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Margaret Wheless

First establish acuity: bleed or consumptive process vs slow onset anemia - Check vitals for hypotension, tachycardia. - Check Hgb trend from prior if available. - Examine patient for pallor, rapid onset fatigue, AMS, feeble pulses and any signs of bleeding. - Consider risk factors such as recent procedure, blood thinner use, falls, new medications. - STAT repeat CBC along with haptoglobin, LDH, HFP(bilirubin) to rule out hemolysis - If no sx/signs of acute bleeding, move onto general anemia eval below. - Note: CBC does not accurately reflect blood loss in acute rapid bleeding scenarios so do not be falsely reassured by normal hematocrit in GI bleeds/trauma patients.


  • Symptoms: fatigue/malaise, dyspnea on exertion, angina (if history of CAD)
  • Signs
    • Pallor, tachycardia, orthostatic hypotension, purpura, glossitis, koilonychia (in IDA)
    • Jaundice (if hemolysis)
    • Splenomegaly: suggests extramedullary hematopoiesis or sequestration
    • Neurologic symptoms: suggests B12 deficiency


  • CBC w/diff, reticulocyte count, peripheral blood smear, iron studies (TIBC, ferritin)
    • Reticulocyte index (RI) > 2%: blood loss vs hemolysis; see below
    • Hemolysis labs: Bilirubin, LDH, haptoglobin
    • RI < 2%: hypoproliferative à stratify based on RBC size
    • Microcytic (<80) vs. Normocytic (80-100) vs. Macrocytic (>100)

Reticulocyte Index >2%


  • Etiology: consumption vs. blood loss
    • Loss: acute bleed vs iatrogenic from labs
    • Hemolysis: microangiopathic hemolytic anemia (MAHA), autoimmune hemolytic anemia (AIHA), intrinsic RBC defects


  • LDH, ↑ indirect bilirubin, ↓ haptoglobin, PT/PTT
  • Note: haptoglobin can be low in cirrhosis (made by liver), recently transfused blood, large hematoma
  • Peripheral blood smear: evaluated for schistocytes, bite cells, spur cells, spherocytes, etc.
  • Direct antiglobulin test (DAT) to evaluate for autoimmune hemolytic anemia

Extrinsic RBC causes

  • If schistocytes ± thrombocytopenia = MAHA: TTP, other TMA syndromes (HUS, drug-induced, complement-mediated), DIC, HELLP, mechanical valves, malignant HTN, cocaine, scleroderma renal crisis
  • If DAT positive = AIHA
  • Consider cold agglutinin titer

Intrinsic RBC causes

  • Sickle cell disease: chronic hemolysis + splenic sequestration crisis where RI is↑ vs aplastic crisis where RI is↓ (see sickle cell section)
  • Hereditary spherocytosis
  • Hereditary elliptocytosis
  • Severe B12 deficiency
  • Spur cell anemia (found in advanced cirrhosis)
  • PNH
  • G6PD: bite cells, Heinz bodies
    • Usually precipitated by drugs: nitrofurantoin, dapsone, sulfonamides, rasburicase, primaquine


  • MAHA
    • DIC: sepsis, malignancy, pregnancy (See “Disseminated Intravascular Coagulation” section)
      • Treat underlying cause
      • If active bleeding: FFP, cryoprecipitate (to keep fibrinogen>100), and platelets
    • TTP: Order ADAMTS13 (prior to plasma transfusion or exchange).
      • If concern for TTP you should immediately consult Heme and Nephrology
    • HUS: + shiga toxin, AKI, diarrhea
    • IVF, antibiotics only to treat extra-renal disease, transfusion as necessary
  • AIHA:
    • Cold (rare): IgM binds at temp <37
      • Caused by lymphoproliferative disorder (Waldenstrom’s), mycoplasma, EBV, HIV
      • Consult Heme. Treat underlying condition. Consider rituximab (steroids ineffective)
    • Warm: IgG
      • Idiopathic or associated with lymphoma, SLE, drugs, babesiosis, HIV
      • Can use steroids, IVIG, rituximab

RBC Size Framework

Normocytic anemia: MCV 80-100

  • Etiologies:
    • Anemia of inflammation (formerly chronic disease): (may also be microcytic)
    • Anemia of CKD: low Erythropoietin (EPO) levels
    • Endocrine disease (hypothyroidism, adrenal insufficiency): ↓metabolic demand/O2 requirement
    • Mixed macrocytic/microcytic disease may have a normal MCV: look for ↑RDW
    • Pure red cell aplasia: associated with destructive Ab (CLL, thymoma, parvovirus, autoimmune)
    • Paroxysmal nocturnal hemoglobinuria (PNH)
    • Splenic sequestration
    • Bone marrow failure or infiltration (typically will see pancytopenia)
    • Vitamin C deficiency, copper deficiency
  • Bone marrow biopsy may be indicated if no identifiable cause or anemia is associated with other cytopenia’s Microcytic anemia: MCV <80 (mnemonic: SALTI)
  • Sideroblastic, Anemia of chronic disease, Lead poisoning, Thalassemia and Iron-deficiency
Disease Etiology Evaluation Considerations
Sideroblastic MDS
EtOH, Lead, Isoniazid
Cu deficiency
Fe: ↑↑
Ferritin: ↑ to normal
TIBC: normal
Smear: basophilic stippling
BMBx: ringed sideroblasts
In clinical practice this is usually acquired; either due to alcohol (can resolved with cessation) or primary bone marrow disorder (e.g. MDS-RARS)
Anemia of Inflammation (formerly chronic disease) Chronic inflammation, malignancy, HIV, autoimmune dz, heart failure, etc. Fe/TIBC >18%
Fe: ↓↓
Ferritin: ↑↑
TIBC: ↓↓
Treat underlying disease
Replete Fe if ferritin <100 or TIBC <20%
EPO if Hgb <10 and serum EPO <10
Thalassemia ↓ synthesis of α or β chains leads to ↓ erythropoiesis and ↑ hemolysis
Family Hx of anemia
Mentzer’s index: MCV/RBC <13 = thalassemia
Normal Fe studies; can mimic microcytic anemia and Fe overload from transfusions
Diagnosis: Hb electrophoresis (α will be normal)
α thal more common in Asian/African descent
β thal common in Mediterranean descent
Tx: transfusions, folate, Fe chelator depending on severity
Iron (Fe) deficiency Chronic bleeding: colon cancer, heavy menstrual periods, cirrhosis (portal gastropathy)
Supply: malnutrition, Crohn’s dz, Celiac dz, subtotal gastrectomy, atrophic gastritis
Demand: pregnancy
Fe/TIBC <18%
TIBC:↑ nl to ↑
Ferritin: < 100
Mentzer’s index: >13
Consider celiac testing based on clinical suspicion
Investigate for GIB or source of blood loss
Oral Fe: 6wks to correct anemia, 6mo to replete stores; dose every other day (↑ absorption w/ ↓ GI side effects); add Vit C for ↑ absorption
If can’t tolerate PO consider IV Fe (Avoid when bacteremic)
HFrEF: IV Fe if ferritin <100 OR 100-300 w/ Fe sat <20%

Macrocytic Anemia: MCV >100

  • Non-megaloblastic
    • ETOH, liver disease, hypothyroidism, MDS
    • Medications that impair DNA synthesis: zidovudine, 5-FU, hydroxyurea, ara-C, AZT, MTX
  • Megaloblastic
    • B12 deficiency
      • Presentation: neurologic changes (subacute combined degeneration), paresthesias, ataxia, dementia (reversible with early treatment)
      • Etiology: malnutrition (alcoholics, vegan), pernicious anemia, gastrectomy, Crohn’s disease, chronic pancreatitis, celiac disease
      • Diagnosis: ↓B12, ↑MMA, ↑homocysteine
      • Treatment: either monthly IM or PO B12 (1% paracellular absorption demonstrated to be sufficient for repletion)
    • Folate deficiency
      • Etiology: malnutrition, decreased absorption (e.g. celiac disease), impaired metabolism (MTX, TMP), ↑requirement (hemolysis, malignancy, dialysis)
      • Diagnosis: ↓folate, ↑homocysteine, MMA will be normal
      • Treatment: PO folate 1-4mg daily