Anemia
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Anemia - Overview & Classification
Definition
Anemia is defined as a reduction in blood hemoglobin (Hb) or red cell mass below normal for age and sex. Standard WHO thresholds:
| Population | Hb threshold (g/dL) |
|---|---|
| Men >15 years | <13.0 |
| Women >15 years (non-pregnant) | <12.0 |
| Pregnant women | <11.0 |
| Children 6 months - 5 years | <11.0 |
| Children 5-12 years | <11.5 |
- Harrison's Principles of Internal Medicine 22e (2025): "Anemia is simply defined as blood counts below normal for a given population."
Two Master Classification Schemes
1. Morphologic Classification - by MCV (Red Cell Size)
This is the most clinically practical starting point.
A. Microcytic Anemia (MCV <80 fL)
Caused by any process that interferes with hemoglobin synthesis - less Hb = smaller cell. Mnemonic: TAILS
| Cause | Mechanism |
|---|---|
| Thalassemia | Deficient globin chain synthesis |
| Anemia of chronic disease (some) | Impaired iron reutilization (hepcidin ↑) |
| Iron deficiency | Unable to synthesize heme |
| Lead poisoning | Inhibits heme synthesis enzymes |
| Sideroblastic anemia | Defect in heme synthesis (ring sideroblasts) |
B. Macrocytic Anemia (MCV >100 fL)
Two subtypes:
Oval macrocytes (megaloblastic - DNA synthesis defect):
- Vitamin B12 deficiency
- Folate deficiency
- Medications (methotrexate, hydroxyurea, anticonvulsants)
- Myelodysplastic syndrome
Round macrocytes (non-megaloblastic - membrane defect):
- Alcohol use disorder
- Liver disease
- Hypothyroidism
- Reticulocytosis (large immature RBCs)
- Dysproteinemia, smoking, hypoxia
C. Normocytic Anemia (MCV 80-100 fL)
Broad differential - least specific category:
- Aplastic anemia
- Anemia of chronic disease (most cases)
- Renal disease (↓ EPO)
- Endocrinopathies (hypothyroidism, adrenal insufficiency)
- Marrow invasion (myeloma, metastases, granulomas)
- Early iron deficiency (before MCV falls)
- Sickle cell disease (homozygous)
- Pure red cell aplasia
2. Mechanistic Classification - by Pathophysiology
Based on reticulocyte count as the key discriminator:
| Reticulocyte count | Mechanism | Interpretation |
|---|---|---|
| High (>100,000/µL) | Hyperproduction (attempted compensation) | Blood loss OR Hemolysis |
| Low/normal | Underproduction | Bone marrow failing to compensate |
A. Blood Loss
- Acute: trauma, surgical hemorrhage
- Chronic: GI lesions (ulcers, cancers), menorrhagia - leads to iron deficiency
B. Hemolysis (Increased Destruction)
Intrinsic (Congenital/Inherited):
| Defect | Examples |
|---|---|
| RBC membrane disorders | Hereditary spherocytosis, hereditary elliptocytosis |
| Enzyme deficiencies | G6PD deficiency (HMP shunt), Pyruvate kinase deficiency (glycolytic) |
| Hemoglobin abnormalities | Sickle cell disease, unstable hemoglobins, thalassemia |
| Acquired genetic defects | Paroxysmal nocturnal hemoglobinuria (PNH) |
Extrinsic (Acquired):
| Defect | Examples |
|---|---|
| Immune-mediated | Autoimmune hemolytic anemia (warm/cold), transfusion reactions, hemolytic disease of newborn |
| Microangiopathic (MAHA) | TTP, HUS, DIC, defective cardiac valves |
| Infections | Malaria, babesiosis |
| Toxic/chemical injury | |
| Sequestration | Hypersplenism |
Lab hallmarks of hemolysis: ↑ LDH, ↓ haptoglobin, ↑ unconjugated bilirubin, ↑ reticulocytes, hemoglobinuria, schistocytes or spherocytes on smear.
C. Underproduction (Hypoproliferative)
"At least 75% of all cases of anemia are hypoproliferative." - Harrison's 22e
| Subcategory | Causes |
|---|---|
| Nutritional deficiency | Iron (most common worldwide), B12, folate, copper, vitamin C |
| Lack of EPO | Chronic kidney disease (GFR <30), anemia of inflammation (hepcidin ↑ blocks iron) |
| Marrow replacement (myelophthisic) | Metastases, granulomas (TB, histoplasmosis), multiple myeloma - shows leukoerythroblastic picture on smear |
| Absent red cell precursors | Aplastic anemia (all cell lines), pure red cell aplasia (only erythroid; parvovirus B19, autoimmune) |
| Stem cell defects | MDS, AML, CML |
Diagnostic Approach (Step-by-Step)
Anemia confirmed (CBC)
|
↓
Reticulocyte count
|
_____|______
| |
HIGH LOW
(>100k/µL) (<25k/µL)
| |
Blood loss? Check MCV
Hemolysis? → Microcytic → Iron studies, Hb electrophoresis
(↑LDH, → Macrocytic → B12, folate, peripheral smear
↓haptoglobin) → Normocytic → BMP (creatinine), TFTs,
bone marrow biopsy if needed
Key initial labs:
- CBC with differential - MCV, RDW, WBC, platelets
- Reticulocyte count (absolute)
- Peripheral blood smear - most informative single test
- Iron studies - serum iron, TIBC, ferritin, transferrin saturation
- B12 and folate levels (if macrocytic)
- LDH, haptoglobin, indirect bilirubin (if hemolysis suspected)
- Renal function, TFTs, EPO level (for normocytic)
- Bone marrow biopsy - if leukoerythroblastic picture or pancytopenia
Quick Summary Table for Exams
| Type | MCV | Retic | RDW | Key finding |
|---|---|---|---|---|
| Iron deficiency | ↓ | ↓ | ↑ | ↓ ferritin, ↑ TIBC |
| Thalassemia minor | ↓ | N/↑ | N | Normal ferritin, Hb electrophoresis abnormal |
| Anemia of chronic disease | N/↓ | ↓ | N | ↑ ferritin, ↓ TIBC |
| B12/Folate deficiency | ↑ | ↓ | ↑ | Hypersegmented neutrophils, oval macrocytes |
| Hemolysis | N/↑ | ↑↑ | ↑ | ↑ LDH, ↓ haptoglobin, spherocytes/schistocytes |
| Aplastic anemia | N | ↓↓ | N | Pancytopenia, hypocellular marrow |
| Renal anemia | N | ↓ | N | ↑ creatinine, ↓ EPO |
Sources: Harrison's Principles of Internal Medicine 22e (2025) | Robbins, Cotran & Kumar - Pathologic Basis of Disease | Goldman-Cecil Medicine (International Ed.)
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