Anemia

Margaret Wheless

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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.

Presentation

• 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

Evaluation

• 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%

Background

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

Evaluation

• 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

Management

• 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
• *S*ideroblastic, *A*nemia of chronic disease, *L*ead poisoning, *T*halassemia and *I*ron-deficiency

Disease	Etiology	Evaluation	Considerations
Sideroblastic	MDS Idiopathic 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% Fe:↓↓ 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