Bone Marrow Failure Workup

Laboratory features of bone marrow failure include a single cytopenia, as in pure red cell aplasia, and amegakaryocytic thrombocytopenic purpura or pancytopenia, as in aplastic anemia.

Peripheral blood findings

Anemia is common, and red cells appear morphologically normal. The reticulocyte count usually is less than 1%, indicating a lack of red cell production. Occasionally, the mean cell volume is elevated, with macrocytosis.

Platelet counts are lower than normal, with a paucity of platelets in the blood smear. Platelet size is normal, but a low platelet count may cause greater heterogeneity in size.

Agranulocytosis (ie, a decrease in all granular white blood cells, including neutrophils, eosinophils, and basophils) and a decrease in monocytes are observed. A relative lymphocytosis occurs (ie, increased percentage) without an increase in numbers.

Ham test

The Ham test, or sucrose hemolysis test, result may be positive in a patient with underlying paroxysmal nocturnal hemoglobinuria, but a recent transfusion with packed red blood cells may induce a false-negative test result (ie, testing normal, transfused red cells). Folate, vitamin B-12, and serum erythropoietin levels usually are increased.

Fanconi anemia screening

Fanconi anemia should be considered in all young adults and children with hypoplastic or aplastic anemia^[2] or cytopenia, unexplained macrocytosis, myelodysplastic syndrome, acute myelogenous leukemia, epithelial malignancies, or subtle, but characteristic, physical anomalies.

The criterion standard screening test for Fanconi anemia is based on the characteristic hypersensitivity of Fanconi anemia cells to the crosslinking agents (eg, mitomycin C, diepoxy butane [DEB], cisplatin). Expose a culture of replicative cells (ie, phytohemagglutinin [PHA]–stimulated peripheral blood lymphocytes or skin fibroblasts) to low doses of mitomycin C or DEB. Then examine the cells in metaphase, looking for evidence of chromosomal breaks and radial chromosomes.

Identification of gene mutations

Mutated genes can be identified by retroviral complement studies, by direct sequencing, or by denaturing high-performance liquid chromatography (DHLP).

Dyskeratosis congenita screening

Screening for dyskeratosis congenita should be considered in children and adults who have (1) bone marrow failure, acute myelogenous leukemia, or myelodysplastic syndrome; (2) negative mitomycin C and DEB test results, which would rule out Fanconi anemia; and either (3) hypopigmented macules, reticulated hypopigmentation, dystrophic nails, or oral leukoplakia or (4) evidence in their family history, obtained via genomic deoxyribonucleic acid (DNA) screening, of X-linked or autosomal dominant forms of dyskeratosis congenita (DKC1-3).

Diamond-Blackfan anemia and Shwachman-Diamond syndrome characteristics

Diamond-Blackfan anemia is a pure red cell aplasia and usually manifests in early infancy. Shwachman-Diamond syndrome is a syndrome of bone marrow failure (classically neutropenia), exocrine pancreatic insufficiency, and metaphyseal dysostosis that also manifests in early childhood.

Histologic findings

Bone marrow studies provide information to definitively diagnose failure, and the status of precursor cells of each cell line can be examined. Pure red cell aplasia characteristically affects erythroid progenitor cells; amegakaryocytic thrombocytopenia is evidenced by a lack of megakaryocytes. A finding of hypoplastic bone marrow differentiates aplastic anemia from aleukemic leukemia, which produces blast cells in the marrow.

Bone marrow activity can be measured by radiographic methods. Ferrokinetic studies have been conducted using a radioactive label, such as iron-59 or indium-111, both of which are taken up by erythroid cells. Radioactive iron is no longer available in the United States.

Magnetic resonance imaging (MRI) can be used to differentiate densities and intensity signals of bone marrow fat cells from densities and intensity signals of hematopoietic cells.

Positron emission tomography (PET) scanning with radiolabeled oxygen can measure the metabolic activity difference between hypoplastic marrow and cellular marrow.

A bone marrow aspirate and biopsy should be performed to assess the cellularity and morphology of the residual cells. In general, the marrow is replaced with fat cells and stromal cells are replaced with lymphocytes, with very few hematopoietic cells. Occasionally, localized pockets of marrow are present (ie, from a sampling error), which can be misleading. To evaluate cellularity, the core biopsy specimen should be at least 1 cm long.

Residual erythroid cells may show evidence of dysplasia with nuclear-cytoplasmic maturation dissociation (commonly described, in the absence of a folate or vitamin B-12 deficiency, as megaloblastoid features).