Page 544 - Williams Hematology ( PDFDrive )

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

Antineoplastic drugs such as alkylating agents, antimetabolites, 40,000/μL (40 × 10 /L). Macrocytes may be present in the blood film
9
and certain cytotoxic antibiotics have the potential for producing mar- and the mean cell volume (MCV) increased. The absolute neutrophil
row aplasia. In general, this is transient, is an extension of their phar- and monocyte count are low. An absolute neutrophil count fewer than
9
macologic action, and resolves within several weeks of completing 500/μL (0.5 × 10 /L) along with a platelet count fewer than 30,000/μL
9
chemotherapy. Although unusual, severe marrow aplasia can follow use (30 × 10 /L) is indicative of severe disease, and a neutrophil count below
of the alkylating agent, busulfan, and may persist indefinitely. Patients 200/μL (0.2 × 10 /L) denotes very severe disease (see Table 35–1). Lym-
9
may develop marrow aplasia 2 to 5 years after discontinuation of alky- phocyte production is thought to be normal, but patients may have
lating agent therapy. These cases often evolve into hypoplastic myelo- mild lymphopenia. Platelets function normally. Significant qualitative
dysplastic syndromes. changes of red cell, leukocyte, or platelet morphology on the blood film
are not features of classical acquired aplastic anemia. On occasion, only
Stromal Microenvironment and Growth Factors one cell line is depressed initially, which may lead to an early diagnosis
Short-term clonal assays for marrow stromal cells have shown variable of pure red cell aplasia or amegakaryocytic thrombocytopenia. In such
defects in stromal cell function in patients with aplastic anemia. Serum patients, other cell lines will fail shortly thereafter (days to weeks) and
levels of stem cell factor (SCF) have been either moderately low or nor- permit a definitive diagnosis. Table 35–4 is a plan for the initial labora-
mal in several studies of aplastic anemia. 123,124 Although SCF augments tory investigation.
the growth of hematopoietic colonies from aplastic anemia patient’s
marrows, its use in patients has not led to clinical remissions. Another Plasma Findings
early acting growth factor, FLT-3 ligand, is 30- to 100-fold elevated in The plasma contains high levels of hematopoietic growth factors,
the serum of patients with aplastic anemia, although the pathobiologic including erythropoietin, TPO, and myeloid colony-stimulating factors.
125
effect of this change is unclear. Fibroblasts grown from patients with Growth factor levels need not be measured, however, for clinical care.
59
severe aplastic anemia have subnormal cytokine production. However, Plasma iron values are usually high, and Fe clearance is prolonged,
127
126
serum levels of granulocyte colony-stimulating factor, erythropoietin, with decreased incorporation into red cells.
and thrombopoietin (TPO) are usually high. Synthesis of IL-1, an
128
early stimulator of hematopoiesis, is decreased in mononuclear cells Marrow Findings
from patients with aplastic anemia. Studies of the microenvironment Morphology The marrow aspirate typically contains numerous spic-
129
have shown relatively normal stromal cell proliferation and growth fac- ules with empty, fat-filled spaces, and relatively few hematopoietic
tor production. These findings, coupled with the limited response of cells. Lymphocytes, plasma cells, macrophages, and mast cells may be
130
patients with aplastic anemia to growth factors, suggest that cytokine present. On occasion, occasional spicules are cellular or even hyper-
deficiency is not the etiologic problem in most cases. The most compel- cellular (“hot spots”), but megakaryocytes usually are reduced. These
ling argument is that most patients transplanted for aplastic anemia are focal areas of residual hematopoiesis do not appear to be of prognostic
cured with allogeneic donor stem cells and autologous stroma. 131 significance. Residual granulocytic cells generally appear normal, but
A rare exception to the negligible pathogenetic role of hematopoi- it is not unusual to see mild macronormoblastic erythropoiesis, pre-
etic growth factors in the etiology of aplastic anemia is the homozygous sumably as a result of the high levels of erythropoietin. Marrow biopsy
or mixed heterozygous mutation of the TPO receptor gene, MPL, which is essential to confirm the overall hypocellularity (Fig. 35–2), as a poor
can cause amegakaryocytic thrombocytopenia that evolves, later, into
aplastic anemia (Chap. 117). Furthermore, eltrombopag, a TPO recep-
tor agonist, can stimulate mono, or in some patients, bilineage or tri-
lineage recovery of blood counts that may be sustained off therapy (see TABLE 35–4. Approach to Diagnosis
“Treatment: Cytokines” below).
History and Physical Examination
CLINICAL FEATURES • Complete blood counts, reticulocyte count, and examination of
The onset of symptoms of aplastic anemia may be gradual with pallor, the blood film
weakness, dyspnea, and fatigue as a result of the anemia. Dependent • Marrow aspiration and biopsy
petechiae, bruising, epistaxis, vaginal bleeding, and unexpected bleed- • Marrow cell cytogenetics to evaluate clonal myeloid disease
ing at other sites secondary to thrombocytopenia are frequent present- • DNA stability test as a marker of Fanconi anemia
ing signs of the underlying marrow disorder. Rarely, it may be more
dramatic with fever, chills, and pharyngitis or other sites of infection • Immunophenotyping of red and white cells, especially for CD55,
resulting from severe neutropenia and monocytopenia. Physical exami- CD59 to exclude PNH
nation generally is unrevealing except for evidence of anemia (e.g., • Direct and indirect antiglobulin (Coombs) test to rule out
conjunctival and cutaneous pallor, resting tachycardia) or cutaneous immune cytopenia
bleeding (e.g., ecchymoses and petechiae), gingival bleeding and intra- • Serum lactate dehydrogenase (LDH) and uric acid, which if
oral purpura. Lymphadenopathy and splenomegaly are not features of increased may reflect neoplastic cell turnover
aplastic anemia; such findings suggest an alternative diagnosis such as a • Liver function tests to assess evidence of any recent viral
clonal myeloid or lymphoid disease. hepatitis
• Screening tests for hepatitis viruses A, B, and C
LABORATORY FEATURES • Screening tests for EBV, cytomegalovirus (CMV), and HIV
Blood Findings • Serum B and red cell folic acid levels to rule out cryptic meg-
12
Patients with aplastic anemia have varying degrees of pancytopenia. aloblastic pancytopenia
Anemia is associated with a low reticulocyte index. The reticulocyte

count is usually less than 1 percent and may be zero despite the high lev- • Serum iron, iron-binding capacity, and ferritin as a baseline prior
to chronic transfusion therapy
els of erythropoietin. Absolute reticulocyte counts are usually fewer than

Kaushansky_chapter 35_p0513-0538.indd 519 9/19/15 12:24 AM