What is the appropriate next work‑up for a patient whose CBC shows macrocytosis (MCV 106 fL), elevated mean corpuscular hemoglobin, mild thrombocytopenia (platelet count 133 ×10⁹/L), slightly increased absolute monocyte count, and a modest rise in immature granulocytes?

Immediate Bone Marrow Evaluation is Warranted

Given the constellation of macrocytosis (MCV 106 fL), mild thrombocytopenia (133 ×10⁹/L), elevated immature granulocytes, and increased monocytes, you should proceed directly to bone marrow aspiration and biopsy with cytogenetic analysis to evaluate for myelodysplastic syndrome (MDS) or other primary bone marrow pathology. 1

Why Bone Marrow Evaluation Takes Priority

The combination of findings in this CBC raises significant concern for MDS rather than simple nutritional deficiency:

• Macrocytosis with thrombocytopenia is a hallmark presentation of MDS, particularly when MCV exceeds 100 fL and platelet counts fall below 150 ×10⁹/L 1
• Elevated immature granulocytes (3% with absolute count 0.2 ×10⁹/L) suggests dysplastic hematopoiesis, as this finding is uncommon in nutritional deficiencies 1
• Increased absolute monocyte count (1.3 ×10⁹/L) can indicate myelodysplastic or myeloproliferative overlap syndromes 1
• Multiple cytopenias affecting two lineages (thrombocytopenia plus the borderline hemoglobin at 14.8 g/dL) warrant bone marrow examination per ESMO guidelines 1

The ESMO 2021 guidelines explicitly state that patients with new or worsening cytopenias should undergo bone marrow aspirate/biopsy with cytogenetics, particularly when macrocytosis is present as an early manifestation of MDS 1

Concurrent Nutritional Work-Up

While arranging bone marrow biopsy, simultaneously order:

• Vitamin B12 level – macrocytosis with MCV >100 fL requires B12 assessment 2, 3
• Folate level – must be checked concurrently to exclude combined deficiency 2, 3
• Reticulocyte count – a low/normal count (as expected here given no anemia) points toward production defects like MDS rather than hemolysis 3, 4
• Peripheral blood smear review – look specifically for hypersegmented neutrophils (megaloblastic) versus dysplastic features (pseudo-Pelger-Huët cells, hypolobulated megakaryocytes) 3, 4
• TSH and liver function tests – to exclude hypothyroidism and liver disease as non-megaloblastic causes 3, 4

Critical Diagnostic Algorithm

Step 1: Order bone marrow aspiration/biopsy with conventional cytogenetics immediately 1

Step 2: While awaiting bone marrow results, obtain B12, folate, reticulocyte count, peripheral smear, TSH, and comprehensive metabolic panel 2, 3

Step 3: Review peripheral smear for:

• Macro-ovalocytes and hypersegmented neutrophils → suggests megaloblastic anemia from B12/folate deficiency 3, 4
• Dysplastic features (hypolobulated neutrophils, abnormal granulation) → supports MDS 1

Step 4: If B12 is indeterminate (180-350 pg/mL), add methylmalonic acid (MMA) testing to confirm functional deficiency 2, 5

Why Not Start with B12/Folate Alone?

Several features argue against simple nutritional deficiency as the sole explanation:

• Thrombocytopenia is uncommon in isolated B12 deficiency unless the deficiency is severe and longstanding 1
• Elevated immature granulocytes are not typical of megaloblastic anemia and suggest primary marrow pathology 1
• The absolute monocyte elevation is more consistent with myelodysplastic/myeloproliferative features 1
• Delaying bone marrow evaluation risks missing early MDS, which has better outcomes when detected at lower-risk stages 1

The ESMO guidelines emphasize that macrocytosis can be a manifestation of MDS and recommend bone marrow evaluation for patients with unexplained cytopenias and macrocytosis, even when blast counts are normal 1

Common Pitfalls to Avoid

Never give folate supplementation before ruling out and treating B12 deficiency – this can precipitate subacute combined degeneration of the spinal cord, an irreversible neurological complication 2

Do not assume nutritional deficiency explains all findings – the combination of thrombocytopenia, macrocytosis, and immature granulocytes requires bone marrow evaluation to exclude MDS 1

Do not delay bone marrow biopsy while treating empirically – if MDS is present, early diagnosis allows risk stratification and appropriate therapy 1

When to Refer to Hematology

Refer immediately for patients with unexplained cytopenias, particularly when combined with macrocytosis and dysplastic features 1, 3

The hematologist will coordinate bone marrow evaluation and interpret cytogenetics using the IPSS-R scoring system, which incorporates cytogenetic risk, blast percentage, hemoglobin, platelet count, and neutrophil count to determine prognosis and guide treatment 1

Surveillance if MDS is Confirmed

If bone marrow reveals MDS, the Clinical Cancer Research guidelines recommend:

• CBC with differential every 3-4 months for high-risk conditions 1
• Repeat bone marrow with cytogenetics annually or sooner if counts worsen 1
• Early HLA typing of patient and family members if allogeneic transplant may be considered 1