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Chapter 30 Aplastic Anemia 403

become pregnant, especially if thrombocytopenia and a PNH clone younger patients, hereditary forms of the syndrome should be inves-
are present. tigated by appropriate testing for germline alterations. The syndrome
can be a presentation of lymphomas and seen in the context of
hemolysis.
Hepatitis

9
Hepatitis-associated AA has several distinctive features. Typically, an Paroxysmal Nocturnal Hemoglobinuria and
uneventful episode of apparent viral hepatitis in a young man is Aplastic Anemia
followed in 1–2 months, during convalescence from the liver inflam-
mation, by very severe pancytopenia. Depression of blood cell counts There is a strong association between AA and PNH (see Chapter 31).
during the course of hepatitis is common; leukopenia, atypical lym- These diseases are frequently diagnosed concurrently or sequentially
phocytosis, macrocytosis, and thrombocytopenia mimic in milder in the same individual, and they share similar clinical and pathologic
forms the hematologic changes of AA. However, posthepatitis AA has features (i.e., pancytopenia and BM hypocellularity). The presence
a very poor prognosis, with early estimates of mortality of 90% at 1 of an expanded PNH clone is associated with HLA-DR15 and has
year, and a history of AA with hepatitis has been considered an indica- been reported as a good prognostic marker for responsiveness to
tion for early BM transplantation. Patients with posthepatitis AA can immunosuppressive therapy. Clinical BM failure can be present at
successfully undergo BM transplantation without an increased risk the onset of PNH or can develop after diagnosis. By flow cytom-
of venoocclusive disease. Patients with hepatitis-associated aplasia etry of granulocytes for glycosylphosphoinositol-anchored proteins,
have markers of immune system activation and respond well to there is expansion of a PNH clone in 50% or more of AA cases
intensive immunosuppressive therapy. Almost all cases have been at presentation. Longitudinal studies of patients with de novo
non-A, non-B, non-C. Posthepatitis AA is linked to fulminant hepa- PNH or PNH developing from AA indicate a low probability of
titis of childhood and acute seronegative hepatitis. Acute viral hepatitis spontaneous remission; in most patients, the contribution of the
that is seronegative differs clinically from hepatitis C disease; paren- PNH clones remains stable for years, but hemolytic disease can
teral exposure is not a risk factor, liver functions abnormalities are develop.
more severe during the acute phase, and late complications are more
common. Even next generation sequencing has failed to find evidence
of infection in seronegative hepatitis. Collagen Vascular Diseases
AA is a component of the collagen vascular syndrome called eosino-
Postmononucleosis Aplastic Anemia philic fasciitis. This severe, scleroderma-like disease is characterized by
fibrosis of subcutaneous and fascial tissue, localized skin induration,
Acute infection with Epstein-Barr virus (EBV) causes infectious eosinophilia, hypergammaglobulinemia, and an elevated erythrocyte
mononucleosis that is commonly associated with neutropenia and sedimentation rate. The rheumatologic symptoms of fasciitis respond
other hematologic abnormalities but, like acute hepatitis, is only to corticosteroids, but the associated AA has a very poor prognosis. A
rarely complicated by AA. However, EBV may be involved in the few patients have survived after BM transplantation or immunosup-
cause of AA more frequently than originally appreciated, because a pressive therapy. More rarely, AA has complicated systemic lupus
large number of primary EBV infections are unrecognized. Pancyto- erythematosus and rheumatoid arthritis, but in many cases, the role of
penia can be first observed during the acute mononucleosis syndrome concomitant drug therapy is confounding. Rarely, AA can accompany
or shortly thereafter. Some patients have recovered spontaneously, Sjögren syndrome, multiple sclerosis, and immune thyroid disease.
and others after therapy with corticosteroids or ATG. EBV can AA occasionally occurs in individuals with hypogammaglobulinemia
occasionally be demonstrated in the BM cells of patients with appar- or congenital immunodeficiency syndrome, thymoma, or thymic
ently idiopathic AA, in association with serologic evidence of a hyperplasia.
primary or reactivated viral infection.
LABORATORY EVALUATION
Hemophagocytic Syndrome
Peripheral Blood
The BM is hypocellular in approximately one-third of cases with
hemophagocytic syndrome. In this disorder, there can be progression In typical cases of AA, all the blood cell counts are depressed. The
from BM hypercellularity to aplasia; myelofibrosis is also common. blood smear usually shows obvious paucity of platelets and leukocytes
Pancytopenia occurs in most cases; anemia is a universal finding; but normal RBC morphology; toxic granulations can be present in
thrombocytopenia and neutropenia are also common. In contrast to neutrophils. Automated cell counting shows erythrocyte macrocytosis
typical AA, these patients appear systemically ill and have a fulminant and a normal RBC distribution of width. Platelet size is normal and
course, with fever and constitutional symptoms, and peripheral not increased as in immune peripheral destruction, but the low
blood-cell count depression is often associated with abnormalities of number can cause greater heterogeneity of size. Prior transfusions
other organ systems: hepatosplenomegaly, elevation of transaminases alter platelet numbers, relative reticulocyte counts, and hemoglobin
lymphadenopathy, cutaneous eruptions, and pulmonary infiltrates. values. Although relative lymphocytosis is common, most patients
The syndrome is associated with a wide variety of diseases. In the also have decreased absolute numbers of monocytes and lymphocytes.
infectious category, viral infections are most common and include The severity of AA can be graded based on the peripheral blood cell
EBV, cytomegalovirus, herpes simplex, herpes zoster, B19 parvovirus, counts (see Table 30.6 and box on Diagnostic Algorithm in Aplastic
and HIV-1; bacterial and parasitic infections have also been associ- Anemia).
ated with hemophagocytosis. Hemophagocytosis can be observed on
supravital or Wright-Giemsa staining of the BM of patients with
idiopathic AA, and it is also a morphologic feature of graft rejection DIAGNOSIS OF APLASTIC ANEMIA
after BM transplantation. In virus-associated hemophagocytosis,
there is evidence of immune system activation. The sera of patients Although the ultimate diagnosis of AA rests on the interpretation of
have been shown to contain high levels of IFN-γ, TNF-α, interleukin an adequate BM biopsy specimen, important clues to the cause of
(IL)-6, soluble CD8, and soluble IL-2 receptor, and T cells overpro- pancytopenia can be obtained from the history, physical examination,
duce IFN-γ in vitro. The clinical response to cyclosporine is consistent and laboratory data. Pancytopenia that is not primarily hematologic
with a T cell–mediated pathophysiology of hematopoietic failure. In in origin but secondary to other disease processes is usually an obvious