What are the causes of anemia (low red blood cell count)?

Causes of Anemia (Low Red Blood Cell Count)

Anemia can be classified based on Mean Corpuscular Volume (MCV) and reticulocyte index (RI) to systematically identify the underlying cause, with iron deficiency being the most common cause worldwide. 1

Classification by Red Blood Cell Size (MCV)

Microcytic Anemia (MCV < 80 fL)

• Iron deficiency: Most common cause globally 2, 3
  • Due to blood loss, poor nutrition, impaired absorption, or increased needs
• Thalassemia: Genetic disorder of hemoglobin synthesis
• Anemia of chronic disease/inflammation: Often with normal to slightly low MCV
• Sideroblastic anemia: Abnormal incorporation of iron into hemoglobin

Normocytic Anemia (MCV 80-100 fL)

• Acute blood loss: Presents with hemodynamic changes if severe
• Hemolysis: Destruction of red blood cells
• Bone marrow failure: Decreased production of all cell lines
• Anemia of chronic inflammation: Common in chronic diseases
• Renal insufficiency: Due to decreased erythropoietin production
• Mixed nutritional deficiencies: Combined deficiencies may result in normal MCV

Macrocytic Anemia (MCV > 100 fL)

• Megaloblastic: Due to vitamin B12 or folate deficiency
  • Insufficient uptake or inadequate absorption (lack of intrinsic factor)
• Non-megaloblastic: Associated with alcoholism
• Medication-induced: Drugs like hydroxyurea or diphenytoin 2
• Myelodysplastic syndromes: Bone marrow disorders

Classification by Mechanism (Reticulocyte Index)

Low Reticulocyte Index (RI < 1.0) - Decreased Production

• Iron deficiency: Most common cause globally
• Vitamin B12/folate deficiency: Impaired DNA synthesis
• Aplastic anemia: Bone marrow failure
• Bone marrow infiltration: Cancer or cancer-related therapy effects
• Chronic kidney disease: Decreased erythropoietin production 2
• Anemia of chronic inflammation: Cytokine-mediated suppression

High Reticulocyte Index (RI > 2.0) - Increased Loss/Destruction

• Acute or chronic blood loss: GI bleeding, heavy menstruation
• Hemolysis: Immune or non-immune mediated destruction
  • Autoimmune hemolytic anemia
  • Microangiopathic hemolytic anemia
  • Hereditary spherocytosis or other membrane defects
  • Hemoglobinopathies

Disease-Specific Causes

Chronic Disease-Associated Anemia

• Heart failure: Associated with hemodilution and inflammatory cytokines 4
• Chronic kidney disease: Due to erythropoietin deficiency and uremic toxins 2
• Cancer: Multiple mechanisms including bleeding, bone marrow infiltration, and inflammation 2
• Inflammatory bowel disease: Due to blood loss, malabsorption, and inflammation 3
• Rheumatologic disorders: Inflammatory cytokines inhibit erythropoiesis

Nutritional Deficiencies

• Iron deficiency: Most common nutritional cause
• Vitamin B12 deficiency: Due to pernicious anemia, malabsorption, or dietary insufficiency
• Folate deficiency: Poor diet or increased requirements (pregnancy)
• Mixed deficiencies: Often seen in malnourished patients

Medication-Induced Anemia

• Myelosuppressive drugs: Chemotherapy, certain antibiotics
• Hemolysis-inducing drugs: Oxidant drugs in G6PD deficiency
• Drugs affecting folate metabolism: Methotrexate, trimethoprim

Diagnostic Approach

1. Complete Blood Count (CBC): Assess hemoglobin, MCV, RBC count
2. Reticulocyte count/index: Determine if anemia is due to decreased production or increased loss
3. Iron studies: Ferritin, transferrin saturation, serum iron, TIBC
   • Iron deficiency: Low ferritin (<30 ng/mL), low transferrin saturation (<15%) 2
   • Anemia of chronic disease: Normal/high ferritin, low transferrin saturation
4. B12 and folate levels: For macrocytic anemias
5. Hemolysis evaluation: If suspected - haptoglobin, indirect bilirubin, LDH, Coombs test
6. Kidney function tests: For suspected renal causes
7. Bone marrow examination: When bone marrow disorders are suspected

Special Considerations

• Pregnancy: Increased iron requirements (approximately 1000 mg during pregnancy)
• Elderly: Often have multiple contributing factors
• Children: Rapid growth increases iron requirements
• Chronic diseases: May have complex, multifactorial anemia

Common Pitfalls

• Accepting a dietary cause without investigating blood loss in iron deficiency
• Misinterpreting ferritin levels in the presence of inflammation (may be falsely normal/elevated)
• Failing to consider mixed causes of anemia
• Not investigating anemia in patients with chronic diseases
• Overlooking medication effects on red blood cell production or survival

By systematically evaluating anemia based on MCV and reticulocyte index, clinicians can efficiently identify the underlying cause and initiate appropriate treatment to address the specific mechanism of anemia.