How to diagnose and treat a patient with normocytic anemia and normal WBC and platelet counts?

Diagnostic Approach to Normocytic Anemia with Normal WBC and Platelets

This patient has normocytic anemia (Hb 9.6 g/dL, MCV 92.6 fL) with preserved white blood cell and platelet counts, requiring a systematic evaluation focused on reticulocyte count, iron studies, and peripheral blood smear to differentiate between decreased red cell production versus increased destruction or loss. 1

Initial Diagnostic Workup

The following tests are essential to determine the underlying cause:

• Reticulocyte count (corrected for anemia) - This distinguishes between hypoproliferative anemia (low reticulocytes) and hemolytic/blood loss anemia (elevated reticulocytes) 1, 2
• Iron parameters - Serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT), and serum ferritin to assess iron availability and stores 1
• Peripheral blood smear - Evaluates red cell morphology for abnormalities such as schistocytes, spherocytes, or hypochromic cells 1, 3
• Lactate dehydrogenase (LDH) and indirect bilirubin - Confirms hemolysis if reticulocytes are elevated 4
• Haptoglobin level - Decreased haptoglobin combined with elevated reticulocytes is pathognomonic for hemolysis 4
• Vitamin B12 and folate levels - Excludes nutritional deficiencies that can present with normocytic anemia 1
• Renal function tests - Chronic kidney disease is a common cause of normocytic anemia 1
• Stool guaiac test - Screens for occult gastrointestinal bleeding if iron deficiency is suspected 1

Diagnostic Algorithm Based on Reticulocyte Response

If Reticulocyte Count is LOW or NORMAL (Hypoproliferative Anemia):

Most common causes include:

• Anemia of chronic disease - The most frequently encountered normocytic anemia, found in 6% of hospitalized patients, characterized by normal to high ferritin with low TSAT 2
• Chronic kidney disease - Evaluate serum creatinine and estimated GFR; anemia of CKD is typically normocytic and normochromic 1
• Bone marrow suppression - Consider medications, malignancy, or primary bone marrow disorders if other causes excluded 1
• Early iron deficiency - Can present as normocytic before becoming microcytic; TSAT <16% and ferritin <12 ng/mL indicate absolute iron deficiency in the general population 1

Key diagnostic distinction: In anemia of chronic disease, ferritin is typically normal to elevated (>100 ng/mL) with low TSAT, whereas iron deficiency shows low ferritin (<12-30 ng/mL) with low TSAT 1

If Reticulocyte Count is ELEVATED (Hemolytic or Blood Loss Anemia):

This indicates compensated or partially compensated hemolysis:

• Confirm hemolysis with decreased haptoglobin, elevated LDH, and elevated indirect bilirubin 4
• Examine peripheral smear for spherocytes (hereditary spherocytosis), schistocytes (microangiopathic hemolysis), or other morphologic abnormalities 1, 3
• Consider hereditary hemolytic anemias such as hereditary spherocytosis, pyruvate kinase deficiency, or mild thalassemia variants 4
• Evaluate for acquired causes including autoimmune hemolysis (perform direct Coombs test), drug-induced hemolysis, or hypersplenism 1

Critical pitfall: Normal MCV can mask combined pathology - microcytosis from iron deficiency can be neutralized by macrocytosis from hemolysis, resulting in falsely normal MCV despite dual pathology 4, 5

Treatment Approach

For Hypoproliferative Anemia:

Anemia of Chronic Disease:

• Treat the underlying inflammatory or chronic condition 6, 2
• Consider erythropoiesis-stimulating agents (ESAs) only if hemoglobin ≤10 g/dL and serum erythropoietin ≤500 mU/dL 1
• Target hemoglobin increase of <2 g/dL, not normalization, to avoid complications 1

Iron Deficiency (Absolute or Functional):

• For TSAT ≤30% and ferritin ≤500 ng/mL, initiate iron supplementation 1
• Oral iron trial (1-3 months) is appropriate for non-dialysis CKD patients or those not requiring ESAs 1
• Intravenous iron is preferred for dialysis patients or when oral iron fails; monitor ferritin and avoid exceeding 500 ng/mL to prevent iron overload 1
• Search for source of blood loss if iron deficiency confirmed, particularly gastrointestinal bleeding 1

Chronic Kidney Disease:

• Hemoglobin is the preferred monitoring parameter over hematocrit due to greater measurement accuracy 1
• Iron supplementation should precede ESA therapy; target TSAT >30% and ferritin >500 ng/mL before initiating ESAs 1
• ESAs should be used cautiously, balancing transfusion avoidance against potential cardiovascular risks 1

For Hemolytic Anemia:

Treatment depends on the specific etiology:

• Hereditary spherocytosis - Splenectomy may be curative in severe cases 4
• Autoimmune hemolysis - Corticosteroids or immunosuppression if Coombs-positive 1
• Drug-induced hemolysis - Discontinue offending agent 1
• Compensated hemolysis with normal hemoglobin requires monitoring but may not need active treatment 4

Critical Clinical Pitfalls

• Do not assume iron deficiency based solely on low hemoglobin - Anemia of chronic disease is often mistakenly treated with iron supplements when inflammation is the primary problem 6
• Normal MCV does not exclude iron deficiency - Early iron deficiency or combined deficiencies can present with normal MCV 1, 5
• Reticulocyte count must be corrected for degree of anemia - Use corrected reticulocyte index or absolute reticulocyte count to accurately assess bone marrow response 1, 4
• Preserved WBC and platelet counts do not exclude bone marrow pathology - Isolated anemia can occur in early myelodysplastic syndrome or selective red cell aplasia 1
• Hyperglycemia falsely elevates MCV and calculated hematocrit - Use hemoglobin for monitoring in diabetic patients 1

When to Consider Bone Marrow Examination

Bone marrow biopsy and aspirate are indicated when:

• Diagnosis remains unclear after initial workup 1, 3
• Abnormal peripheral blood smear suggests primary bone marrow disorder 1
• Multiple cytopenias develop (even if mild) suggesting myelodysplasia or infiltrative process 1
• Unexplained normocytic anemia persists despite correction of identified deficiencies 3