102,103 Total body exposure to between 1 and 2.5 Gy (100 to 250 rad)
leads to gastrointestinal symptoms and depression of leukocyte counts, but most patients recover. A
dose of 4.5 Gy leads to death in half the individuals (LD50) owing to marrow failure. Higher doses in the
range of 10 Gy are universally fatal unless the patient receives extensive supportive care followed by
marrow transplantation. Aplastic anemia associated with nuclear accidents was seen after the disaster
that occurred at the Chernobyl nuclear power station in the Ukraine in 1986.104,105,106 and 107

VIRUSES

A striking relationship between hepatitis and the subsequent development of aplastic anemia has been
the subject of a number of case reports; this association was emphasized by two major reviews in the
1970s.108,109 In the aggregate, these reports summarized findings in over 200 cases. In many
instances, the hepatitis was improving or had resolved when the aplastic anemia was noted 4 to 12
weeks later. Approximately 10 percent of cases occurred more than 1 year after the initial diagnosis of
hepatitis. Most patients were young (18 to 20 years), two-thirds were male, and their survival was short
(10 weeks). Although hepatitis A and B have been implicated in aplastic anemia in a small number of
cases, most cases are related to non-A, non-B hepatitis.110,111 Severe aplastic anemia developed in 9
of 31 patients who underwent liver transplantation for non-A, non-B hepatitis but in none of 1463
patients transplanted for other indications.112 Several lines of evidence indicate there is no association
with hepatitis C virus, suggesting that a hitherto unknown viral agent is involved.113,114 and 115

EBV has been implicated in the pathogenesis of aplastic anemia.116,117 The onset usually occurs within
4 to 6 weeks of infection. In some cases infectious mononucleosis is subclinical, with a finding of atypical
lymphocytes in the blood film and serological results consistent with a recent infection. EBV has been
detected in marrow cells,118 but it is uncertain whether aplasia results from a direct effect or an
immunologic response by the host. Some patients have recovered following therapy with antithymocyte
globulin.113,116,118

A number of other viruses have been implicated in the pathogenesis of marrow failure. B-19 parvovirus,
the cause of fifth disease, leads to transient erythroid aplasia but is not known to induce aplastic
anemia.113,119 HHV-6 has caused severe marrow aplasia subsequent to bone marrow transplantation
for other disorders.120 HIV infection is frequently associated with varying degrees of cytopenia. The
marrow is often cellular, but occasional cases of aplastic anemia have been noted.121,122 and 123 In
these patients, marrow hypoplasia may result both from viral suppression and from the many drugs
used to control viral replication in this disorder.

MISCELLANEOUS CAUSES

Rheumatoid arthritis is not ordinarily associated with severe aplastic anemia, but an epidemiologic study
in France revealed a sevenfold increase in the incidence of aplastic anemia in patients with this
disorder.124 It is uncertain whether the aplastic anemia is related directly to rheumatoid arthritis or to
the various drugs used to treat the condition (gold salts, D-penicillamine, and nonsteroidal agents).
Occasional cases of aplastic anemia are seen in conjunction with systemic lupus erythematosus.125 In
vitro studies have suggested the presence of an antibody126,127 or suppressor cell128,129 directed
against hematopoietic progenitor cells. Patients have recovered after plasmapheresis,126,127
glucocorticoids,129 or cyclophosphamide therapy,128,130 suggesting a possible immune etiology.

Eosinophilic fasciitis, an uncommon connective tissue disorder with painful swelling and induration of
the skin and subcutaneous tissue, has been associated with aplastic anemia on at least 14
occasions.131,132,133 and 134 Although it may be antibody-mediated in some cases, it has been largely
unresponsive to therapy. One patient improved with immunosuppressive therapy using ATG and
cyclosporine.133 In another case, a partial remission was achieved following therapy with ATG.

There are a number of reports of pregnancy-associated aplastic anemia, but the relationship between
the two conditions is not clear.135,136,137,138,139,140 and 141 In some patients, preexisting aplastic
anemia is exacerbated with pregnancy, only to improve following termination of the
pregnancy.136,139,140 In other cases, the aplasia develops during pregnancy with recurrences during
subsequent pregnancies.136,140,141 Termination of pregnancy or delivery may improve the marrow
function, but the disease may progress to a fatal outcome even after delivery.135,136,137,138,139,140
and 141 Therapy may include elective termination of early pregnancy, supportive care,
immunosuppressive therapy, or marrow transplantation after delivery.

HEREDITARY APLASTIC ANEMIA

FANCONI ANEMIA

The most common form of constitutional aplastic anemia was described in three brothers by Fanconi in
1927.142 Since that time nearly 800 cases have been recorded, either by reports in the literature or
through an International Fanconi Anemia Registry.143,144,145 and 146

Fanconi anemia is inherited as an autosomal recessive condition. It is estimated to be present in one in a

million individuals, although it is more frequent in Afrikaners of European descent and in southern Italy.

At least eight gene mutations have been associated with the development of Fanconi anemia. The genes
have been designated FAA through FAH. The great majority of patients have mutations of FAA or FAC. It
has been proposed that the A and C gene products, which are cytoplasmic proteins, form a complex
with the products of genes B, E, F, and G, which are adaptors or phosphorylators; the complex
translocates to the nucleus, where it subserves its normal function. In the presence of a mutant gene
product, normal function is disturbed leading to effects in sensitive tissues, including hematopoietic
cells. Mutation of the D product appears to effect tissue cells through a different mechanism, perhaps
downstream from the complex.147,148

Blood counts and marrow cellularity are often normal until 5 to 10 years of age, when pancytopenia
develops gradually over an extended interval. Thrombocytopenia may precede the development of
granulocytopenia and anemia. The marrow becomes hypocellular, and in vitro colony assays reveal a
decrease in CFU-GM and BFUʹE.145 It is often associated with abnormal skin pigmentation typical of
café-au-lait lesions. Growth retardation results in short stature. Skeletal anomalies, especially dysplastic
radii and thumbs, occur in half the patients. Heart, kidney, and eye defects may be present.
Microcephaly and mental retardation may be present. Hypogonadism occurs. Hematologic and visceral
manifestations are combined in more than a third of patients, but some may have anemia and
inconspicuous somatic changes whereas others may have the anomalies with little hematopoietic
disorder. A few may be virtually unaffected.145,146 and 147 In the past, children with a similar onset of
aplastic anemia without congenital abnormalities were thought to have a different disorder termed
Estren-Dameshek syndrome.149 These children, whose lymphocytes show sensitivity to diepoxybutane,
have the same inherited disorder without skeletal abnormalities.144

Random chromatid breaks are present in myeloid cells, lymphocytes, and chorionic villus preparations.
This chromosome damage is intensified after exposure to DNA cross-linking agents such as mitomycin C
or diepoxybutane. The hypersensitivity of the chromosomes of marrow cells or lymphocytes to the
latter agent is used as a diagnostic test for this condition. Cell-cycle progression is prolonged at the G2 to
M transition phase of the cell mitotic cycle, and the cells are more susceptible to oxygen toxicity when
cultured in vitro.147 It is important to test the lymphocytes from pediatric patients with aplastic anemia
for sensitivity to diepoxybutane, since therapy for Fanconi anemia differs from that used for idiopathic
aplastic anemia.

Most patients with Fanconi anemia do not respond to ATG or cyclosporine but do improve with
androgen preparations, often for as long as several years. Relapses occur gradually, with eventual death
by age 10 to 20 years from progressive marrow failure or from conversion to acute myelogenous
leukemia (approximately 10 percent of patients). Allogeneic stem cell transplantation is curative for this
disorder.150,277 A marked reduction in dosage of the marrow-conditioning regimen of
cyclophosphamide and radiation is necessary owing to the undue sensitivity of the tissues to alkylating
agents.150

DYSKERATOSIS CONGENITA AND SCHWACHMAN-DIAMOND SYNDROME

Dyskeratosis congenita and Schwachman-Diamond syndrome (pancreatic insufficiency with

neutropenia) are two rare disorders that may also evolve into aplastic anemia. Dyskeratosis is usually
inherited as a recessive X-chromosomeʹlinked disorder although rare cases are autosomal. The disease
is reflected in reticulate skin pigmentation, leukoplakia, and dystrophic nails. A variety of noncutaneous
anomalies have also been observed. The skin and mucosal lesions appear in adolescence, and aplastic
anemia usually develops in early adulthood.151 Schwachman-Diamond syndrome is manifest by
pancreatic insufficiency and steatorrhea. Neutropenia is present in virtually all patients and
granulocytopenia and thrombocytopenia in about one-third to one-half. Thus a substantial plurality of
patients have bi- or tricytopenia with hypoplastic marrows. There is a significant risk of progression to
myelogenous leukemia.152,278 Severe hematopoietic dysfunction can be treated successfully with
allogeneic stem cell transplantation.

CLINICAL FEATURES

EPIDEMIOLOGY

The incidence of aplastic anemia is estimated to be 2 to 5 cases per 1,000,000 population per year based
on retrospective studies.83 The incidence rates in Sweden (13 cases per 1,000,000 per year),153 Israel
(8 cases per 1,000,000 per year),84 and the United States (5 to 12 new cases per 1,000,000 per
year)154,155 suggest that the rate in industrialized countries is about 5 to 10 cases per 1,000,000 per
year.

SIGNS AND SYMPTOMS

The onset of aplastic anemia may be insidious, with a gradual fall in red cells leading to pallor, weakness,
and fatigue, or it may be more dramatic with fever, chills, and pharyngitis or other infections resulting
from neutropenia. Dependent petechiae, bruising, and bleeding secondary to thrombocytopenia are
seen often and may be the initial clue to the underlying marrow disorder.

Physical examination is generally unrevealing except for evidence of infection or bleeding. Oral purpuric
lesions (wet purpura) suggest a platelet count of less than 10,000/µl (10 × 109/liter), which portends a
higher risk for cerebral hemorrhage. Retinal hemorrhages may be seen with severe anemia or
thrombocytopenia. Lymphadenopathy or splenomegaly are not ordinarily found in aplastic anemia; such
findings suggest recent infection or an alternative diagnosis such as leukemia or lymphoma.

LABORATORY FEATURES

BLOOD FINDINGS

Patients with aplastic anemia have varying degrees of pancytopenia. Anemia is associated with a low
reticulocyte index.156 The reticulocyte count is usually less than 1.0 percent and may be zero.
Macrocytosis may result from the high levels of erythropoietin,157 stimulating the few residual
erythroblasts to mature more rapidly,158 or from an abnormal clone of erythroid cells, such as is seen in
myelodysplasia or paroxysmal nocturnal hemoglobinuria.10,11,12 and 13 The total leukocyte count is
low; the differential cell count reveals a marked decrease in neutrophils. The absolute neutrophil count
is the most important prognostic feature, with a count of less than 500/µl (0.5 × 109/liter) associated
with increased risk of infections and less than 200/µl (0.2 × 109/liter) associated with a dire prognosis.
Lymphocyte production is thought to be normal, but patients may have mild lymphopenia. Platelets are
reduced, but they function normally. On occasion, only one cell line is depressed initially, which may
lead to an early diagnosis of red cell aplasia or amegakaryocytic thrombocytopenia. In such patients,
other cell lines will fail shortly thereafter (days to weeks) and permit a definitive diagnosis.
MARROW FINDINGS

MORPHOLOGY

The marrow aspirate typically contains numerous spicules with empty fatty spaces and relatively few
hematopoietic cells. Lymphocytes, plasma cells, macrophages, and mast cells may be prominent, but
this probably reflects a lack of other cells rather than an increase in these elements. On occasion, some
spicules are cellular or even hypercellular, but megakaryocytes are usually reduced. These areas of
residual hematopoiesis do not appear to be of prognostic significance. Residual granulocytic cells
generally appear normal, but it is not unusual to see mild dysplastic or megaloblastoid features in the
erythroid cells. At times they are macrocytic or macronormoblastic, presumably due to the high levels of
erythropoietin. Marrow biopsy is essential to confirm the overall hypocellularity (Fig. 31-1), since a poor
yield of cells is seen on marrow aspirates in a number of other hematologic disorders.

FIGURE 31-1 Marrow biopsy in aplastic anemia. The marrow is devoid of hematopoietic cells and
contains only scattered lymphocytes and stromal cells.

Severe aplastic anemia has been defined by the International Aplastic Anemia Study Group159 as a
marrow of less than 25 percent cellularity, or less than 50 percent cellularity with less than 30 percent
hematopoietic cells, with at least two of the following: neutrophil count less than 500/µl (0.5 ×
109/liter), platelet count less than 20,000/µl (20 × 109/liter), and anemia with a corrected reticulocyte
index of less than 1 percent. Those patients with a neutrophil count less than 200/µl (0.2 × 109/liter)
have an extremely poor prognosis and are characterized as having very severe aplastic anemia.160

If a lymphocytosis is noted in the marrow or blood, a tartrate-resistant acid phosphatase determination

as well as immunophenotyping should be done to exclude early cases of hairy-cell leukemia161 or acute
lymphocytic leukemia.162

PROGENITOR CELL GROWTH

In vitro granulocytic-monocytic (CFU-GM) and erythroid (BFUʹE) colony assays reveal a marked
reduction in progenitor cells.19,20,21,22,23,24 and 25,29,30,31,32,33,34 and 35 In some instances,
improvement in colony growth after incubation with anti-T-cell monoclonal antibodies may predict
improvement after immunosuppressive therapy163; this has not, however, been a universal finding.

CYTOGENETICS

Cytogenetic analysis may be difficult to perform owing to low cellularity; thus, multiple aspirates may be
required to provide sufficient cells for study. The results are often normal in aplastic anemia and
abnormal in myelodysplastic syndromes; one study, however, suggested that 4 percent of patients with
otherwise typical aplastic anemia had abnormalities usually seen in myelodysplasia.164 Two of three
patients with aplastic anemia and cytogenetic abnormalities who did not have marrow transplants
progressed to a myelodysplastic syndrome, suggesting that the cytogenetic abnormalities of such
patients represent or will soon evolve into a clonal (neoplastic) disorder.

RADIOLOGIC FINDINGS

NMRI can be used to distinguish between marrow fat and hematopoietic cells.165 This may provide a
better overall estimate of marrow aplasia than morphologic techniques and may differentiate
hypoplastic myelodysplastic syndrome from aplastic anemia.166,167

PLASMA AND URINE FINDINGS

Studies should include assessment of antibodies to hepatitis A, B, and C; hepatitis B antigen; heterophile
determination; and antibodies to EBV. A sucrose hemolysis test and leukocyte and red cell
immunophenotyping6,7 and 8 should be done prior to transfusions to exclude paroxysmal nocturnal
hemoglobinuria (see Chap. 36).

The serum has high levels of hematopoietic growth factors, including erythropoietin, thrombopoietin,
and myeloid colony-stimulating factors.48,49 and 50

Serum iron values are usually high, and 59Fe clearance is prolonged, with decreased incorporation into
circulating red cells.168 Ferrokinetic studies or marrow scanning following injection of technetium sulfur
colloid or indium chloride may be required to assess overall marrow cellularity and function.

DIFFERENTIAL DIAGNOSIS

Both marrow aspirate and biopsy are essential to show the overall marked hypocellularity and to
exclude other causes of pancytopenia. Several disorders may be confused with severe aplastic anemia at
the initial presentation. Approximately 10 percent of patients with myelodysplastic syndromes present
with hypoplasia rather than a hypercellular marrow. This possibility is suspected if there is abnormal
blood film morphology, as seen with myelodysplasia (see Chap. 92). Marrow erythroid precursors in
myelodysplasia have both megaloblastoid and dysplastic features, with dumbbell and cloverleaf nuclei,
Howell-Jolly bodies, and increased siderotic granules. Granulocyte precursors have reduced granulation,
with abnormal blue cytoplasm in the promyelocytes and acquired Pelger-Huüet anomalies in the mature
cells. Megakaryocytes may have hyperlobulation or may have a single nucleus in a small cell (unilobular
micromegakaryocytes). Cytogenetic abnormalities are often found but are not essential for the diagnosis
of myelodysplastic syndromes. MRI studies may be useful in differentiating severe aplastic anemia from
myelodysplastic syndromes by showing a diffuse cellular pattern in the latter disorders.165,166 and 167
Paroxysmal nocturnal hemoglobinuria is usually identified by a positive sucrose hemolysis test, or
abnormal CD59 red cell membrane proteins as detected by flow cytometry.6,7 and 8

Acute lymphocytic leukemia may initially have a hypoplastic phase, but even then clumps of lymphocytic
cells are often seen.162 Less often, hairy-cell leukemia may be preceded by a hypoplastic phase.161
Both conditions can be differentiated from severe aplastic anemia by use of special stains such as
tartrate-resistant acid phosphatase for hairy-cell leukemia and by immunophenotyping using flow
cytometry for acute lymphocytic leukemia.

TREATMENT

The median survival of untreated patients with aplastic anemia [neutrophil count <500/µl (0.5 ×
109/liter)] is 3 to 6 months, with only 20 percent surviving beyond a year.169 Very severe aplastic
anemia [neutrophils <200/µl (0.2 × 109/liter)] has an extremely poor prognosis.160 Those patients with
less severe disease [i.e., neutrophils >1000/µl (1.0 × 109/liter)], who do not require red cell or platelet
transfusions, may be treated conservatively with supportive care, as there are occasional cases of
spontaneous recovery.

MARROW TRANSPLANTATION

Prompt and aggressive therapy is usually indicated for most patients with severe disease. The major
curative approach is allogeneic marrow transplantation.170 and 171 This treatment modality is
described in Chap. 18. Only one-third of all patients have compatible donors. Many transplants have
been performed using partially matched siblings or unrelated histocompatible donors recruited through
the National Marrow Donor Program or similar organizations in other countries.172 Umbilical cord
blood may evolve as an alternative source of unrelated donors for transplantation.173

IMMUNOSUPPRESSIVE THERAPY

ANTILYMPHOCYTE AND ANTITHYMOCYTE GLOBULIN

Many cases of aplastic anemia may be mediated by a cellular immune reaction directed against
hematopoietic stem or progenitor cells. The recovery of their own cells was observed in some recipients
of mismatched allogeneic transplants after treatment with ALG.174 Improvement occurred in benzene-
or 32P-induced aplastic anemia in rabbits after ALG treatment and transplantation with mismatched
marrow cells.175,176 The requirement for high-dose immunosuppressive treatment to allow
engraftment in half the syngeneic transplants170,177 also supports the concept of a cellular immune
reaction. Subsequently, many investigators found evidence of T-cellʹmediated suppressor mechanisms
by in vitro marrow culture studies.20,23,29,31,32,33,34,35 and 36 Some of these observations were
undoubtedly due to transfusion sensitization, but a number of studies supported the notion of an active
immune (T-lymphocyteʹmediated) suppressor mechanism being responsible for the aplasia. Although
ALS and ATG appear to act by reducing cytotoxic T cells, these preparations also release hematopoietic
growth factors from certain T cells.178,179

There is about a 50 percent response rate with ALS or ATG.180,181,182,183 and 184 Therapy is given for
4 to 10 days with doses of 15 to 40 mg/kg daily. Since the antisera are prepared in horses, it is important
to perform skin tests against horse serum prior to administration.185 If positive, pretreatment with
glucocorticoids for 24 h lessens reactions. Fever and chills are common during the first day of treatment;
these can be reduced with oral prednisone, 20 mg, daily. During treatment, accelerated platelet
destruction is often seen. This leads to an increase in transfusion requirements over the 10-day
treatment interval. Serum sickness occurs commonly 7 to 10 days from the first dose. This is
characterized by spiking fevers, skin rashes, and arthralgias. The clinical manifestations of serum
sickness can be prevented by increasing prednisone to 60 to 80 mg daily, from day 10 to day 17 of the
treatment course.

GLUCOCORTICOIDS

Marrow recovery can occur after very high doses of glucocorticoids.186,187 Methylprednisolone in the
range of 500 to 1000 mg daily for 3 to 14 days has been successful, but the side effects can be severe.
These include marked glycosuria, electrolyte disturbances, gastric distress, psychosis, increased
infections, and aseptic necrosis of the hips.

Repeated responses to immunosuppressive therapy have been observed. As shown in Fig. 31-2, a 45-
year-old woman with severe aplastic anemia responded completely to ATG and remained well for nearly
9 months. At relapse, she received a second course of ATG and recovered for another 6 months. She
developed an anaphylactic reaction with a third exposure to ATG. There were several subsequent
responses to 14-day infusions of methylprednisolone (1 g/day), but no appreciable responses to
nandrolone decanoate, cyclosporine, or goat antilymphocyte globulin; she became refractory to therapy
and died of fungal sepsis.

FIGURE 31-2 Responses to repeated cycles of immunosuppressive therapy. A 45-year-old woman with
severe aplastic anemia had two complete responses following treatment with horse antithymocyte
globulin (ATG). After an anaphylactic reaction on the third exposure, she received 1 g of
methylprednisolone (MP), intravenously daily for 14 days. This led to a partial response on three
occasions. She was essentially unresponsive to further treatment with nandrolone decanoate (DECA),
cyclosporine (CSA), or goat antilymphocyte globulin (ALG).
CYCLOSPORINE

Another approach to immunosuppressive therapy uses cyclosporine, a cyclic polypeptide that inhibits IL-
2 production by T lymphocytes and prevents expansion of cytotoxic T cells in response to IL-2. After the
initial report in 1984 of its ability to induce remission,188 many groups have utilized cyclosporine as
primary treatment,189,190,191 and 192 in patients refractory to ATG or
glucocorticoids,190,191,192,193,194 and 195 in combination with granulocyte colony-stimulating
factors,196,197 or in varying combinations with other modes of therapy.198 Cyclosporine is
administered orally at 3 to 7 mg/kg per day for at least 4 to 6 months. Dosage adjustments may be
required to maintain trough blood levels of 300 to 500 ng/ml. Renal impairment is common and may
require increased hydration or dose adjustments to keep creatinine values below 2 mg/dl. Responses
are usually seen by 3 months and may range from achieving transfusion independence to complete
remission. Approximately 25 percent of patients respond to this agent, but the response rate has ranged
from 0 to 80 percent in various reports.198

Although immunosuppression with ALG or ATG has the longest experience and a seemingly better
response rate, there are certain advantages to cyclosporine. This drug does not require hospitalization
or use of central venous catheters. Fewer platelet transfusions are required during the first few weeks of
therapy, where accelerated platelet needs are seen in patients receiving ALG or ATG. It is unclear
whether cyclosporine should be considered primary therapy for most patients, with views ranging from
cautious optimism to marked reservation concerning its effectiveness. A French cooperative trial
showed equal effectiveness of ATG plus prednisone compared to cyclosporine.199 In this crossover
study of newly diagnosed patients, survivals of about 65 percent were observed 12 months after
diagnosis. Improved in vitro tests to predict responsiveness may help tailor specific therapy for each
patient in the future.194

COMBINATION THERAPY

Both low-dose and high-dose methylprednisolone have been used in combination with ATG and
oxymethylone.200,201 Responses and survival were similar in both groups of patients. Androgens have
been used in conjunction with immunosuppressive agents in randomized trials with both negative202
and positive results.201,203 Nonrandomized trials suggest that coadministration of androgens with ATG
or ALG improves the response rate.204 At this time, it is unclear whether androgen preparations should
be added to primary therapy; their use should be avoided in patients with posthepatitis aplastic anemia
or in those with abnormal liver function tests.

Several trials have examined the effect of adding cyclosporine to basic regimens of ALG and
glucocorticoids. Overall response rates increased from 47 percent to 70 percent in one study205 and
from 39 percent to 65 percent in another.206 With combined therapy a 67 percent response rate was
noted at 3 months, which improved to 78 percent at 1 year.207 Although granulocyte colony-stimulating
factor alone may be detrimental,208 its addition to ALG, glucocorticoids, and cyclosporine appeared to
improve response rates.209 Eighty-three percent of 40 patients with very severe aplastic anemia had
trilineage reconstitution and became transfusion independent within 4 months of therapy.

These encouraging results with immunosuppressive therapy are in some instances equal to the results
after marrow transplantation.210,211 and 212 The results from UCLA indicated a 49 percent survival for
146 patients treated with ATG alone.210 This did not differ from the survival of age-matched patients
that underwent bone marrow transplantation during the same time interval. However, the survival after
transplants improved after 1984, from 43 percent to 72 percent, indicating better results with improved
transplant protocols. Similar results were seen in Seattle,211 where 227 patients were treated with ATG
alone, and 168 received bone marrow transplants. The actuarial survival at 15 years was 38 percent
following ATG therapy and 69 percent after bone marrow transplant. However, later results with
combination immunosuppressive therapy showed better results. Forty-eight children treated at
Memorial Sloan-Kettering between 1983 and 1992 had a 10-year survival of 76 percent for bone marrow
transplantation and 74 percent for combined immunosuppressive therapy.212 Thus,
immunosuppression may be preferable for patients who are greater than 30 to 40 years of age and who
may experience delay in finding a suitable donor. Marrow transplants are, however, curative for aplastic
anemia, whereas many long-term sequelae have been found after immunosuppressive therapy.213,214
and 215 Several surveys have shown a substantial rate of relapse or conversion to other stem cell
disorders. Of 358 patients responding to immunosuppressive therapy, 74 relapsed after a mean of 2.1
years. The actuarial incidence was 35 percent at 10 years.216 In the Swiss experience,217 29 of 129
patients treated with ALG developed myelodysplasia, leukemia, paroxysmal nocturnal hemoglobinuria,
or combined disorders. This tendency to relapse and to develop clonal hematologic disorders has been
reviewed by the European Cooperative Group for Bone Marrow Transplantation in 468 patients, most of
whom received ATG.218 The risk of a hematologic complication increased continuously and reached 57
percent at 8 years after immunosuppressive therapy. A further survey indicated 42 malignancies in 860
patients treated with immunosuppression, whereas only 9 malignancies were seen in 748 patients who
received marrow transplants.219 Careful morphologic review of the blood and marrow before and after
therapy may distinguish those patients at risk for late hematologic complications.220

HIGH-DOSE CYCLOPHOSHAMIDE

High-dose cyclophosphamide has been used as a unique form of immunosuppression.221 Although it

would seem inappropriate to administer high doses of chemotherapy to patients with severe marrow
aplasia, this approach was based on observations of autologous recovery after preparative therapy for
allogeneic transplants.221 Ten patients received cyclophosphamide at 45 mg/kg per day intravenously
for 4 days with or without cyclosporine for an additional 100 days. Gradual neutrophil and platelet
recovery ensued over 3 months. Seven patients responded completely and remain in remission 11 years
after treatment.

ANDROGENS
A variety of androgenic and anabolic steroids have been used for aplastic anemia. Testosterone,
methyltestosterone, testosterone enanthate, fluoxymesterone, norethandrolone, oxymetholone,
nandrolone decanoate, danazol, and etiocholanolone have all been employed. These agents stimulate
the production of erythropoietin, and their metabolites stimulate erythropoiesis when added to marrow
cultures in vitro.222

Randomized trials have not shown efficacy when androgens were used as primary therapy for severe or
moderately severe aplastic anemia.159,202 However, a French study showed that high doses of
androgens were superior to low doses in patients with only moderately severe aplasia.223 Large series
of patients were reported in which survival seemed improved as compared with historical controls,224
but this could equally be attributed to better supportive care. Many physicians use androgens in those
patients with moderate degrees of marrow aplasia who have failed initial treatment with
immunosuppressive agents. The response of one patient who was resistant to fluoxymesterone, ATG,
and cyclosporine is shown in Fig. 31-3. There was progressive marrow recovery after 5 months of
treatment with etiocholanolone and nandrolone decanoate.225

FIGURE 31-3 Response to etiocholanolone and nandrolone decanoate. A 62-year-old woman with severe
aplastic anemia failed to improve after treatment with fluoxymesterone (Halotestin)(1¯, ×5 months),
methylprednisolone (M Pred)(2

, 14 days), antithymocyte globulin (ATG) (3¯, 10 days), or cyclosporine (CYS)(4

, ×1 month). Marrow recovery occurred during therapy with 3-b-etiocholanolone and nandrolone
decanoate. (Reproduced from Seewald et al,225 with permission.)

Androgens should be continued for at least 3 to 6 months, since responses may require prolonged
treatment. Nandrolone decanoate, 400 mg intramuscularly per week, is a good initial drug. Concerns
about local hematomas are usually obviated by firm local pressure for 30 min following injection. Long-
term survivors after androgen therapy have essentially the same progression to clonal hematologic
disorders as patients treated with immunosuppressive agents.224

CYTOKINES
Despite their effectiveness in accelerating recovery from chemotherapy, these agents have been far less
effective in achieving long-term benefits in patients with severe aplastic anemia. Daily treatment with
granulocyte-macrophage colony-stimulating factor226,227 and 228 or granulocyte colony-stimulating
factor229 has improved marrow cellularity and increased neutrophil counts approximately 1.5- to 10-
fold. Unfortunately, in nearly all patients, the blood counts return to baseline within several days of
cessation of therapy. Although occasional patients show evidence of trilineage marrow recovery with
long-term therapy,229,230,231 and 231 the vast majority do not respond. In fact, physicians have been
cautioned not to use hemopoietic growth factors as primary therapy.208 Repeated transfusions of
blood and platelets while awaiting definitive therapy by bone marrow transplant or immunosuppression
can reduce the chances of responding to such therapy. Therapy with myeloid growth factors is probably
best reserved for instances of proved infections or as a preventive measure prior to dental work or other
procedures that would compromise mucosal barriers. Doses of 250 to 300 µg daily by subcutaneous
injection are easiest to administer and seem to be associated with the fewest side effects.

IL-1, a potent stimulator of marrow stromal cell production of other cytokines, and IL-3 have been
ineffective in small numbers of patients with severe aplastic anemia.233,234 These disappointing results
with cytokines are not unexpected, as previous work has suggested high serum levels of growth factors
in patients with aplastic anemia. Moreover, the majority of patients appear to have a stem cell defect,
which may be unresponsive to factors that act on more mature progenitor cells.

OTHER THERAPY

High doses of intravenous gamma globulin have been given to small numbers of patients with severe
aplastic anemia235,236 and 237 because of its success in treating certain cases of antibody-mediated
pure red cell aplasia. Some improvement was noted in four of six patients treated. Other treatments
that are occasionally successful include lymphocytapheresis238,239 and acyclovir240 (perhaps owing to
a viral etiology in some cases).

SPLENECTOMY

Removal of the spleen does not increase hematopoiesis but may increase neutrophil and platelet counts
two- to threefold and improve survival of transfused red cells or platelets in highly sensitized
individuals.241 The surgical morbidity and mortality in patients with virtually no platelets makes this a
questionable therapeutic procedure.

SUPPORTIVE CARE

All patients should have immediate HLA typing performed.242 Where marrow transplant is a
consideration, HLA typing of all siblings should be performed as soon as possible. Blood and platelet
transfusions should be used sparingly, if at all, in potential transplant recipients to minimize
sensitization. Most young adults can tolerate hemoglobin levels of 7 to 8 g/dl; platelets need to be given
only for active hemorrhage or severe thrombocytopenia with platelet counts less than 10,000/µl (10 ×
109/liter). It is important not to transfuse patients with red cells or platelets from family members, since
this may sensitize patients to minor histocompatibility antigens, increasing the risk of graft rejection
after marrow transplantation. Following a marrow transplant, or in those individuals in whom
transplantation is not a consideration, family members may be ideal donors for platelet apheresis
products.

It is important to assess the risk of bleeding in each individual patient and not to transfuse solely on the
basis of platelet counts. Some patients tolerate platelet counts of 8000 to 10,000/µl (8 to 10 × 109/liter)
without undue bruising or bleeding.243 In some cases, administration of 4 to 12 g daily of e-
aminocaproic acid seems to reduce the bleeding tendency and to avoid transfusion requirements
without influencing the platelet counts.244 Pooled random-donor platelets may be used until
sensitization ensues, although it is preferable to use single-donor platelets from the onset to minimize
sensitization to HLA or platelet antigens. Subsequently, single-donor apheresis products or HLA-matched
platelets may be required.

Platelet refractoriness has been a major problem with long-term transfusion support. This may occur
transiently, with fever or infection, or as a lasting problem secondary to HLA sensitization. In the past,
this occurred in approximately 50 percent of patients after 8 to 10 weeks of transfusion support.
Filtration of blood and platelet concentrates to remove leukocytes reduces this problem to
approximately 15 to 20 percent of patients receiving chronic transfusions.245 In some patients who are
refractory to platelets, this problem can be overcome by administering high-dose intravenous gamma
globulin246,247 or by immunoabsorbent pheresis, using a column to remove circulating IgG
complexes.248

Packed red cells are usually given to alleviate symptoms of anemia; transfusions are often indicated at
hemoglobin values below 7 to 8 g/dl. These products should also be given through leukocyte-removal
filters to lessen leukocyte and platelet sensitization and to reduce subsequent transfusion reactions.
Since each unit of red cells provides approximately 200 to 250 mg of iron, there are long-term
consequences of transfusion-induced hemosiderosis. This is not usually a major problem in patients who
respond to transplantation or immunosuppressive therapy but is an issue in nonresponders who require
continued support. Consideration should be given to chelation therapy with deferoxamine to avoid or
reduce severe iron overload.249

CMV antibody titers should be obtained on admission; until these results are available, only CMV-
negative blood products should be given to potential transplant recipients to minimize problems with
CMV infections after transplantation. Once a patient is shown to be CMV-positive, this restriction is no
longer necessary. Leukocyte-depletion filters will also decrease the risk of transmitting CMV.

Neutropenic precautions should be applied to hospitalized patients with neutrophil counts less than
1000/µl (1 × 109/liter). Precautions vary widely from institution to institution. One approach is to use
private rooms, with requirements for face masks and hand-washing with antiseptic soap. Fresh fruits
and vegetables should be avoided to prevent bacterial colonization or infection. When patients with
aplastic anemia become febrile, cultures should be obtained from the blood, urine, and any suspicious
lesions. Broad-spectrum antibiotics should be initiated promptly, without awaiting culture results (see
Chap. 17). The choice of antibiotics depends on local practices; major organisms of concern include
Staphylococcus aureus, S. epidermidis (in patients with venous access devices), and gram-negative
organisms. Patients with persistent culture-negative fevers should receive antifungal treatment with
fluconazole, itraconazole, or amphotericin.

In the past, leukocyte transfusions were used on a daily basis to reduce the short-term mortality from
infections. Approximately 1010 leukocytes were obtained from normal donors by apheresis. However,
there was generally a high proportion of mononuclear cells rather than neutrophils in these products.
With a 1- to 2-h half-life in febrile patients, it was unusual to detect more than 100 to 200 neutrophils
per microliter for more than a few hours after transfusion. The yield of neutrophils can be increased by
administering GM-CSF or G-CSF to the donor,250 but most physicians avoid using white cell products
since present-day antibiotics are usually sufficient to carry a patient through an episode of sepsis.
Notable exceptions include documented invasive aspergillosis unresponsive to amphotericin
(particularly in the post-transplant setting) and infections with organisms resistant to all known
antibiotics.

COURSE AND PROGNOSIS

Before marrow transplantation and immunosuppressive therapy, more than 25 percent of the patients
died within 4 months of diagnosis; half succumbed within 1 year.169,251,252 Marrow transplantation is
highly successful and curative for 75 to 85 percent of untransfused patients and for 55 to 60 percent of
those with multiple previous transfusions. Unfortunately, as many as 20 to 30 percent of transplant
survivors suffer the deleterious consequences of severe graft-versus-host disease. Immunosuppressive
therapy leads to a marked improvement in about 50 to 70 percent of the patients; some are
hematologically normal, but many continue with moderate anemia or thrombocytopenia. Relapse
occurs in about 15 percent of patients, and indeed the underlying stem cell defect may progress over 10
years to paroxysmal nocturnal hemoglobinuria, a myelodysplastic syndrome, or acute myelogenous
leukemia in as many as 40 percent of initial responders to immunosuppressive
therapy.213,214,215,216,217,218 and 219

At diagnosis, the prognosis is largely related to the absolute neutrophil count and platelet count. In the
past, the prognosis appeared worse when the disease followed hepatitis.108,109,253 Recent results
with immunosuppression254 or bone marrow transplant255 are equivalent to that seen with idiopathic
or drug-induced cases. Children appear to respond better than adults, both with transplantation and
with androgen therapy, especially those with mild or moderate disease. Constitutional aplastic anemia
responds temporarily to androgens and glucocorticoids but is invariably fatal unless treated by
transplantation.145,150

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