What causes low hemoglobin (Hb) and hematocrit (Hct) levels?

Causes of Low Hemoglobin and Hematocrit

Low hemoglobin (Hb) and hematocrit (Hct) levels are primarily caused by decreased red blood cell production, increased red blood cell destruction, or blood loss, with chronic kidney disease, iron deficiency, and chronic inflammation being the most common etiologies. 1

Classification by Mechanism

1. Decreased Production of Red Blood Cells

• Chronic Kidney Disease (CKD)

  • Decreased erythropoietin production occurs as kidney function declines
  • Anemia develops early in CKD and becomes nearly universal in stage 5 2
  • Severity correlates with degree of GFR loss (noticeable decline in Hb when GFR <60 mL/min/1.73m² in men and <45 mL/min/1.73m² in women) 2

• Nutritional Deficiencies

  • Iron deficiency - most common cause worldwide 1
    • Laboratory findings: ferritin <30 μg/L, transferrin saturation <20%, increased TIBC 1
  • Vitamin B12 deficiency - causes megaloblastic anemia (MCV >100 fL) 1
  • Folate deficiency - also causes megaloblastic anemia 1

• Bone Marrow Disorders

  • Aplastic anemia - failure of bone marrow to produce blood cells
  • Myelodysplastic syndrome (MDS) - ineffective hematopoiesis
  • Leukemia and other malignancies infiltrating bone marrow 2
  • Myelofibrosis - replacement of bone marrow with fibrous tissue

2. Increased Destruction of Red Blood Cells (Hemolysis)

• Autoimmune hemolytic anemia

  • Positive Coombs test, elevated LDH, low haptoglobin 1
  • Common in chronic lymphocytic leukemia and non-Hodgkin's lymphoma 2

• Mechanical hemolysis

  • Prosthetic heart valves
  • Microangiopathic conditions (TTP, HUS, DIC)

• Hereditary disorders

  • Thalassemias - reduced or absent synthesis of alpha or beta globin chains 3
  • Sickle cell disease - abnormal hemoglobin structure
  • Glucose-6-phosphate dehydrogenase deficiency

3. Blood Loss

• Acute hemorrhage

  • Trauma, surgery, gastrointestinal bleeding
  • Initially normocytic with elevated reticulocyte count as compensation 1

• Chronic blood loss

  • Gastrointestinal bleeding (ulcers, malignancy, inflammatory bowel disease)
  • Heavy menstrual bleeding in women 1
  • Leads to iron deficiency anemia over time

4. Anemia of Chronic Disease/Inflammation

• Second most common type after iron deficiency 4
• Associated with:
  • Chronic inflammatory conditions (rheumatoid arthritis, IBD)
  • Autoimmune diseases
  • Cancer
  • Infections
• Mediated by hepcidin and inflammatory cytokines 4
• Laboratory findings: low iron, low transferrin, normal/elevated ferritin 4

Classification by Red Blood Cell Size (MCV)

Microcytic Anemia (MCV <80 fL)

• Iron deficiency anemia
• Thalassemia
• Anemia of chronic disease (can be microcytic or normocytic)
• Sideroblastic anemia 1

Normocytic Anemia (MCV 80-100 fL)

• Acute blood loss
• Hemolysis
• Anemia of chronic disease/inflammation
• Renal insufficiency
• Bone marrow failure 1

Macrocytic Anemia (MCV >100 fL)

• Vitamin B12 deficiency
• Folate deficiency
• Alcoholism
• Myelodysplastic syndrome
• Medication-induced (chemotherapy, antiretrovirals) 1

Special Considerations

Age-Related Factors

• Anemia prevalence increases with age but is not a normal consequence of aging 2
• In older individuals, anemia is associated with:
  • Increased mortality risk
  • Loss of independent functioning
  • Physical decline
  • Falls and fractures
  • Cognitive decline
  • Cardiovascular events 5

Altitude Considerations

• Hemoglobin levels increase with altitude
• For every 1,000m above sea level, Hb increases by approximately:
  • 0.6 g/dL in women
  • 0.9 g/dL in men 2

Diagnostic Approach

1. Complete blood count with indices

   • Assess Hb, Hct, MCV, MCH, MCHC, RBC count
   • Calculate reticulocyte index to determine if bone marrow is responding appropriately 1

2. Iron studies

   • Serum ferritin (<45 μg/L suggests iron deficiency)
   • Transferrin saturation (<20% suggests iron deficiency)
   • Total iron binding capacity (TIBC) 1

3. Additional testing based on clinical suspicion

   • Vitamin B12 and folate levels
   • Kidney function tests (BUN, creatinine, eGFR)
   • Hemolysis workup (haptoglobin, LDH, indirect bilirubin)
   • Inflammatory markers (CRP)
   • Bone marrow examination when indicated 2, 1

Clinical Pearls and Pitfalls

• Pitfall: Relying solely on hemoglobin and hematocrit without assessing iron status can miss early iron depletion 6
• Pitfall: Recent blood transfusions can falsely elevate reticulocyte counts 1
• Pitfall: Ferritin is an acute phase reactant and may be falsely elevated in inflammatory states despite iron deficiency 1
• Pearl: In CKD patients, anemia evaluation should be initiated when Hb <13.5 g/dL in adult males and <12.0 g/dL in adult females 2
• Pearl: The severity of anemia in chronic diseases often correlates with the severity of the underlying condition 4

By understanding these mechanisms and following a systematic diagnostic approach, clinicians can identify and address the specific cause of low hemoglobin and hematocrit, leading to more effective treatment and improved patient outcomes.