Iron Deficiency (low ferritin, high TIBC, high RDW) vs. Thalassemia (normal/high ferritin, low RDW, target cells) vs. Anemia of Chronic Disease (high ferritin, low TIBC).
Reticulocyte Production Index (RPI) > 2% indicates hemolysis or acute hemorrhage; RPI < 2% indicates marrow hypoplasia, aplasia, or early deficiency.
B12 vs. Folate: Hypersegmented neutrophils in both; B12 has elevated methylmalonic acid (MMA) AND homocysteine; Folate has elevated homocysteine ONLY.
Identifies Autoimmune Hemolytic Anemia (AIHA): Warm (IgG, extravascular in spleen, spherocytes) vs. Cold (IgM, intravascular, Mycoplasma/EBV).
The MCV-Guided Algorithmic Flowchart
The initial diagnostic step in any anemia evaluation is examining the Mean Corpuscular Volume (MCV):
| MCV Tier | Common Diagnoses | Differentiating Confirmatory Tests |
|---|---|---|
| Microcytic (< 80 fL) | Iron deficiency, Thalassemia trait, Anemia of chronic disease, Sideroblastic anemia, Lead poisoning | Ferritin, Iron, TIBC, Transferrin Saturation, Hemoglobin electrophoresis, Bone marrow Prussian blue |
| Normocytic (80-100 fL) | Hemolytic anemia (autoimmune, G6PD, sickle cell, PNH), Aplastic anemia, Acute blood loss, Chronic renal failure | Reticulocyte count, Peripheral blood smear, Haptoglobin, LDH, Indirect bilirubin, Direct Antiglobulin (Coombs) |
| Macrocytic (> 100 fL) | Vitamin B12 deficiency, Folate deficiency, Alcohol abuse, Hypothyroidism, Myelodysplastic syndrome (MDS) | Serum B12, Serum folate, Methylmalonic acid, Homocysteine, TSH, Bone marrow biopsy |
Vitamin B12 vs. Folate Deficiency Master Guide
Both cause megaloblastic anemia characterized by macro-ovalocytes and hypersegmented neutrophils (≥ 5 lobes in ≥ 5% of neutrophils):
- Vitamin B12 (Cobalamin) Deficiency: Pernicious anemia (anti-intrinsic factor antibodies), ileal resection, vegan diet. Neurologic signs present: Subacute combined degeneration (SCD) of the spinal cord (dorsal columns: loss of vibration/proprioception; lateral corticospinal tracts: spasticity/hyperreflexia). Laboratory hallmark: Elevated Methylmalonic Acid (MMA) and elevated Homocysteine.
- Folate (Vitamin B9) Deficiency: Poor diet (alcoholism), pregnancy, antifolate drugs (methotrexate, trimethoprim). No neurologic deficits. Laboratory hallmark: Normal MMA and elevated Homocysteine.
- Splenic Innervation: Sympathetic preganglionic fibers from T5-T9 pass through the greater splanchnic nerve to the celiac ganglion. Splenic enlargement in hemolytic anemia causes capsule stretch, producing left upper quadrant tenderness and left shoulder pain (Kehr sign via phrenic nerve C3-C5).
- Rib Cage Mechanics in Severe Anemia: Compensatory hyperdynamic circulation and tachypnea induce bilateral inhalation rib somatic dysfunctions and thoracic outlet restrictions.
- OMT Precaution: Avoid aggressive splenic pump or direct left upper quadrant palpation in infectious mononucleosis or hemolytic crisis due to splenic rupture risk.
- Never administer folate monotherapy to a patient with macrocytic anemia without first checking or correcting Vitamin B12; folate corrects the hematologic abnormalities while permitting permanent, irreversible neurologic destruction (subacute combined degeneration).
- In any male or postmenopausal female with iron deficiency anemia, gastrointestinal malignancy (colon cancer) must be presumed until excluded by upper and lower endoscopy.
- In patients with G6PD deficiency, never administer oxidant drugs (rasburicase, primaquine, dapsone, sulfamethoxazole, nitrofurantoin); causes massive acute intravascular hemolysis.