Severe Symptomatic Anemia

Anemia causing symptomatic impairment — iron deficiency, anemia of chronic disease, or CKD-related; requiring workup and often transfusion

Symptoms / Associated Sx

  • Fatigue, weakness, exertional dyspnea (most common)

  • Pallor (conjunctival, palmar, nail beds), tachycardia

  • Palpitations, chest pain/angina (demand ischemia)

  • Headache, difficulty concentrating

  • Pica (ice chewing = pagophagia — classic for iron deficiency), restless legs syndrome

  • Koilonychia (spoon nails), angular cheilitis, glossitis (iron deficiency — severe/chronic)

Denies

  • Acute hemorrhage event (rules out acute blood loss as primary etiology)

  • Fever, bone pain, lymphadenopathy (rules out hematologic malignancy if absent)

  • Jaundice, dark urine, back pain (rules out hemolytic anemia)

  • Family history of hemolytic or hereditary anemia disorders

Social History (SHx)

Dietary history (vegetarian/vegan → iron, B12 deficiency; alcohol → folate/B12), menstrual history (heavy periods → iron loss), chronic disease (CKD, IBD, malignancy, CHF, rheumatoid arthritis), prior GI workup, prior anemia diagnosis, renal replacement therapy.

Main Etiology

  • Iron deficiency anemia (IDA): Blood loss (GI, menstrual), inadequate intake, malabsorption (celiac, post-gastric surgery)

  • Anemia of chronic disease (ACD): Chronic inflammation (RA, IBD, malignancy, CKD) → hepcidin elevation → iron sequestration

  • CKD-related anemia: Decreased erythropoietin production + iron deficiency + uremic toxins

  • B12/folate deficiency: Dietary, malabsorption, pernicious anemia, methotrexate

  • Thalassemia trait: Microcytic anemia with normal/elevated ferritin; common in Mediterranean, Southeast Asian, African populations

Most Common DDx

  • Iron deficiency anemia (microcytic; low ferritin <30; low iron; high TIBC; low transferrin saturation; responds to iron — distinguish from ACD by ferritin level)

  • Anemia of chronic disease (normocytic or mildly microcytic; ferritin normal-to-high; low TIBC; underlying chronic illness; iron infusion less effective without treating underlying disease)

  • B12 deficiency (macrocytic MCV; hypersegmented neutrophils on smear; low serum B12; elevated MMA and homocysteine; neurologic symptoms — paresthesias, ataxia)

  • Folate deficiency (macrocytic; low serum folate; elevated homocysteine but normal MMA — distinguishes from B12; dietary or methotrexate-related)

  • Thalassemia trait (microcytic + low MCV but RBC count HIGH; normal ferritin; Mentzer index <13 suggests thalassemia; Hgb electrophoresis confirms)

  • Hemolytic anemia (elevated LDH, elevated indirect bilirubin, low haptoglobin; reticulocytosis; peripheral smear abnormal)

  • Aplastic anemia (pancytopenia; hypocellular bone marrow; no chronic disease needed)

DATA

  • CBC with differential (MCV — microcytic: IDA, thalassemia; normocytic: ACD, CKD; macrocytic: B12/folate)

  • Reticulocyte count + reticulocyte production index (RPI <2 = hypoproliferative; >2 = blood loss or hemolysis)

  • Iron studies: serum iron, TIBC, transferrin saturation, ferritin

  • B12, folate (if macrocytic or dietary risk)

  • Peripheral blood smear (morphology — hypochromic/microcytic: IDA; hypersegmented PMNs: B12/folate; schistocytes: hemolysis/TMA)

  • CMP (creatinine — CKD; LFTs; albumin)

  • Hemoglobin electrophoresis (if thalassemia suspected)

  • Reticulocyte Hgb (Chr) — most sensitive early marker of functional iron deficiency

  • CRP/ESR (ferritin is an acute phase reactant — can be elevated even with IDA in chronic inflammation)

  • EPO level (low in CKD anemia; elevated in other causes)

  • Stool FOBT / FIT test; GI workup (colonoscopy/EGD) if IDA in men or postmenopausal women

Home Meds

  • PPIs (reduce iron absorption — separate from iron supplements by 2h)

  • Metformin (B12 malabsorption with long-term use)

  • Methotrexate (folate antagonist — ensure folate supplementation)

  • ESA (erythropoiesis-stimulating agents — if on for CKD; assess compliance and dose)

  • NSAIDs (chronic GI blood loss)

Plan

  • Transfusion (if symptomatic and severe):

    • Threshold Hgb <7 (stable); <8 (cardiovascular disease, ACS, elderly symptomatic)

    • 1 unit pRBCs at a time; reassess after each unit; do not transfuse asymptomatic stable patients to a "number"

  • Iron deficiency anemia:

    • Oral iron: ferrous sulfate 325 mg PO every other day (superior absorption vs. daily per recent evidence) — take on empty stomach; vitamin C enhances absorption; separate from PPIs by 2h

    • IV iron (preferred if: intolerant of PO, malabsorption, IBD, CKD, heart failure, ongoing blood loss, Hgb <8 with symptoms): Ferric carboxymaltose (Injectafer) 750 mg IV × 2 doses 7 days apart OR Iron sucrose 200 mg IV × 5 doses OR Low-molecular-weight iron dextran 1000 mg IV × 1 (total dose infusion)

    • Identify and treat underlying cause of iron deficiency (GI workup mandatory in men and postmenopausal women)

  • Anemia of chronic disease:

    • Treat underlying inflammatory condition (primary intervention)

    • IV iron if functional iron deficiency (transferrin saturation <20% despite normal/elevated ferritin)

    • ESA (erythropoiesis-stimulating agents — epoetin alfa or darbepoetin) only in CKD or cancer-related anemia; avoid in active malignancy outside of chemotherapy-related indications (increased mortality/thrombosis risk)

  • CKD-related anemia:

    • Iron repletion first: target ferritin >200–500 ng/mL and transferrin saturation >20% (IV iron preferred)

    • ESA therapy: Darbepoetin alfa 0.45 mcg/kg SQ/IV q4 weeks (or epoetin alfa 50–100 units/kg SQ/IV 3× weekly); target Hgb 10–11.5 g/dL (do NOT target Hgb >13 — increased cardiovascular events)

    • Nephrology co-management for ESA dosing and monitoring

  • B12 deficiency:

    • Cyanocobalamin 1000 mcg IM daily × 7 days → weekly × 4 weeks → monthly (pernicious anemia or malabsorption)

    • High-dose oral B12 2000 mcg PO daily (effective even without intrinsic factor via passive absorption)

  • Folate deficiency: Folic acid 1–5 mg PO daily × 1–4 months; always replace B12 first (or simultaneously) — folate without B12 can mask neurologic damage

  • Identify source of iron loss: colonoscopy + EGD in all men and postmenopausal women with IDA

  • Trend CBC, reticulocyte count, iron studies weekly (oral iron) or 2–4 weeks (IV iron)

  • PT/OT if deconditioning; dietitian consult if nutritional deficiency

  • Discharge: Iron supplementation (oral or IV based on severity/tolerance); B12/folate as appropriate; GI follow-up for source identification; nephrology if CKD-related; Hgb recheck in 2–4 weeks; treat underlying chronic disease

Red Flags

  • Hgb <7 + angina/chest pain → demand ischemia / Type 2 MI → EKG, troponin, transfuse to Hgb ≥8; cardiology

  • New-onset severe anemia in men or postmenopausal women → malignancy workup (colon cancer, gastric cancer) before attributing to benign cause

  • Pancytopenia + severe anemia → aplastic anemia or hematologic malignancy → bone marrow biopsy; hematology urgently

  • Neurologic symptoms (paresthesias, ataxia, cognitive decline) + macrocytic anemia → B12 deficiency → treat immediately (neurologic damage is irreversible if prolonged)

  • ESA in cancer patients outside of chemotherapy-related anemia → increased mortality and thrombosis — avoid

Senior IM Resident Pearls

  • Ferritin is an acute phase reactant — can be falsely normal or elevated in iron deficiency with coexisting inflammation (ACD + IDA); CRP >5 invalidates ferritin as a standalone iron marker; use transferrin saturation <20% as additional criterion

  • Mentzer index: MCV ÷ RBC count; <13 suggests thalassemia; >13 suggests IDA — useful screening tool when distinguishing microcytic anemia etiologies

  • Every-other-day oral iron is superior to daily dosing — reduces hepcidin surge that blocks absorption with consecutive daily doses (Moretti et al.)

  • ESA target Hgb 10–11.5 g/dL in CKD — targeting >13 increases cardiovascular events and mortality (TREAT, CHOIR trials); never normalize Hgb with ESA

  • Common mistake: Replacing folate without checking B12 — folate corrects macrocytic anemia but does not treat subacute combined degeneration of the spinal cord; neurologic damage progresses silently

  • Common mistake: Attributing iron deficiency in a 55-year-old male to "dietary" without colonoscopy — colorectal cancer must be excluded in all men and postmenopausal women with IDA

ORDERS

Labs

Admission

  • CBC with diff

  • CMP

  • BMP

  • Reticulocyte count + RPI

  • Iron studies (Fe, Ferritin, TIBC, TSAT)

  • Peripheral smear

  • Type & Screen

  • Type & Cross

Additional

  • Vitamin B12

  • Folate

  • CRP

  • ESR

  • LDH

  • Haptoglobin

  • Indirect bilirubin

  • Hemoglobin electrophoresis

  • EPO level (CKD)

  • Reticulocyte Hgb (Chr)

  • FOBT/FIT

Trending

  • CBC daily

  • Retic count q3–7 days

  • Iron studies q2–4 weeks after treatment

  • Hgb after each transfusion

Imaging

Iron Deficiency Workup

  • Colonoscopy

  • EGD

If Malignancy Concern

  • CT Chest

  • CT Abdomen/Pelvis

Procedures

Blood Transfusion

  • 1 unit PRBC at a time

  • Recheck Hgb after each unit

Bone Marrow Biopsy

If:

  • Pancytopenia

  • Aplastic anemia concern

  • Hematologic malignancy concern

Medications

Transfusion

Hgb <7

  • Transfuse PRBC

Hgb <8

  • CAD

  • ACS

  • Elderly symptomatic

  • Active angina

Goal:

  • Symptom improvement

  • Not a specific number

Iron Deficiency

Oral Iron

  • Ferrous sulfate 325 mg PO every other day

  • Vitamin C 500 mg PO daily

IV Iron (Preferred if severe)

Ferric Carboxymaltose

  • 750 mg IV x2 doses (7 days apart)

OR

Iron Sucrose

  • 200 mg IV x5 doses

OR

Iron Dextran

  • 1000 mg IV x1

B12 Deficiency

Cyanocobalamin

  • 1000 mcg IM daily x7 days

  • Then weekly x4 weeks

  • Then monthly

OR

  • B12 2000 mcg PO daily

Folate Deficiency

Folic Acid

  • 1–5 mg PO daily

Always replace B12 first or simultaneously.

CKD Anemia

Darbepoetin Alfa

  • 0.45 mcg/kg SQ q4 weeks

OR

Epoetin Alfa

  • 50–100 units/kg SQ/IV TIW

Target:

  • Hgb 10–11.5

Never target >13.

Hold

  • NSAIDs

  • Excessive phlebotomy

  • PPIs if possible (reduce iron absorption)

  • Methotrexate without folate replacement

Consults

Gastroenterology

  • All men with IDA

  • Postmenopausal women with IDA

  • FOBT positive

Hematology

  • Severe anemia

  • Pancytopenia

  • Hemolysis

  • Unclear etiology

  • ESA management

Nephrology

  • CKD anemia

  • ESA initiation

Cardiology

If:

  • Chest pain

  • Elevated troponin

  • Demand ischemia

Nutrition

  • Nutritional deficiencies

PT/OT

  • Weakness

  • Deconditioning

Nursing

  • Telemetry if severe anemia

  • Fall precautions

  • Strict I&O

  • Orthostatic vitals

  • Monitor transfusion reactions

Notify physician:

  • Chest pain

  • Syncope

  • New hypoxia

  • Hgb drop >1 g/dL

  • Active bleeding

Follow-Up

  • CBC daily

  • Iron studies after treatment

  • Retic response in 1 week

  • Colonoscopy results

  • EGD results

  • Hemolysis labs

  • B12/Folate results

Expected response:

  • Retic rise: 3–5 days

  • Hgb rise: ~1 g/dL per unit PRBC

  • Iron therapy: Hgb rise ~1–2 g/dL every 2–3 weeks