What is the pathophysiology of anemia?

Pathophysiology of Anemia

Anemia is fundamentally caused by three major pathophysiologic mechanisms: decreased production of functional red blood cells, increased destruction of red blood cells, or blood loss, all leading to reduced oxygen-carrying capacity of the blood. 1

Definition and Classification

• Anemia is defined as a reduction in hemoglobin concentration, red blood cell count, or packed cell volume below normal levels (typically <13.5 g/dL in men and <12.0 g/dL in women) 2
• Severity is classified as mild (Hb 10-11.9 g/dL), moderate (Hb 8.0-9.9 g/dL), or severe (Hb <8.0 g/dL) 3

Major Pathophysiologic Mechanisms

1. Decreased Production of Red Blood Cells

• Erythropoietin Deficiency: Specialized interstitial cells in the kidney cortex sense tissue hypoxia and produce erythropoietin in response; kidney disease impairs this production 3
• Iron Deficiency: Iron is essential for hemoglobin synthesis; deficiency leads to microcytic anemia and is the most common nutritional cause of anemia worldwide 1
• Vitamin Deficiencies: B12 and folate deficiencies impair DNA synthesis in rapidly dividing erythroblasts, leading to ineffective erythropoiesis and macrocytic anemia 3, 1
• Bone Marrow Disorders: Direct infiltration by cancer cells, myelodysplastic syndromes, or radiation/chemotherapy-induced myelosuppression can reduce red blood cell production 1, 2
• Inflammation-Mediated: Inflammatory cytokines (TNF-α, IL-6) cause:
  • Inadequate erythropoietin production despite anemia
  • Suppressed erythropoietic response of red cell precursors
  • Increased hepcidin synthesis, leading to iron sequestration and reduced iron availability for erythropoiesis 3

2. Increased Destruction of Red Blood Cells

• Hemolysis: Premature destruction of red blood cells can be:
  • Immune-mediated (autoimmune hemolytic anemia)
  • Drug-induced
  • Due to mechanical factors (damaged heart valves)
  • Result of intrinsic red cell defects (hemoglobinopathies, enzyme deficiencies) 2
• Methemoglobinemia: Oxidation of ferro-iron (Fe²⁺) to ferri-iron (Fe³⁺) in hemoglobin creates methemoglobin, which cannot transport oxygen effectively, resulting in "functional anemia" 3

3. Blood Loss

• Acute Hemorrhage: Rapid blood loss from trauma or internal bleeding 1
• Chronic Blood Loss: Slow, persistent bleeding from gastrointestinal tract, heavy menstrual bleeding, or tumor sites 3, 1

Complex Pathophysiology in Specific Conditions

Anemia in Chronic Heart Failure

• Multifactorial etiology with prevalence ranging from 6-70% of heart failure patients 3
• Contributing factors include:
  • Iron deficiency (50-70% of cases)
  • Hemodilution due to expanded plasma volume
  • Inflammatory cytokine production (TNF-α, IL-6)
  • Renal dysfunction with reduced erythropoietin production
  • Medication effects (ACE inhibitors, anticoagulants)
  • Hepcidin-mediated iron sequestration 3
• Associated with worse outcomes: increased all-cause mortality (RR 1.47), hospitalization (RR 1.28), and heart failure hospitalization (RR 1.43) 3

Anemia in Chronic Kidney Disease

• Nearly universal in advanced CKD (stage 5) 1
• Primarily caused by decreased erythropoietin production from damaged kidney cells 3
• Additional factors include:
  • Iron deficiency (absolute or functional)
  • Shortened red cell survival
  • Uremic toxins suppressing erythropoiesis
  • Chronic inflammation 3, 1

Anemia in Cancer

• Multiple simultaneous mechanisms often contribute:
  • Direct bone marrow infiltration by malignant cells
  • Cytokine-mediated inflammation
  • Chemotherapy or radiation-induced myelosuppression
  • Nutritional deficiencies
  • Chronic blood loss from tumor sites 3, 1

Physiologic Consequences of Anemia

• Decreased oxygen-carrying capacity leads to tissue hypoxia 4
• Compensatory mechanisms include:
  • Increased cardiac output
  • Redistribution of blood flow to vital organs
  • Increased oxygen extraction
  • Rightward shift of the oxygen-hemoglobin dissociation curve 4
• When anemia develops gradually, these compensatory mechanisms allow adaptation to lower hemoglobin levels 4, 5
• In acute anemia or in patients with limited cardiopulmonary reserve, these mechanisms may be insufficient, leading to symptoms 4

Diagnostic Approach

• Complete blood count with reticulocyte count to assess bone marrow response 1, 2
• Peripheral blood smear examination for morphological clues 2
• Iron studies (serum iron, ferritin, total iron binding capacity, transferrin saturation) 1, 2
• Kidney function tests (GFR, creatinine) when renal cause is suspected 1
• Vitamin B12 and folate levels 1, 2
• Special tests as indicated (Coombs test for hemolysis, bone marrow examination) 3, 2

Clinical Implications

• Multiple mechanisms often contribute simultaneously to anemia, especially in complex medical conditions 1
• Ferritin may be falsely elevated despite true iron deficiency in chronic inflammatory states 1
• Normal hemoglobin values vary by sex, race, smoking status, and altitude 1
• The combination of anemia, chronic kidney disease, and heart failure (cardio-renal anemia syndrome) has particularly poor outcomes 3

Understanding the pathophysiologic mechanisms of anemia is essential for appropriate diagnosis and treatment, as addressing the underlying cause is the cornerstone of management.