Anemia - Comprehensive Clinical Reference

Definition & Diagnostic Thresholds

• Men: Hb < 13.0 g/dL
• Women (non-pregnant): Hb < 12.0 g/dL
• Pregnant women: Hb < 11.0 g/dL

Classification

1. Morphologic (MCV-based)

Note: Anemia of chronic disease is often normocytic but can be microcytic (due to cytokine-mediated iron sequestration).

2. Mechanistic (Reticulocyte-based)

• Elevated reticulocytes (> 100,000/uL or reticulocyte production index > 2) - increased loss or destruction:
  • Bleeding (acute)
  • Hemolysis (intrinsic or extrinsic)
• Low/normal reticulocytes - underproduction:
  • Nutritional deficiency (iron, B12, folate, copper)
  • EPO deficiency (chronic kidney disease)
  • Marrow failure (aplastic anemia)
  • Marrow infiltration (myelophthisic)
  • Inflammation

Iron Deficiency Anemia (IDA)

• Chronic blood loss - most common in high-resource countries (GI: peptic ulcer, colon cancer, hemorrhoids; gynecologic: menorrhagia)
• Inadequate dietary intake - most common globally; also in exclusively milk-fed infants, elderly, food-insecure individuals
• Increased demand - pregnancy, infancy
• Malabsorption - celiac disease, gastritis, post-gastrectomy

1. Depleted stores: low serum ferritin, absent bone marrow iron staining - no anemia yet
2. Iron-restricted erythropoiesis: low serum iron, elevated TIBC, transferrin saturation < 20%
3. Frank IDA: microcytic/hypochromic anemia

Anemia of Chronic Disease/Inflammation (ACI)

1. Upregulate hepatic hepcidin - blocks ferroportin - iron trapped in macrophages and enterocytes
2. Blunt renal EPO synthesis
3. Shorten RBC survival
4. Blunt marrow erythroid response

Megaloblastic Anemias

Folate Deficiency

• Causes: Inadequate dietary intake (most common), malabsorption (celiac), increased demand (pregnancy, chronic hemolytic anemia), drugs (methotrexate inhibits DHFR; phenytoin blocks absorption)
• Folate stores last only 3-4 months (vs. B12 stores lasting 5-20 years)
• No neurologic manifestations
• Folate is absorbed in the proximal small intestine (jejunum)
• Treatment: Folic acid 1 mg/day PO

Vitamin B12 (Cobalamin) Deficiency

• Causes: Almost never dietary (B12 is heat-stable, abundant in animal foods) except strict vegans. Usually malabsorption:
  • Pernicious anemia (most common cause) - autoimmune atrophic gastritis destroying parietal cells, eliminating intrinsic factor (IF); anti-IF antibodies and anti-parietal cell antibodies present
  • Gastrectomy (no IF)
  • Ileal disease/resection (Crohn's, Whipple's) - site of IF-B12 complex absorption (cubilin receptor)
  • Pancreatic insufficiency (can't cleave haptocorrin to release B12)
  • Gastric atrophy/achlorhydria (elderly)
  • Metformin (reduces cubilin expression)
• Neurologic manifestations (unique to B12 deficiency): Subacute combined degeneration of spinal cord - demyelination of posterior columns (proprioception loss, vibration loss) and lateral corticospinal tracts (spastic weakness, hyperreflexia). Peripheral neuropathy. Psychiatric changes.

  Caution: Giving folate alone in B12 deficiency corrects the anemia but does not prevent - and may worsen - the neurologic damage.

• Treatment: IM cyanocobalamin 1000 mcg daily x 7 days, then weekly x 4, then monthly. High-dose oral B12 (1000-2000 mcg/day) is effective even in pernicious anemia (passive absorption).

Hemolytic Anemias

Extravascular vs. Intravascular Hemolysis

Inherited Hemolytic Anemias

• Autosomal dominant; defects in spectrin, ankyrin, or band 3 (membrane cytoskeleton proteins)
• Spherocytes are rigid, trapped in spleen, destroyed by splenic macrophages (extravascular)
• Lab: spherocytes on smear, elevated MCHC, negative Coombs (distinguishes from AIHA), abnormal osmotic fragility/EMA binding test, abnormal ektacytometry
• Treatment: folate supplementation; splenectomy for moderate-severe HS (give vaccines first - pneumococcal, meningococcal, H. flu)

• X-linked; most common enzyme deficiency worldwide
• G6PD protects RBCs from oxidative stress via NADPH/glutathione
• Triggers: infections, oxidant drugs (dapsone, primaquine, rasburicase), fava beans
• Presents with episodic hemolysis; Heinz bodies (denatured Hb) on crystal violet stain; bite cells on routine smear
• G6PD level may be falsely normal during acute episode (reticulocytes have high G6PD); test 2-3 months later

• Autosomal recessive; point mutation (Glu → Val) at position 6 of beta-globin
• Deoxygenated HbS polymerizes - RBC deformation into sickle shape
• RBC lifespan reduced to < 20 days (vs. 120 days normal); 1 in 500 African Americans affected
• Complications: Vaso-occlusive pain crises, acute chest syndrome, stroke, avascular necrosis (femoral head), autosplenectomy (by age 5 - susceptibility to encapsulated organisms), priapism, retinopathy, renal papillary necrosis, hydroxyurea-responsive fetal Hb induction
• Heterozygotes (HbAS - sickle trait): usually asymptomatic; 1 in 12 African Americans
• Treatment: Hydroxyurea (increases HbF), transfusions, stem cell transplant (potentially curative), crizanlizumab (anti-P-selectin), voxelotor (anti-sickling)

• Quantitative defects in globin chain synthesis (alpha or beta chains)
• Beta-thalassemia major: severe transfusion-dependent anemia; iron overload is a major complication (chelation with deferasirox/deferoxamine)
• Diagnosed by hemoglobin electrophoresis

Acquired Hemolytic Anemias

• Warm AIHA (70%): IgG antibodies react at 37°C; extravascular hemolysis; associated with CLL, SLE, drugs (methyldopa, penicillin); positive direct Coombs (DAT) for IgG. Treatment: steroids, rituximab, splenectomy.
• Cold AIHA (cold agglutinin disease): IgM antibodies react at < 30°C; complement activation - intravascular and extravascular; associated with Mycoplasma pneumoniae, EBV, lymphoma; positive DAT for C3d. Treatment: avoid cold, rituximab.

• Mechanical fragmentation of RBCs in small vessels - schistocytes (helmet cells) on smear
• Causes: TTP (ADAMTS13 deficiency), HUS (E. coli O157:H7 Shiga toxin), DIC, malignant hypertension, HELLP syndrome, mechanical heart valves

• Acquired mutation in PIG-A gene - loss of GPI-anchored proteins (CD55, CD59) that inhibit complement
• Complement-mediated intravascular hemolysis, thrombosis (hepatic vein - Budd-Chiari, sagittal sinus), cytopenias
• Diagnosed by flow cytometry (CD55/CD59 deficiency on RBCs and granulocytes)
• Treatment: Eculizumab (C5 complement inhibitor) or ravulizumab

Aplastic Anemia

• Primary mechanism: activated Th1 cells (likely triggered by drug/infection exposure to neoantigen) produce IFN-gamma/TNF-alpha, suppressing HSCs
• Secondary mechanism: intrinsic stem cell defects (telomerase mutations in 5-10%; short telomeres in ~50%)
• Immunosuppression restores hematopoiesis in 60-70%, supporting immune etiology

• Pancytopenia with hypocellular bone marrow (< 25% cellularity)
• Severity classification based on ANC + platelet counts (severe: ANC < 500; very severe: ANC < 200)

• < 40 years, HLA-matched sibling available: allogeneic HSCT (preferred; curative)
• Not transplant candidates: Immunosuppression with anti-thymocyte globulin (ATG) + cyclosporine + eltrombopag (TPO receptor agonist)
• Minimize transfusions prior to transplant (avoid allosensitization)

Diagnostic Approach Summary

Anemia confirmed on CBC
         |
         v
Reticulocyte count (absolute)
         |
    _____|_____
   |           |
Elevated      Low/Normal
(> 100k)     (Underproduction)
   |               |
Bleeding?    MCV classification
 or           Microcytic → IDA, thalassemia, ACI
Hemolysis?    Macrocytic → B12/folate, drugs, MDS
              Normocytic → CKD, aplastic, infiltration
   |
Hemolysis workup:
LDH, indirect bili, haptoglobin, smear
Direct Coombs (AIHA?)
Schistocytes (MAHA?)
Spherocytes (HS, AIHA?)
Flow cytometry (PNH?)
Hemoglobin electrophoresis (hemoglobinopathy?)

Key Lab Comparisons

• Harrison's Principles of Internal Medicine, 22E (2025), Chapter 66
• Robbins & Kumar Basic Pathology, Chapter 10
• Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 14
• Lippincott Biochemistry, 8th Ed., Chapter 3
• Goldman-Cecil Medicine, Chapter 144