What is the appropriate diagnostic work‑up and initial management for a 77‑year‑old man presenting with leukopenia, neutropenia, low mean corpuscular hemoglobin, and low red‑cell distribution width?

Diagnostic Work-Up for a 77-Year-Old Male with Leukopenia, Neutropenia, Low MCH, and Low RDW

This presentation most likely represents iron-deficiency anemia with concurrent leukopenia requiring immediate iron studies, peripheral blood smear, and investigation for gastrointestinal blood loss, while simultaneously evaluating for medication-induced neutropenia or underlying bone marrow pathology.

Initial Laboratory Evaluation

Order the following tests immediately to establish the diagnosis:

• Serum ferritin is the single most specific test for iron deficiency, with levels <30 μg/L confirming depleted iron stores in the absence of inflammation 1, 2
• Transferrin saturation (TSAT) <16–20% confirms iron-deficient erythropoiesis and is less affected by inflammation than ferritin 1, 2
• C-reactive protein (CRP) must be measured concurrently because ferritin is an acute-phase reactant that can be falsely elevated in inflammatory, infectious, malignant, or hepatic conditions 1, 2
• Complete blood count with manual differential to quantify the absolute neutrophil count and assess for bi- or pancytopenia, which would suggest bone marrow failure 3
• Peripheral blood smear is essential to evaluate red cell morphology (hypochromia, microcytosis), assess for dysplasia, and exclude other causes of cytopenia 4, 3
• Reticulocyte count assesses bone marrow response; a low or inappropriately normal value indicates impaired red cell production 5, 2

Interpretation of Iron Studies in the Elderly

In patients without inflammation:

• Ferritin <30 μg/L confirms iron deficiency 1, 2
• A cut-off of 45 μg/L provides optimal sensitivity and specificity in routine practice 1, 4

In the presence of inflammation (elevated CRP):

• Ferritin up to 100 μg/L may still indicate iron deficiency 5, 1
• Ferritin >150 μg/L makes absolute iron deficiency unlikely even with concurrent inflammation 1, 2
• TSAT <16–20% confirms iron deficiency when ferritin appears falsely normal 1, 2

Critical pitfall: In elderly males with chronic inflammation, malignancy, or hepatic disease, ferritin may be falsely elevated despite true iron deficiency; always add TSAT to confirm the diagnosis 4

Distinguishing Iron Deficiency from Other Causes of Microcytosis

The combination of low MCH with low RDW is unusual and requires careful interpretation:

• Low RDW (<14%) with microcytosis typically suggests thalassemia trait, where red cells are uniformly small 1, 6
• However, iron deficiency usually elevates RDW (>14%) because it creates a mixed population of older normocytic cells and newer microcytic cells 1, 6
• A low RDW in this 77-year-old male makes thalassemia trait less likely given the age of presentation; acquired causes are more probable 1
• If iron studies are normal despite low MCH, order hemoglobin electrophoresis to exclude thalassemia trait, particularly if the patient has Mediterranean, African, or Southeast Asian ancestry 1, 2

Evaluation of Concurrent Leukopenia and Neutropenia

The combination of anemia and leukopenia requires assessment for:

Medication-Induced Cytopenia

• Review all medications for drugs known to cause neutropenia, including antibiotics, anticonvulsants (e.g., valproate), antithyroid agents, and chemotherapy 7, 8
• Neutropenia can occur at any time during therapy, even after years of stable treatment, as documented with valproate after 8 years 7

Bone Marrow Pathology

• Bi- or pancytopenia usually implies insufficient bone marrow production and warrants bone marrow aspiration and biopsy 3
• In a 77-year-old male, consider myelodysplastic syndrome, chronic myelomonocytic leukemia, or bone marrow infiltration by malignancy 5, 3
• Peripheral blood smear showing dysplasia strongly suggests myelodysplastic syndrome and mandates bone marrow examination 3

Hypersplenism or Autoimmune Destruction

• Increased utilization and destruction of white blood cells can occur with hypersplenism or immunoneutropenia 8

Mandatory Investigation for Gastrointestinal Blood Loss

In elderly males with confirmed iron deficiency, gastrointestinal blood loss is the most common cause and must be investigated:

• Men with hemoglobin <110 g/L warrant fast-track gastrointestinal referral for bidirectional endoscopy 4
• Upper endoscopy with duodenal biopsies screens for celiac disease (present in 2–3% of iron-deficiency cases), gastric cancer, peptic ulcer disease, NSAID-induced gastropathy, and angiodysplasia 4
• Colonoscopy is particularly high-yield in older adults for detecting colonic carcinoma, adenomatous polyps, and angiodysplasia 4
• Do not attribute iron deficiency solely to dietary insufficiency in elderly males; mandatory GI evaluation is essential 4

Management of Neutropenia

If the absolute neutrophil count is <1000/μL:

• Assess for fever and signs of infection immediately 3, 8
• Agranulocytosis with fever is life-threatening and requires hospital admission with immediate broad-spectrum antibiotics to reduce mortality 3

If neutropenia is mild (ANC 1000–1500/μL) and asymptomatic:

• Discontinue any potentially offending medications and recheck complete blood count in 1–2 weeks 7, 8
• If neutropenia persists after medication withdrawal, proceed to bone marrow examination 3, 8

Immediate Treatment Protocol

While diagnostic work-up proceeds:

• Begin oral iron supplementation with ferrous sulfate 325 mg (65 mg elemental iron) once to three times daily if iron deficiency is confirmed 2, 4
• A rise in hemoglobin of ≥10 g/L within 2 weeks confirms iron-deficiency anemia even when initial iron studies are equivocal 1, 2
• Continue iron supplementation for 3–6 months after hemoglobin normalizes to replenish iron stores 2, 4

If oral iron fails or malabsorption is present:

• Consider intravenous iron (iron sucrose or ferric carboxymaltose) with an expected hemoglobin increase of ≥2 g/dL within 4 weeks 4

Common Pitfalls to Avoid

• Do not assume all microcytic anemia is iron deficiency; anemia of chronic disease, thalassemia, and sideroblastic anemia require different management 1, 4
• Do not rely on ferritin alone in elderly patients; inflammation, malignancy, and liver disease can falsely elevate ferritin despite true iron deficiency 1, 4
• Do not overlook combined deficiencies; iron deficiency can coexist with vitamin B12 or folate deficiency, recognizable by elevated RDW 4
• Do not delay gastrointestinal investigation to "optimize" the patient with iron therapy alone; the bleeding source must be identified promptly 4
• Do not dismiss leukopenia as benign; persistent neutropenia after medication withdrawal requires bone marrow examination 3, 8