Workup for Normocytic Anemia
The workup for normocytic anemia (MCV 80-100 fL) should begin with a reticulocyte count to distinguish between decreased RBC production and increased RBC destruction/loss, followed by targeted testing based on this result. 1
Initial Laboratory Assessment
Minimum required tests include: 1
- Complete blood count (CBC) with red cell indices (MCV, RDW)
- Reticulocyte count (corrected for degree of anemia - calculate reticulocyte index)
- Peripheral blood smear review
- Serum ferritin
- Transferrin saturation (TfS)
- C-reactive protein (CRP) or inflammatory markers
Algorithmic Approach Based on Reticulocyte Index
Low or Normal Reticulocyte Index (RI <2.0): Decreased RBC Production 1
This indicates bone marrow failure to respond appropriately. Order the following tests: 1
Iron studies: Serum iron, total iron-binding capacity (TIBC), transferrin saturation, ferritin
- Even with normal MCV, functional iron deficiency can occur, especially with inflammation 1
- Ferritin <30 ng/mL indicates iron deficiency without inflammation 1
- Ferritin 30-100 ng/mL with inflammation suggests combined iron deficiency and anemia of chronic disease 1
- Ferritin >100 ng/mL with TfS <20% indicates anemia of chronic disease 1
Renal function: Creatinine and blood urea nitrogen 1
- Renal insufficiency is a common cause of normocytic anemia with low reticulocytes 1
Inflammatory markers: ESR, CRP if not already obtained 1
Additional testing if above unrevealing: 1
- Vitamin B12 and folate levels (can present as normocytic before becoming macrocytic)
- Thyroid function tests
- Differential white blood cell count and platelet count (to assess for pancytopenia)
If diagnosis remains unclear after these tests, obtain hematology consultation for possible bone marrow examination to evaluate for aplastic anemia, myelodysplastic syndrome, or bone marrow infiltration. 1
Elevated Reticulocyte Index (RI >2.0): Increased RBC Destruction or Loss 1
This indicates the bone marrow is responding appropriately. Immediately evaluate for: 1
Hemolysis workup: 1
- Lactate dehydrogenase (LDH) - elevated
- Haptoglobin - decreased
- Indirect (unconjugated) bilirubin - elevated
- Direct antiglobulin test (Coombs test) - to identify immune-mediated hemolysis
- Peripheral smear examination for schistocytes, spherocytes, or other abnormal RBC morphology
Hemorrhage evaluation: 1
- Stool guaiac test for occult gastrointestinal bleeding 1
- Assess for clinical signs of bleeding (melena, hematochezia, menorrhagia, hematuria)
- Consider imaging if internal bleeding suspected
Critical Pitfalls to Avoid
Do not assume normal ferritin excludes iron deficiency in the presence of inflammation. Ferritin is an acute phase reactant and can be falsely elevated; use transferrin saturation and consider ferritin up to 100 ng/mL as potentially indicating iron deficiency when inflammation is present. 1
Do not overlook combined deficiencies. Microcytosis and macrocytosis can coexist and neutralize each other, resulting in a falsely normal MCV; an elevated RDW suggests this scenario. 1
Do not delay peripheral smear review. Visual examination is critical and may reveal findings not apparent from automated indices alone, such as schistocytes (hemolysis), target cells (liver disease), or abnormal white cells (hematologic malignancy). 1
Extended Workup for Unclear Cases
If the cause remains unclear after initial testing, proceed with: 1
- Soluble transferrin receptor (helps distinguish iron deficiency from anemia of chronic disease)
- Percentage of hypochromic red cells
- Reticulocyte hemoglobin content
- Bone marrow aspiration and biopsy (with hematology consultation)
The most common causes of normocytic anemia are hemorrhage, hemolysis, bone marrow failure, anemia of chronic inflammation, and renal insufficiency. 1 The reticulocyte count is the single most important discriminating test to guide further evaluation. 1