In a patient with low red blood cell count, hemoglobin, and hematocrit, what is the next step in evaluation and management?

Anemia Workup: Next Steps After Low RBC, Hemoglobin, and Hematocrit

Order a complete blood count with red cell indices (MCV, MCH, MCHC, RDW), reticulocyte count, iron studies (serum ferritin and transferrin saturation), and a peripheral blood smear immediately to classify the anemia and guide further evaluation. 1

Initial Laboratory Assessment

The first priority is to characterize the anemia morphologically and assess bone marrow response:

• Obtain MCV to classify the anemia as microcytic (<80 fL), normocytic (80-100 fL), or macrocytic (>100 fL), which narrows the differential diagnosis substantially 2, 1
• Measure RDW (red cell distribution width) because an elevated RDW with microcytosis strongly suggests iron deficiency, even when MCV is only borderline low 1
• Order an absolute reticulocyte count to distinguish impaired erythropoiesis (low/normal count) from hemolysis or acute blood loss (elevated count) 2, 1
• Request a peripheral blood smear to identify red cell morphology abnormalities, hypersegmented neutrophils (B12/folate deficiency), or schistocytes (hemolysis) 1

Iron Status Evaluation

Iron deficiency is the most common cause of anemia and must be assessed in every patient:

• Serum ferritin <30 μg/L confirms iron deficiency in the absence of inflammation 2, 1
• Transferrin saturation <15-20% supports iron deficiency and is less affected by inflammation than ferritin 2, 1
• Measure C-reactive protein (CRP) concurrently with ferritin because inflammation falsely elevates ferritin, potentially masking iron deficiency 1
• In the presence of elevated CRP, use transferrin saturation as the primary indicator of iron deficiency rather than ferritin alone 1

Reticulocyte Count Interpretation

The reticulocyte response determines your next diagnostic steps:

• A low or normal reticulocyte count (<2%) indicates inadequate bone marrow response, prompting evaluation for nutritional deficiencies (iron, B12, folate), chronic kidney disease, or bone marrow disorders 2, 1
• An elevated reticulocyte count (>2%) suggests appropriate marrow response to blood loss or hemolysis, requiring hemolysis workup with haptoglobin, LDH, indirect bilirubin, and peripheral smear for schistocytes 1

MCV-Based Diagnostic Algorithm

Microcytic Anemia (MCV <80 fL)

• Iron deficiency is the most common cause; confirm with ferritin and transferrin saturation 2, 1
• If iron studies are normal, consider thalassemia trait (especially in Southeast Asian, Mediterranean, or African populations) and order hemoglobin electrophoresis 1
• Thalassemia trait typically shows marked microcytosis (MCV <75 fL), normal or low-normal RDW (<14%), and normal iron studies 1

Normocytic Anemia (MCV 80-100 fL)

• Check serum creatinine and estimated GFR to evaluate for chronic kidney disease as a cause of erythropoietin deficiency 2, 1
• Measure vitamin B12 and folate levels to exclude early megaloblastic anemia 1
• Assess thyroid-stimulating hormone (TSH) because hypothyroidism is a common reversible cause 1
• If reticulocyte count is elevated, proceed with hemolysis evaluation (haptoglobin, LDH, indirect bilirubin, direct antiglobulin test) 1

Macrocytic Anemia (MCV >100 fL)

• Measure serum vitamin B12 and folate levels as first-line tests for megaloblastic anemia 2, 1
• Review medication history for thiopurines, methotrexate, anticonvulsants, or chemotherapy agents that cause macrocytosis 1
• If B12/folate are normal, consider hypothyroidism, liver disease, or bone marrow disorders 1

Additional Targeted Testing

Based on clinical context and initial results:

• Stool guaiac test for occult blood when iron deficiency is confirmed, to detect gastrointestinal bleeding 1
• Hemolysis panel (haptoglobin, LDH, indirect bilirubin) if reticulocyte count is elevated 1
• Direct antiglobulin (Coombs) test if hemolysis is suspected to identify autoimmune hemolytic anemia 1

Common Diagnostic Pitfalls

• Mixed deficiencies (iron + B12/folate) can normalize MCV while elevating RDW; therefore, always order both iron studies and vitamin levels even when MCV appears normal 1
• Ferritin interpretation requires clinical context—it rises as an acute-phase reactant during inflammation, chronic disease, malignancy, or liver disease, potentially masking iron deficiency 1
• Do not rely on MCV alone to exclude iron deficiency; early iron deficiency may present with normal MCV but elevated RDW and low MCH 1
• Anemia is not a normal consequence of aging; it always warrants investigation for underlying pathology 1

When to Refer to Hematology

• Pancytopenia (low RBC, WBC, and platelets) requires bone marrow evaluation for aplastic anemia or myelodysplastic syndrome 1
• Unexplained anemia after comprehensive workup 1
• Suspected hemolytic anemia with positive Coombs test or schistocytes on smear 1
• Severe anemia (hemoglobin <7 g/dL) without obvious cause 3