Macrocytic Anemia: Low RBC Count with Elevated MCV and MCH
A low red blood cell count combined with high MCV and MCH indicates macrocytic anemia, most commonly caused by vitamin B12 or folate deficiency, though medications, alcohol use, hypothyroidism, and bone marrow disorders must also be considered. 1, 2
What This Pattern Means
Your blood work shows macrocytic anemia—fewer red blood cells than normal, but each cell is larger (high MCV) and carries more hemoglobin (high MCH) than typical. 3 This specific combination points toward several key diagnostic possibilities:
Most Common Causes
Vitamin B12 or folate deficiency is the leading cause of megaloblastic macrocytosis, particularly when MCV exceeds 100 fL and often reaches >120 fL. 1, 2 This occurs because these vitamins are essential for proper DNA synthesis during red blood cell production, resulting in fewer but abnormally large cells. 3
Medication effects can mimic vitamin deficiency, including hydroxyurea, azathioprine, 6-mercaptopurine, anticonvulsants, and methotrexate. 2, 4 These drugs interfere with DNA synthesis but through different mechanisms than nutritional deficiencies.
Chronic alcohol consumption causes macrocytosis independent of nutritional deficiencies through direct toxic effects on bone marrow. 4, 5, 6
Hypothyroidism can produce macrocytosis even without anemia initially, though your low RBC count suggests a more advanced process. 4
Myelodysplastic syndrome (MDS) and other bone marrow disorders become increasingly important considerations, especially in older adults with concurrent low white blood cell or platelet counts. 3
Diagnostic Workup Required
Initial Laboratory Tests
Measure vitamin B12 and folate levels immediately, as these are the most treatable causes and deficiency can lead to irreversible neurologic damage if B12 deficiency persists untreated. 1, 2, 4
Check reticulocyte count to distinguish between decreased red blood cell production (low reticulocyte index suggesting bone marrow dysfunction, vitamin deficiency, or MDS) versus increased production from blood loss or hemolysis (high reticulocyte index). 1, 2 A normal reticulocyte index ranges between 1.0-2.0. 1
Obtain peripheral blood smear examination to look for megaloblastic changes (hypersegmented neutrophils, oval macrocytes) that confirm megaloblastic anemia versus other causes. 2, 3
Measure red cell distribution width (RDW), as elevated RDW (>15%) combined with low RBC count (<4.0 × 10¹²/L) and normal platelet parameters strongly suggests vitamin B12 deficiency over other causes like alcohol-related macrocytosis. 5
Additional Targeted Testing
Assess thyroid function (TSH) to exclude hypothyroidism as a contributing factor. 4
Review all current medications for drugs known to cause macrocytosis, particularly chemotherapy agents, immunosuppressants, and anticonvulsants. 2, 4
Obtain alcohol use history, as chronic consumption is a frequent cause of non-megaloblastic macrocytosis. 4, 5, 6
Consider homocysteine and methylmalonic acid levels if B12 levels are borderline (200-400 pg/mL), as these provide more sensitive indicators of tissue-level deficiency. 4
Critical Diagnostic Distinctions
Megaloblastic vs. Non-Megaloblastic
The distinction between megaloblastic (B12/folate deficiency) and non-megaloblastic macrocytosis is crucial because treatment differs fundamentally. 3
Megaloblastic anemia shows:
- MCV typically >110 fL and often >120 fL 1
- Low or normal reticulocyte count 6
- Hypersegmented neutrophils on blood smear 3
- Elevated RDW 5
Non-megaloblastic macrocytosis shows:
- MCV usually 100-110 fL 1
- May have elevated reticulocytes if regenerative 6
- Normal neutrophil segmentation 3
When to Suspect Serious Bone Marrow Disease
Refer to hematology urgently if you have concurrent leukopenia (low white blood cells) or thrombocytopenia (low platelets) alongside your macrocytic anemia, as this suggests MDS or other myeloid neoplasms requiring bone marrow biopsy. 3
Common Pitfalls to Avoid
Do not assume alcohol or medications are the cause without measuring B12 and folate first, as vitamin deficiencies require specific replacement therapy and can cause permanent neurologic damage if missed. 2, 4
Ferritin levels may be falsely elevated in the presence of chronic inflammation even when true iron deficiency coexists, potentially masking combined deficiencies. 1
Normal B12 levels do not completely exclude B12 deficiency if levels are in the low-normal range (200-400 pg/mL); consider measuring methylmalonic acid and homocysteine in this scenario. 4
Reticulocytosis from recent bleeding or hemolysis can elevate MCV because reticulocytes are larger than mature red blood cells, potentially confusing the picture. 6 Check the reticulocyte count to identify this scenario.