Anemia Workup
Systematic MCV-based approach: microcytic (iron deficiency #1), normocytic (chronic disease, hemolysis, bleeding), macrocytic (B12/folate, MDS, alcohol). Every anemia deserves a reticulocyte count.
🔍 Overview
Overview
Anemia = Hgb < 13 (men) or < 12 (women). Affects ~25% of hospitalized patients. The approach is MCV-driven: Microcytic (MCV < 80): iron deficiency (#1 worldwide), thalassemia, anemia of chronic disease (can be micro or normo), sideroblastic, lead poisoning. Normocytic (MCV 80-100): anemia of chronic disease/inflammation (#1 inpatient), acute blood loss, hemolysis, CKD (EPO deficiency), mixed deficiency. Macrocytic (MCV > 100): B12/folate deficiency, MDS, alcohol/liver disease, hypothyroidism, medications (methotrexate, hydroxyurea, AZT). The reticulocyte count is the most underordered and most important second test -it tells you whether the marrow is responding appropriately (high retic = destruction/loss) or failing (low retic = production problem).
🧪 Workup
Workup
- Step 1 -CBC + reticulocyte count + peripheral smear
- Reticulocyte index > 2%: marrow is responding → blood LOSS or DESTRUCTION (hemolysis)
- Reticulocyte index < 2%: marrow failure → production problem
- Step 2 -MCV-based workup:
- Microcytic: Iron studies (ferritin, TIBC, serum iron, transferrin sat). Ferritin < 30 = iron deficiency (in inflammation: ferritin < 100 is likely iron deficient). Thalassemia: Mentzer index (MCV/RBC < 13 = thalassemia trait), Hgb electrophoresis.
- Normocytic: BMP (CKD), CRP/ESR (chronic disease), hemolysis labs (LDH, haptoglobin, indirect bili, DAT), reticulocyte count. If hemolysis: Coombs positive = autoimmune (AIHA). Coombs negative = mechanical (TTP, DIC, valve), PNH, G6PD, sickle cell.
- Macrocytic: B12 + folate (if equivocal: methylmalonic acid for B12, homocysteine for both). TSH. LFTs. Peripheral smear (hypersegmented neutrophils = megaloblastic). Consider bone marrow biopsy if unexplained (MDS).
- Iron studies interpretation:
- Iron deficiency: ferritin ↓, TIBC ↑, iron ↓, TfSat < 20%
- Chronic disease: ferritin ↑ (or normal), TIBC ↓, iron ↓, TfSat 15-20%
- Iron deficiency + chronic disease: ferritin 30-100 (unreliably elevated by inflammation), TIBC variable. Check soluble transferrin receptor (sTfR) -elevated = true iron deficiency even with inflammation.
🚨 Management
Management
- Iron deficiency anemia:
- Oral: ferrous sulfate 325 mg (65 mg elemental Fe) every other day on empty stomach with vitamin C IRON-MIDE, 2020. Every-other-day dosing is as effective as daily (hepcidin rebound). Avoid with PPIs, calcium, coffee.
- IV iron: if oral intolerant, CKD, inflammatory bowel disease, Hgb < 7, or pre-surgical. Iron sucrose 200 mg × 5 doses or ferric carboxymaltose 750 mg × 2 or low-molecular-weight iron dextran 1000 mg × 1 (single dose, monitor for anaphylaxis × 1h).
- Always find the source: premenopausal women → menstrual loss. Men or postmenopausal → GI source until proven otherwise (EGD + colonoscopy). Celiac screening if no GI source found.
- B12 deficiency: IM cyanocobalamin 1000 mcg daily × 7d → weekly × 4wk → monthly lifelong. High-dose oral (1000-2000 mcg/day) is an alternative for compliant patients without malabsorption.
- Anemia of chronic disease: Treat underlying condition. EPO-stimulating agents (epoetin alfa, darbepoetin) for CKD (target Hgb 10-11, not higher [TREAT, CREATE]). IV iron if concurrent iron deficiency (TfSat < 20%, ferritin < 100).
- Transfusion: Hgb < 7 (restrictive threshold TRICC, 1999). < 8 if ACS or symptomatic. 1 unit at a time → recheck.
💊 Medications
Medications
| Drug | Dose | Route | Notes |
|---|---|---|---|
| Ferrous sulfate | 325 mg (65 mg elemental) every other day | PO | Empty stomach + vitamin C for absorption. Every-other-day = daily efficacy with fewer GI SEs. Avoid PPIs, Ca, coffee. IRON-MIDE, 2020 |
| Epoetin alfa | 50-300 IU/kg TIW | SQ | CKD anemia (target Hgb 10-11). VTE risk if Hgb > 11. Iron replete first (TfSat > 20%, ferritin > 100). TREAT, 2009 |
🏥 Rounds
Pimp Questions
❓ What is the most important second test after CBC in anemia workup?
Reticulocyte count. It differentiates production problems (low retic: marrow failure, nutrient deficiency) from destruction/loss (high retic: hemolysis, bleeding). Calculate the reticulocyte index (RI) = retic % × (patient Hgb / normal Hgb) ÷ maturation factor. RI > 2 = appropriate marrow response. RI < 2 = inadequate. Most underordered test in anemia workup.
❓ How do you diagnose iron deficiency in a patient with concurrent inflammation?
Ferritin is an acute phase reactant -inflammation falsely elevates it. A "normal" ferritin of 60 in a patient with CRP of 80 may actually represent iron deficiency. Rules: (1) ferritin < 30 = iron deficient regardless of inflammation. (2) Ferritin 30-100 with inflammation = likely iron deficient. (3) Best additional test: soluble transferrin receptor (sTfR) -elevated in true iron deficiency, NOT affected by inflammation. TfSat < 20% also supports iron deficiency.
❓ Why should oral iron be taken every other day rather than daily?
IRON-MIDE, 2020 demonstrated that every-other-day dosing is as effective as daily for iron repletion. The mechanism: an oral iron dose triggers hepcidin release (iron-regulatory hormone) that peaks at 24h and blocks iron absorption for ~48h. A second daily dose is largely not absorbed and only causes GI side effects (nausea, constipation). Every-other-day dosing allows hepcidin to fall between doses → better absorption per dose with fewer side effects.
❓ When must you find the source of iron deficiency anemia?
Always in men and postmenopausal women -GI malignancy (colon cancer) until proven otherwise. Get EGD + colonoscopy. In premenopausal women, menstrual loss is the most common cause, but if heavy menstruation doesn't explain the severity, or if there are GI symptoms → scope. Also consider: celiac disease (anti-TTG), gastric bypass (iron absorption site bypassed), chronic NSAID use (GI erosions).
❓ What peripheral smear findings help differentiate causes of anemia?
Target cells: thalassemia, iron deficiency, liver disease. Schistocytes: TTP, DIC, mechanical valve hemolysis. Spherocytes: autoimmune hemolysis (AIHA), hereditary spherocytosis. Hypersegmented neutrophils: B12/folate deficiency (megaloblastic). Teardrop cells + leukoerythroblastic: myelofibrosis/marrow infiltration. Sickle cells: SCD. Rouleaux: myeloma, inflammation. Bite cells/Heinz bodies: G6PD deficiency.
Clinical Examples
📋 Case 1, Iron Deficiency with Occult GI Malignancy
Patient: 62-year-old postmenopausal woman presents with fatigue and exertional dyspnea over 3 months. No overt bleeding. PMH: GERD on omeprazole.
Key findings: Hgb 7.8, MCV 68, ferritin 6, TIBC 480, TfSat 5%, reticulocyte index 0.4%. Smear: microcytic hypochromic RBCs, pencil cells. FIT positive.
Management:
- Transfuse 1 unit pRBC (symptomatic, Hgb < 7 threshold) TRICC, 1999
- IV iron (ferric carboxymaltose 750 mg x 2 doses)
- EGD + colonoscopy: cecal mass found, biopsy confirmed adenocarcinoma
Teaching point: New iron deficiency anemia in a man or postmenopausal woman = GI malignancy until proven otherwise. Never just replace iron without finding the source.
📋 Case 2, B12 Deficiency Mimicking Leukemia
Patient: 45-year-old woman with history of gastric bypass presents with fatigue, paresthesias in feet, and unsteady gait for 6 months.
Key findings: Hgb 8.0, MCV 118, WBC 3.2, platelets 110 (pancytopenia). Smear: macro-ovalocytes, hypersegmented neutrophils. B12 undetectable, methylmalonic acid markedly elevated.
Management:
- IM cyanocobalamin 1000 mcg daily x 7 days, then weekly x 4 weeks, then monthly lifelong
- Monitor for reticulocyte crisis at day 5-7
- Monitor potassium and phosphate (drop during rapid erythropoiesis)
Teaching point: Severe B12 deficiency causes pancytopenia mimicking leukemia. Always check B12 before bone marrow biopsy. Hypersegmented neutrophils are pathognomonic for megaloblastic anemia. Neurologic damage may be irreversible.
📋 Case 3, Mixed Anemia of Chronic Disease + Iron Deficiency
Patient: 58-year-old man with rheumatoid arthritis on methotrexate admitted for flare. Hgb 9.4, MCV 82.
Key findings: Ferritin 85 (ambiguous in inflammation), TIBC 220 (low), TfSat 15%, CRP 68, soluble transferrin receptor (sTfR) elevated at 4.2. Reticulocyte index 0.8.
Management:
- Elevated sTfR confirms concurrent iron deficiency despite "normal" ferritin
- IV iron sucrose 200 mg x 5 doses (oral poorly absorbed in active inflammation)
- Treat underlying RA flare to reduce hepcidin-mediated iron sequestration
Teaching point: Ferritin is an acute phase reactant. A "normal" ferritin of 85 with CRP of 68 likely represents iron deficiency. In inflammation, ferritin less than 100 is suggestive of concurrent iron deficiency. sTfR is the best differentiating test.
Sample Presentation
Mrs. Martinez is a 52-year-old postmenopausal woman presenting with fatigue × 3 months. No bleeding, no melena. PMH: GERD on omeprazole. Labs: Hgb 8.2, MCV 72, ferritin 8, TIBC 450, TfSat 8%, reticulocyte index 0.5%.
Key Points: Classic iron deficiency anemia -microcytic, low ferritin, high TIBC, low TfSat, low retic (production problem). Postmenopausal woman = GI source until proven otherwise. Needs EGD + colonoscopy. Start oral iron (every other day with vitamin C). Consider IV iron if oral intolerant or Hgb < 7. Celiac screen (anti-TTG) if GI workup negative. PPI may impair iron absorption.
- Reticulocyte count at day 5-7 -after starting B12 or iron. Expected "retic crisis" = brisk reticulocytosis confirming marrow response.
- CBC + reticulocyte at 2-4 weeks -Hgb should begin rising. If not → reassess diagnosis, compliance, concurrent iron deficiency.
- Ferritin at 8-12 weeks -on oral iron. Target ferritin > 100 (or > 200 in CKD). Continue oral iron 3-6 months after Hgb normalizes to replete stores.
- K⁺, PO₄ -drop during rapid erythropoiesis (B12 repletion, EPO therapy). Monitor and replace.
- Iron studies before EPO -functional iron deficiency is #1 cause of EPO resistance. TfSat < 20% or ferritin < 100 → give IV iron.
- Hemolysis markers -if autoimmune: DAT, LDH, haptoglobin, reticulocyte count. Trending LDH is the simplest way to monitor hemolytic activity.
📋 Summary
Summary
Start With the MCV
Microcytic below 80, normocytic 80 to 100, macrocytic above 100. The MCV is an average, so a mixed deficiency (iron plus B12) can produce a perfectly normal MCV. A wide RDW is the clue that two populations are present, and the smear confirms it.
Always Get a Reticulocyte Count
It separates the two mechanisms in one test. Low means underproduction (deficiency, marrow disease, anemia of chronic disease, renal failure). High means destruction or loss (hemolysis or bleeding). It takes 3 to 5 days to rise, so an early normal count after an acute bleed is not reassurance.
Microcytic: Iron Deficiency Until Proven Otherwise
Ferritin is the single best test; below 30 confirms deficiency. Ferritin is an acute phase reactant, so inflammation raises it: with active inflammation a value up to about 100, or a transferrin saturation below 20%, still supports deficiency. Then thalassemia (a very low MCV with a near-normal hemoglobin and normal iron studies), anemia of chronic disease, sideroblastic anemia, lead.
Iron Deficiency Is a Symptom, Not a Diagnosis
Find the source. In any man, or any postmenopausal woman, iron deficiency is gastrointestinal blood loss until proven otherwise and needs endoscopy in both directions. In premenopausal women, menorrhagia is the usual cause, but do not stop looking if the history does not fit. Also consider celiac disease and H. pylori as malabsorptive causes.
Dose Oral Iron Every Other Day
Ferrous sulfate 325 mg (65 mg elemental) every other day. Daily dosing raises hepcidin, which blocks absorption of the next dose, so alternate-day dosing achieves equal or better absorption with far fewer GI side effects. Give on an empty stomach with vitamin C, and separate from PPIs, calcium and tea. IV iron for malabsorption, intolerance, ongoing loss or CKD.
Macrocytic: Split It Megaloblastic or Not
Megaloblastic (B12, folate): hypersegmented neutrophils, high LDH, high indirect bilirubin from ineffective erythropoiesis. Non-megaloblastic: alcohol, liver disease, hypothyroidism, myelodysplasia, drugs (methotrexate, hydroxyurea, zidovudine, antiepileptics). Check methylmalonic acid when B12 is borderline, since it is more sensitive than the B12 level itself.
Give B12 Before Folate, Not After
Folate corrects the anemia in B12 deficiency but does nothing for the neurologic damage, which then progresses irreversibly (subacute combined degeneration). Check both, and replace B12 first. Ask about metformin, PPIs, gastrectomy, ileal disease and a vegan diet.
Normocytic: Use the Retic to Branch
Low retic: anemia of chronic disease (low iron with a low or normal TIBC and a normal or high ferritin), chronic kidney disease (erythropoietin deficiency), early iron deficiency, marrow infiltration. High retic: hemolysis or bleeding, so send LDH, haptoglobin, bilirubin and a Coombs test. Transfuse restrictively, above 7 g/dL (above 8 in acute coronary syndrome), and use erythropoiesis-stimulating agents only in CKD, iron-replete, targeting 10 to 11 g/dL, since higher targets increase thrombosis and death.
📄 One Pager
Text version
One-Pager
Anemia Workup
MCV → Retic → Smear
Algorithm
Step 1: CBC + retic + smear. Step 2: MCV-based labs (micro → iron studies; normo → hemolysis labs + CKD; macro → B12/folate). Step 3: Bone marrow if unexplained.
Iron Studies Cheat Sheet
IDA: ferritin ↓, TIBC ↑, TfSat ↓. ACD: ferritin ↑, TIBC ↓, TfSat low-normal. IDA+ACD: ferritin 30-100, check sTfR. Hemolysis: LDH ↑, haptoglobin ↓, retic ↑, DAT±.
Trials
TRICC 1999 (restrictive transfusion) · IRON-MIDE 2020 (every-other-day iron) · TREAT 2009 (EPO in CKD)
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