What are the causes of very low hemoglobin (Hb) and hematocrit (Hct) levels?

Causes of Very Low Hemoglobin and Hematocrit Levels

Very low hemoglobin (Hb) and hematocrit (Hct) levels are primarily caused by decreased production of red blood cells, increased destruction of red blood cells, or blood loss, with specific etiologies requiring systematic evaluation to determine appropriate treatment. 1

Major Pathophysiologic Categories

1. Decreased Production of Red Blood Cells

• Chronic Kidney Disease: Progressive decline in kidney function leads to reduced erythropoietin production, with anemia becoming nearly universal in CKD stage 5 1
• Nutritional Deficiencies:
  • Iron deficiency (most common nutritional cause) 1
  • Vitamin B12 deficiency 1
  • Folate deficiency 1
• Bone Marrow Disorders:
  • Aplastic anemia (failure of bone marrow to produce blood cells) 2
  • Myelodysplastic syndromes 1
  • Bone marrow infiltration by cancer cells 1
• Anemia of Chronic Disease/Inflammation: Cytokine-mediated iron sequestration decreasing RBC production 1
• Myelosuppression:
  • Chemotherapy-induced 1
  • Radiation-induced 1

2. Increased Destruction of Red Blood Cells (Hemolysis)

• Immune-Mediated Hemolysis:
  • Autoimmune hemolytic anemia (direct antiglobulin test positive) 3
  • Drug-induced immune hemolysis 3
• Non-Immune Hemolysis:
  • Microangiopathic hemolytic anemias (TTP, HUS, DIC) 3
  • Mechanical trauma to RBCs (artificial heart valves, severe burns) 3
  • Hereditary RBC disorders:
    • Membrane defects (hereditary spherocytosis) 3
    • Enzyme deficiencies (G6PD deficiency) 3
    • Hemoglobinopathies (sickle cell disease, thalassemias) 3
  • Infections causing direct RBC destruction 3
  • Oxidative damage to RBCs 3

3. Blood Loss

• Acute Hemorrhage:
  • Trauma 2
  • Gastrointestinal bleeding 1
  • Surgical blood loss 4
  • Obstetric hemorrhage 2
• Chronic Blood Loss:
  • Gastrointestinal bleeding (ulcers, malignancies, inflammatory bowel disease) 1
  • Heavy menstrual bleeding 1
  • Chronic hemorrhage at tumor sites 1

Diagnostic Approach for Very Low Hb/Hct

Initial Laboratory Evaluation

• Complete blood count with peripheral smear examination 1
• Reticulocyte count to assess bone marrow response 1
• Iron studies (serum iron, ferritin, total iron binding capacity, transferrin saturation) 1
• Hemolysis markers (lactate dehydrogenase, haptoglobin, unconjugated bilirubin) 3
• Kidney function tests (GFR, creatinine) 1
• Direct antiglobulin test (Coombs test) for immune-mediated hemolysis 3
• Vitamin B12 and folate levels 1

Important Clinical Considerations

• Anemia in CKD correlates with declining GFR; becomes more prevalent at GFR <60 mL/min/1.73m² 1
• Hemolysis should be suspected with jaundice, hepatosplenomegaly, and reticulocytosis 3, 2
• Normal Hb/Hct values vary by:
  • Sex (lower threshold for anemia: <13.5 g/dL in men, <12.0 g/dL in women) 1
  • Altitude (Hb increases ~0.6 g/dL in women and ~0.9 g/dL in men per 1000m above sea level) 1
  • Race (potentially lower normal values in Black individuals) 1
  • Smoking status (higher normal values in smokers) 1

Special Considerations

Cancer-Related Anemia

• Multiple mechanisms often contribute simultaneously 1:
  • Direct bone marrow infiltration by cancer cells
  • Cytokine-mediated iron sequestration
  • Chronic blood loss from tumor sites
  • Nutritional deficiencies
  • Chemotherapy-induced myelosuppression 1

Pitfalls in Diagnosis

• Relying solely on Hb/Hct without additional iron studies may miss early iron depletion 5
• Hb and Hct are late indicators of iron deficiency, decreasing only when severe iron depletion is present 5
• The commonly assumed Hct/Hb ratio of 3:1 is not always accurate and varies with age 6
• In chronic inflammatory states, ferritin may be falsely elevated despite true iron deficiency 1
• Anemia may have multiple concurrent causes, especially in patients with complex medical conditions 1