What is the next step in evaluating a patient with low red blood cell count, hemoglobin, hematocrit, and platelet count, but normal iron studies and ferritin?

Evaluation of Pancytopenia with Normal Iron Studies

The next step is to obtain a peripheral blood smear, reticulocyte count, vitamin B12 and folate levels, and proceed to bone marrow aspiration with biopsy and cytogenetics to evaluate for myelodysplastic syndrome or other primary bone marrow disorders. 1

Immediate Diagnostic Workup

Essential Laboratory Tests

• Obtain a peripheral blood smear immediately to assess for dysplastic features, blast cells, large granular lymphocytes, and red cell morphology abnormalities that may indicate myelodysplastic syndrome (MDS), aplastic anemia, or other marrow failure syndromes 1

• Measure absolute reticulocyte count to differentiate impaired bone marrow production (low/normal count) from hemolysis or acute blood loss (elevated count); a low reticulocyte count in the setting of pancytopenia strongly suggests bone marrow failure 1, 2

• Check vitamin B12 and folate levels to exclude megaloblastic anemia, which can present with pancytopenia and normal iron studies 1, 2

• Obtain serum erythropoietin level as this helps guide treatment decisions and assess for appropriate marrow response 1

Critical Next Step: Bone Marrow Evaluation

• Bone marrow aspiration with Prussian blue stain for iron and core biopsy are mandatory to evaluate blast percentage, degree of dysplasia in all three lineages, marrow cellularity (hypoplastic vs. hypercellular), presence of ringed sideroblasts, and degree of fibrosis 1

• Bone marrow cytogenetics must be obtained because specific chromosomal abnormalities (del(5q), del(20q), +8, -7/del(7q)) are diagnostic criteria for MDS and provide critical prognostic information 1

• Flow cytometry on bone marrow should assess CD34+ blast percentage and screen for paroxysmal nocturnal hemoglobinuria (PNH) clone and large granular lymphocytic disease, particularly in younger patients with hypoplastic marrows 1

Diagnostic Criteria for MDS

The diagnosis requires stable cytopenia for at least 6 months (or 2 months if specific karyotype or bilineage dysplasia present) plus at least one of three decisive criteria: 1

1. Dysplasia ≥10% in ≥1 of the 3 major bone marrow lineages
2. Blast cell count 5-19%
3. MDS-associated karyotype (del(5q), del(20q), +8, -7/del(7q))

Additional Targeted Testing

• Screen for PNH and HLA-DR15 in younger patients with normal cytogenetics and hypoplastic MDS, as these patients may respond better to immunosuppressive therapy 1

• Consider HIV screening if clinically indicated, as HIV can cause pancytopenia mimicking MDS 1

• Evaluate for familial cytopenias with genetic screening for Fanconi anemia or dyskeratosis congenita in patients with family history, as this affects transplant donor eligibility and treatment response 1

• Bone marrow reticulin staining helps assess for myelofibrosis 1

If Hemolysis is Suspected

• Order hemolysis panel including haptoglobin, lactate dehydrogenase (LDH), indirect bilirubin, and peripheral smear for schistocytes if the reticulocyte count is elevated 2

• Perform direct antiglobulin (Coombs) test to identify autoimmune hemolytic anemia 2

Common Pitfalls to Avoid

• Do not assume iron deficiency is excluded based solely on normal ferritin and iron studies—pancytopenia with normal iron parameters points away from nutritional deficiency and toward primary bone marrow pathology 1

• Do not delay bone marrow evaluation in patients with unexplained pancytopenia, as early diagnosis of MDS or aplastic anemia significantly impacts treatment decisions and prognosis 1

• Recognize that normal hemoglobin and hematocrit ranges do not exclude early bone marrow failure—the combination of low RBC count, hemoglobin, hematocrit, AND platelets requires aggressive investigation 3

• Remember that blast percentage from flow cytometry does not substitute for morphologic assessment by an experienced hematopathologist for prognostic purposes 1

Clinical Context Assessment

• Review medication history carefully for drugs causing marrow suppression (chemotherapy, immunosuppressants, anticonvulsants, methotrexate) 2

• Assess timing, severity, and tempo of cytopenias, prior infections, bleeding episodes, and transfusion requirements to distinguish indolent MDS from evolving acute myeloid leukemia 1

• Evaluate for concomitant inflammatory conditions (rheumatoid arthritis, inflammatory bowel disease) that may complicate interpretation of iron studies 1