What are the causes and treatments of anemia?

Anemia Causes and Treatment

Primary Causes of Anemia

Anemia results from three fundamental mechanisms: decreased red blood cell production, increased red blood cell destruction, or blood loss, with specific etiologies varying by patient population and clinical context.

Decreased Red Blood Cell Production

• Insufficient erythropoietin production is the primary cause in chronic kidney disease patients, where diseased kidneys fail to produce adequate amounts of this hormone 1

• Iron deficiency represents the most common cause of microcytic anemia globally, affecting approximately 2 billion people worldwide and 14% of US adults 2

  • In men and postmenopausal women, gastrointestinal blood loss is the predominant cause 1
  • In premenopausal women, menstrual blood loss accounts for most cases 1
  • Malabsorption from celiac disease, atrophic gastritis, or bariatric surgery contributes significantly 2, 3

• Vitamin deficiencies cause macrocytic anemias 4, 5

  • Vitamin B12 deficiency
  • Folate deficiency

• Bone marrow disorders including bone marrow infiltration by cancer, myelodysplastic syndromes, and aplastic anemia 1, 4

• Anemia of chronic disease/inflammation occurs in chronic kidney disease (24-85% prevalence), heart failure (37-61%), inflammatory bowel disease (13-90%), and cancer (18-82%) 2

Blood Loss

• Gastrointestinal bleeding is found in 60-70% of patients with iron deficiency anemia referred for endoscopy 5

  • Occult bleeding from gastric or colonic malignancy must be excluded 1
  • NSAID use, peptic ulcer disease, and inflammatory bowel disease 2, 3

• Menstrual blood loss causes iron deficiency in approximately 38% of nonpregnant reproductive-age women (nonanemic) and 13% with anemia 2

Increased Red Blood Cell Destruction

• Hemolytic anemias including autoimmune hemolytic anemia and drug-induced hemolysis 1, 4

Additional Contributing Factors in Specific Populations

• Chronic kidney disease patients experience multiple factors: shortened RBC survival, severe hyperparathyroidism, aluminum toxicity, hypothyroidism, and hemoglobinopathies 1

• Cancer patients develop anemia from myelosuppressive chemotherapy, cancer-related inflammation, and bone marrow infiltration 1, 4

• Pregnancy causes iron deficiency in up to 84% of women during the third trimester 2

Diagnostic Approach

Initial evaluation must include complete blood count with reticulocyte count, peripheral blood smear, iron studies (ferritin, transferrin saturation), and vitamin B12/folate levels 1, 4

Iron Deficiency Diagnosis

• Serum ferritin <30 ng/mL is diagnostic in patients without inflammatory conditions 2

  • Ferritin <12 μg/dL is definitively diagnostic of iron deficiency 1
  • In inflammatory states, ferritin may be falsely elevated; use transferrin saturation <20% as alternative 2, 6

• Microcytosis (low MCV) is characteristic but may be absent with combined deficiencies 1

Reticulocyte Index Interpretation

• Low reticulocyte index (normal 1.0-2.0) indicates decreased RBC production, suggesting iron deficiency, vitamin deficiencies, aplastic anemia, or bone marrow dysfunction 1

• High reticulocyte index indicates blood loss or hemolysis 1

Mandatory Gastrointestinal Evaluation

All men and postmenopausal women with iron deficiency anemia require bidirectional endoscopy (upper endoscopy with small bowel biopsy AND colonoscopy or barium enema) to exclude gastrointestinal malignancy 1

• Premenopausal women <40 years may not require bidirectional endoscopy initially 3

• Small intestine investigation (capsule endoscopy, CT/MRI enterography) is indicated only with red flags: involuntary weight loss, abdominal pain, elevated CRP, or transfusion-dependent anemia 1, 3

Treatment Strategies

Iron Deficiency Anemia Treatment

Oral iron supplementation with ferrous sulfate 325 mg daily or on alternate days is first-line therapy for most patients 2

• Alternative dosing: 100-200 mg elemental iron daily, with lower doses if side effects occur 3

• Treatment duration: 3-6 months typically required to normalize hemoglobin and replenish iron stores 3

Intravenous iron is indicated for:

• Oral iron intolerance or side effects 2, 3
• Impaired absorption (celiac disease, post-bariatric surgery, atrophic gastritis) 2, 3
• Chronic inflammatory conditions (CKD, heart failure, IBD, cancer) 2, 6
• Ongoing blood loss 2
• Second and third trimesters of pregnancy 2
• Rapid iron replenishment needed 6

Critical caveat: High-dose intravenous iron carries risks of allergic reactions, hypophosphatemia/osteomalacia, iron overload, and vascular leakage—use with caution 6

Chronic Kidney Disease Anemia

Erythropoiesis-stimulating agents (ESAs) should be used at the lowest dose sufficient to reduce RBC transfusion need, never targeting hemoglobin >11 g/dL 1, 7

• Initial epoetin alfa dosing: 50-100 Units/kg three times weekly for adults; 50 Units/kg three times weekly for pediatric patients 7

• Intravenous route recommended for hemodialysis patients 7

• Critical warning: Targeting hemoglobin >11 g/dL increases risk of death, myocardial infarction, stroke, and thromboembolism 7

• Iron status must be evaluated and iron repletion maintained before and during ESA therapy 1, 7

Cancer-Related Anemia

ESAs are indicated ONLY for anemia from myelosuppressive chemotherapy when at least two additional months of chemotherapy are planned 7

• Adult dosing: 40,000 Units weekly or 150 Units/kg three times weekly 7

• Pediatric dosing (≥5 years): 600 Units/kg intravenously weekly 7

• ESAs are contraindicated when:

  • Anticipated outcome is cure 7
  • Receiving only hormonal agents, biologics, or radiotherapy without myelosuppressive chemotherapy 7
  • Anemia manageable by transfusion alone 7

• Black box warning: ESAs increase risk of tumor progression, recurrence, and shortened overall survival in breast, non-small cell lung, head and neck, lymphoid, and cervical cancers 7

Blood Transfusion Indications

Transfusion decisions must be based on clinical assessment, not hemoglobin thresholds alone 1

• Symptomatic patients should receive transfusion 1

• Asymptomatic patients with significant comorbidities (cardiovascular, pulmonary, cerebrovascular disease) should be considered for transfusion 1

• Asymptomatic patients without comorbidities warrant observation and periodic reevaluation 1

• Packed RBCs are the preferred blood product 1

Vitamin Deficiency Treatment

Oral vitamin B12 supplementation is as effective as intramuscular administration and is underutilized 5

• Folate supplementation for documented folate deficiency 1, 4

Surgery Patients

• Epoetin alfa 300 Units/kg daily for 15 days or 600 Units/kg weekly for elective, noncardiac, nonvascular surgery 7

• DVT prophylaxis is mandatory due to increased thrombosis risk 7

Critical Pitfalls to Avoid

• Never assume iron deficiency without confirming with ferritin or transferrin saturation—microcytosis alone is insufficient 1

• Never overlook gastrointestinal malignancy in men and postmenopausal women with iron deficiency anemia 1

• Never target hemoglobin >11 g/dL with ESAs in any population—this increases mortality and cardiovascular events 1, 7

• Never use ESAs in cancer patients when cure is anticipated or without concurrent myelosuppressive chemotherapy 7

• Never use benzyl alcohol-containing multiple-dose vials in neonates, infants, pregnant women, or lactating women 7

• Always evaluate and treat underlying causes before or concurrent with symptomatic anemia treatment 1, 4, 3