Anemia – Margaret Wheless

General Approach to Diagnosis

  • First evaluate RI (decreased production) vs ↑RI (loss vs hemolysis)
    • Reticulocyte index > 2%: see below 
    • RI < 2%:  hypoproliferative stratify based on RBC size 
      • Microcytic vs. Normocytic vs. Macrocytic
      • Exception to ↓RI is thalassemia where RI can be slightly ↑



  • Symptoms: fatigue/malaise, DOE, angina (if CAD)
  • Hx of systemic illness, ETOH abuse, Family History
  • Signs:
    • Pallor, tachycardia, orthostatic hypotension, purpura, glossitis, koilonychia (IDA)
    • Jaundice (2/2 hemolysis)
    • Splenomegaly: suggests extramedullary hematopoiesis or sequestration
    • Neurologic symptoms: suggests B12 deficiency 



  • CBC w/diff, reticulocyte count, peripheral blood smear, Iron studies (TIBC, Ferritin)
  • Hemolysis labs: Bilirubin, LDH, haptoglobin
  • Nutritional studies: B12, folate


 Reticulocyte Index > 2%


  • Consumption vs Blood loss
  • Loss: acute bleed vs iatrogenic from labs
  • Hemolysis: Microangiopathic hemolytic anemia (MAHA), autoimmune hemolytic anemia, intrinsic RBC defects



  • LDH, ↑indirect bilirubin, ↓haptoglobin, PT/PTT
  • Peripheral blood smear: looking for schistocytes
  • Consider direct antiglobulin test (DAT) if suspicion for autoimmune cause


Extrinsic RBC causes:

  • If schistocytes ± thrombocytopenia = MAHA: TTP, DIC, HUS, HELLP, mechanical valves, malignant HTN, cocaine, scleroderma renal crisis
    • Check Cr and Plt count to evaluate for TTP
    • mechanical valves, malignant HTN, cocaine, scleroderma renal crisis
  • If DAT positive = AIHA
  • Order 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
  • PNH (generally see pancytopenia, RI is lower than expected for severity of anemia)
  • G6PD: bite cells, Heinz bodies on PBS: Usually precipitated by drugs: nitrofurantoin, dapsone, sulfonamides, rasburicase, primaquine



  • MAHA: Caused by DIC, TTP, HUS
    • DIC: sepsis, malignancy, pregnancy
      • Treat underlying cause
      • If active bleeding: FFP, cryoprecipitate (to keep fibrinogen>100) and platelets
    • TTP: Order ADAMTS13
      • Will need PLEX
    • If concern for TTP you should immediately consult Heme and NephrologyHUS: + shiga toxin, AKI, diarrhea
    • Other: mechanical valves, malignant HTN, cocaine, scleroderma renal crisis
      • Treat underlying cause
  • Autoimmune hemolytic anemia (AIHA):
    • Cold: IgM binds at temp <37
      • Caused by lymphoproliferative disorder (Waldenstroms), mycoplasma, EBV, HIV
      • Consult heme. Treat underlying. Consider rituximab (steroids dont work)
    • Warm: IgG
      • Idiopathic or associated with lymphoma, SLE, drugs, babesiosis, HIV
      • Can use steroids, IVIG, ritux



RBC Size Framework

Normocytic Anemia: MCV 80-100

  • Look for pancytopenia (eg. something else may be happening in the BM, splenic sequestration, PNH, etc)
  • Anemia of chronic disease may also be microcytic
  • Mixed macrocytic/microcytic disease: look for ↑RDW
  • CKD: low Erythropoietin (EPO) levels
  • Endocrine disease: ↓metabolic demand/O2 requirement
  • Pure red cell aplasia: associated with destructive Ab (CLL, thymoma, parvovirus, autoimmune)
  • Bone marrow biopsy may be indicated if normocytic with low RI without an identifiable cause or anemia associated with other cytopenia’s


Microcytic anemia: MCV <80 (Mnemonic: SALTI)

  • Sideroblastic, anemia of chronic disease, lead poisoning, thalassemia and iron-deficiency
  • See Table









ETOH, Lead, Isoniazid,

Cu deficiency

Social hx, work, TB,

consider Lead level


Fe:↑  ferritin:↑nl or

TIBC: nl

Smear: basophilic stippling


BMbx: ringed sideroblasts


Anemia of chronic disease

Chronic inflammation, malignancy, HIV autoimmune dz, Inflammation (IL6, TNF α)

Fe/TIBC >18%


Fe: ↓  ferritin:↑  TIBC:↓



Tx: underlying dz


EPO if Hgb <10 and serum EPO <500

Replete Fe if ferritin <100 or TIBC <20%


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 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


Demand: pregnancy

Fe/TIBC <18%


Fe:↓  TIBC:↑ nl to

ferritin: < 15, <41 w/co-morb.


Mentzer’s index: >13


Consider celiac testing based on clinical suspicion


Investigate for GIB or sources 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: BM suppression, macrocytosis independent from cirrhosis or vitamin deficiency
    • Liver disease
    • Hypothyroidism
    • MDS
    • Medications that impair DNA synthesis: zidovudine, 5-FU, hydroxyurea, ara-C, AZT
  • Megaloblastic
    • B12 deficiency
      • Total body stores last 2-3 yr; absorbed in terminal ileum, requires IF
      • Can have 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 (8-41% of pt)
      • Dx: B12, MMA, homocysteine
      • If B12 low normal but have neuro sx, can get MMA to help confirm dx
        • Tx: either monthly IM or sublingual B12 (oral not absorbed if no IF)
    • Folate deficiency
      • Total body stores last 2-3 mo; absorbed mostly in jejunum
      • Etiology: malnutrition, decreased absorption (celiac disease 2/2 damaged jejunum), impaired metabolism (MTX, TMP), ↑requirement (hemolysis, malignancy, dialysis)
      • Dx: ↓folate, ↑homocysteine but wnl MMA
      • Tx: PO folate 1-4 mg daily