Anemia of Central Origin

Abstract

Hypoproliferative anemia results from the inability of bone marrow to produce adequate numbers of red blood cells. The list of conditions that cause hypoproliferative anemia is long, starting from common etiologies as iron deficiency to rarer diagnoses of constitutional bone marrow failure syndromes. There is no perfect diagnostic algorithm, and clinical data may not always clearly distinguish "normal" from "abnormal", yet it is important for practicing clinicians to recognize each condition so that treatment can be initiated promptly. This review describes diagnostic approaches to hypoproliferative anemia, with particular emphasis on bone marrow failure syndromes.

Figure 1

Diagnostic approach to hypoproliferative anemia. ARC: absolute reticulocyte count. RI: reticulocyte index. AA: aplastic anemia. CKD: chronic renal disease. MDS: myelodysplastic syndrome. MMA: methylmalonic acid. LDH: lactate dehydrogenase

Figure 2

Diagnostic approach to bone marrow failure syndromes. MDS: myelodysplastic syndrome. PNH: paroxysmal nocturnal hemoglobinuria. LGL: large granular lymphocytes. PRCA: pure red cell aplasia. RBC: red blood cell. PB: peripheral blood. AA: aplastic anemia

Figure 3

A. Variably hypocellular marrow in aplastic anemia (cellularity <5% to 40%). B. Bone marrow biopsy of a patient with pure red cell aplasia (CD71 stain), revealing lack of erythroid precursors. C. Flow cytomery of bone marrow cells from a patient with pure red cell aplasia. Absence of erythroid lineage is confirmed and quantified. D. Typical bone marrow biopsy in severe aplastic anemia: hypocellular bone marrow replaced with fat. E-G. Examples of atypical megakaryocytes (E: Widely separated lobes without strand. F: small bilobated megakaryoctes. G: small monolobated megakaryocyte). H. Normal megakaryocte for comparison. I. Bone marrow biopsy of a patient with hypocellular MDS. Immunohistochemical staining for CD61 highlights atypical bilobated megakaryoctes. (Figure 3B-C: Courtesy of Dr. Raul Braylan)

Figure 4

Telomere content of leukocytes measured by standardized flow FISH or quantitative PCR. A patient's result is compared to age-adjusted normalized values. Calculated telomere length of total mononuclear cells below the first percentile for age strongly suggests a diagnosis of telomere disease. (Courtesy of Dr. Bogdan Dumitriu)

Figure 5

GATA2 deficiency in the clinic: The patient presented as 18 year-old male with pancytopenia and marrow of AA, and within two years, he developed AML with myelodysplastic morphology. A. Initial bone marrow biopsy at presentation: hypocellular marrow with trilineage hypoplasia compatible with AA. B-E. Bone marrow biopsy two years later: B. AML with myelodysplastic morphology; 30-40% cellularity. C. CD34 immunohistochemistry of biopsy, highlighting increased blasts. D. Dysplastic large osteoclast-like megakaryocyte with separated nuclear lobes, on aspirate smear. E. Pelgeroid PMN, peripheral smear. F. Small mononuclear megakaryocyte, on aspirate smear. G. Increased blasts, 35% on 500 cell differential of aspirate smear. (Courtesy of Dr. Danielle Townsley and Dr. Katherine Calvo).

Figure 6

Bone marrow flow cytometry of lymphoid subsets and monocytes in GATA2 patients. Compared to AA patients, GATA2 patients have disproportionately reduced bone marrow mature B cells (CD10−, CD20+), hematogones (CD10+, CD20−), monocytes (CD14+, CD64+), and NK cells (CD3−, CD56+) (Courtesy of Dr. Katherine Calvo).