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Anemia - Everything from Harrison's Principles of Internal Medicine (22nd Ed., 2025)

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1. Definition

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2. Classification

A. By Red Cell Size (MCV)

B. By Mechanism (Reticulocyte-Based)

• Bleeding
• Hemolysis (acquired: autoimmune, mechanical; congenital: hemoglobinopathies, enzyme defects, membrane defects)

• Nutritional deficiency (iron, B12, folate, copper, Vitamin C)
• Absence of red cell precursors (aplastic anemia, pure red cell aplasia)
• Lack of erythropoietin (renal disease, anemia of inflammation, anemia of aging)
• Marrow replacement (infection, cancer, granulomas)
• Stem cell defects (myelodysplasia, leukemia)

At least 75% of all cases of anemia are hypoproliferative. The most common cause is mild to moderate iron deficiency or inflammation.

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3. Signs & Symptoms

• Tiredness, shortness of breath (reduced O2 delivery)
• Pallor of mucosa and conjunctiva
• Resting tachycardia
• In atherosclerosis: angina, TIA, or stroke from ischemic symptoms
• In nutritional deficiency: pica (iron), neuropathy (B12)
• Flow murmur on cardiac auscultation

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4. Compensatory Mechanisms

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5. Laboratory Evaluation

The CBC

• Red cell number/L
• MCV (mean corpuscular volume)
• Hemoglobin

• Hematocrit = (RBC count × MCV) / 10
• MCH (mean corpuscular hemoglobin) = Hgb / RBC count
• MCHC (mean corpuscular hemoglobin concentration) = Hgb / Hematocrit
• RDW (red cell distribution width) = standard deviation of RBC size / MCV × 100 (normal ~11.5-14.5%)

Iron Studies

Reticulocyte Count

Reticulocyte Production Index (RPI) = (% reticulocytes × patient Hct / normal Hct) / maturation factor

Blood Smear - Key Morphologic Findings

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6. Specific Causes of Anemia

6a. Iron Deficiency Anemia

1. Depletion of iron stores (ferritin falls)
2. Iron-deficient erythropoiesis (transferrin saturation falls, RDW rises)
3. Iron-deficiency anemia (hemoglobin falls, microcytic hypochromic picture)

• Low- to middle-income countries (malnutrition + helminth infections)
• Malaria-endemic regions (iron supplementation paradox - iron deficiency confers some protection from malaria; WHO recommends iron supplementation only when concomitant malaria prevention strategies are in place)
• Frequent blood donors (each unit contains ~200 mg iron)
• Pre-surgical patients: preoperative IV iron preferred if surgery is within 6 weeks

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6b. Anemia of Inflammation (Anemia of Chronic Disease)

1. IL-6 → hepcidin → macrophage iron sequestration → hypoferremia (iron trapped, unavailable for erythropoiesis)
2. TNF-α and IL-1β → suppressed EPO production from kidneys
3. IFN-γ → blunted erythroid progenitor response to EPO
4. Bonus: bone marrow progenitor commitment is reprogrammed toward myeloid lineage (via PU.1 transcription factor)

• Treat the underlying disorder (anti-IL-6 agents such as tocilizumab work in rheumatoid arthritis/Castleman's disease)
• ESAs (erythropoiesis-stimulating agents) in CKD - target Hgb <11.5 g/dL
• IV iron: maintain transferrin saturation 30-40%, ferritin 200-700 μg/L in CKD
• Ferric citrate (oral): binds intestinal phosphate, provides iron, reduces phosphate (useful in advanced CKD)
• Prolyl hydroxylase inhibitors (HIF-stabilizers): approved in some countries - stabilize HIF-2α, upregulate both EPO and duodenal iron absorption
• In CHF: IV iron if ferritin <100 μg/L or transferrin saturation <20% with ferritin 100-300 μg/L

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6c. Anemia of Aging

• Prevalence: ~10% at age 65, ~25% in >85-year-olds, ~50% in hospitalized/institutionalized elderly
• Typically mild (Hgb 11-12 g/dL), multifactorial, often underestimated
• Negative impact on quality of life, muscle weakness, falls, fractures, and independent mortality association
• Black patients experience adverse effects at Hgb levels ~1 g/dL lower than white patients

1. Nutritional (especially iron deficiency)
2. Inflammation including CKD
3. "Unexplained anemia of aging" - testosterone decline (males), stem cell exhaustion, EPO reduction

• Ferritin cutoff for iron deficiency in elderly is higher (45-70 μg/L vs standard lower cutoffs)
• Gastrointestinal malignancy must always be ruled out
• Aspirin for primary CV prevention in elderly → 20% higher risk of anemia/iron deficiency vs placebo

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6d. Acquired Hemolytic Anemia

• Elevated LDH (abundant in RBCs)
• Low haptoglobin (scavenges free hemoglobin - exhausted when hemolysis is ongoing)
• Elevated blood/urine free hemoglobin (hemoglobinuria)
• Elevated reticulocyte count
• Abnormal smear (schistocytes, spherocytes)

• March hemoglobinuria (marathon runners, barefoot ritual dancing, bongo drum playing) - acute, self-inflicted intravascular hemolysis
• Prosthetic heart valves (chronic, microangiopathic) - especially with paraprosthetic regurgitation

• Malaria - the most frequent infectious cause in endemic areas
• Shiga toxin-producing E. coli O157:H7 - the main cause of HUS (more common in children)
• Clostridium perfringens - life-threatening intravascular hemolysis via lecithinase toxin; seen with open wounds, septic abortion, or contaminated blood units

• Drug-related (innocent bystander) - antibody vs drug catches RBCs in the reaction
• True autoimmune - antibody directly against RBC antigen

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6e. Anemia Due to Acute Blood Loss

1. Hypovolemia dominates - the CBC does NOT show anemia yet (hemoglobin concentration unchanged acutely). Clinical signs: tachycardia, tachypnea, decreased pulse pressure, cold pale mottled skin, decreased urine output. Threat to brain and kidneys from hypoperfusion.
2. Hemodilution phase - baroreceptors/stretch receptors trigger vasopressin; fluid shifts from extravascular to intravascular compartment. Hypovolemia converts to anemia. Rule of thumb: if Hgb is 7 g/dL at 3 days, approximately half of total blood volume has been lost.
3. Bone marrow response - elevated reticulocytes and EPO as marrow compensates.

• Grey Turner sign (flank ecchymosis) → retroperitoneal bleeding
• Cullen sign (umbilical ecchymosis) → intraperitoneal/retroperitoneal bleeding
• Dullness to chest percussion → intrapleural bleeding

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6f. Aplastic Anemia & Bone Marrow Failure

• Normocytic anemia from absence of red cell precursors
• Pan-cytopenia (all cell lines affected)
• Diagnosis by bone marrow biopsy
• Treatment: immunosuppression (anti-thymocyte globulin + cyclosporine) or hematopoietic stem cell transplant

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7. Stepwise Approach to Diagnosis

1. History: Previous anemia, prior therapy (iron, transfusions), family history, blood donation, menstrual history (duration, pad/tampon use, clots), symptoms of underlying disease (diarrhea → celiac/IBD)
2. Physical exam: Cardiac flow murmur (consequence), splenomegaly (hemolysis), blood in stool (GI bleeding as cause)
3. Blood smear + reticulocyte count: Morphology points to specific causes; reticulocyte count assesses bone marrow function
4. Guided workup (see algorithm below):

Reticulocyte count
│
├── HIGH → Hemolysis or Bleeding
│   ├── LDH, haptoglobin, direct antibody test (Coombs)
│   ├── Smear: schistocytes → microangiopathic
│   ├── Smear: spherocytes → AIHA or hereditary spherocytosis
│   └── Hemoglobin electrophoresis if sickle cells/thalassemia suspected
│
└── LOW/NORMAL → Underproduction → Guided by MCV
    │
    ├── LOW MCV (microcytic)
    │   ├── Check ferritin first
    │   │   ├── Low ferritin → Iron deficiency
    │   │   └── Normal ferritin → Consider thalassemia
    │   └── RDW helps: high RDW = iron deficiency; low/normal RDW = thalassemia
    │       Anemia of inflammation = diagnosis of exclusion (usually normocytic)
    │
    ├── HIGH MCV (macrocytic) → Guided by smear
    │   ├── Hypersegmented neutrophils + macro-ovalocytes → B12/folate levels
    │   ├── Macro-ovalocytes with normal B12/folate → Myelodysplasia → bone marrow biopsy
    │   └── Round macrocytes → History (liver disease, alcohol, hypothyroidism)
    │
    └── NORMAL MCV (normocytic)
        ├── Renal function (EPO deficiency)
        ├── EPO levels
        ├── Screen for underlying systemic diseases
        └── Bone marrow exam if no cause found

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8. Treatment Principles

• Hypotension
• Signs of cardiac compromise (angina)
• Bone marrow failure (support while awaiting definitive therapy)

• Iron deficiency → oral or IV iron (IV preferred preoperatively if surgery <6 weeks)
• B12 deficiency → B12 supplementation
• Folate deficiency → folate supplementation
• Anemia of inflammation/CKD → ESAs + IV iron
• Hemolytic anemias → treat underlying cause; AIHA → steroids/rituximab
• Aplastic anemia → immunosuppression or bone marrow transplant

• Recombinant EPO - transformed CKD patients on dialysis; reduces transfusion needs in chemotherapy patients
• TGF-β inhibitors (luspatercept) - myelodysplastic syndrome-related anemia
• Complement inhibitors (eculizumab/ravulizumab) - paroxysmal nocturnal hemoglobinuria (PNH) and atypical HUS (aHUS); can be discontinued once full remission is achieved (urine dipstick negative for hemoglobinuria for 3-6 months)
• Prolyl hydroxylase inhibitors (HIF-stabilizers) - approved in some countries for renal anemia, providing both EPO stimulation and improved iron absorption in a single oral drug
• Hepcidin-ferroportin axis inhibitors - under investigation for anemia of inflammation

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9. Quick Summary Table

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