What is the classification, diagnosis, clinical features, and management of anemia?

Anemia: Classification, Diagnosis, Clinical Features, and Management

Definition and Diagnostic Criteria

Anemia is defined as hemoglobin <13.0 g/dL in men and <12.0 g/dL in women, and the initial diagnostic approach must simultaneously classify by morphology (MCV) and bone marrow response (reticulocyte count) to guide targeted treatment. 1, 2

Classification System

Morphologic Classification (Based on MCV)

Microcytic Anemia (MCV <80 fL):

• Iron deficiency anemia (most common globally) 1, 2
• Thalassemia and hemoglobinopathies 1, 2
• Anemia of chronic disease 1, 2
• Sideroblastic anemia 1, 2
• Lead poisoning (rare) 1

Normocytic Anemia (MCV 80-100 fL):

• Acute hemorrhage 1, 2
• Anemia of chronic inflammation 1, 2
• Chronic kidney disease 1, 2
• Hemolysis 1, 2
• Bone marrow failure/aplastic anemia 1
• Primary bone marrow diseases (leukemias, myelodysplastic syndrome) 1

Macrocytic Anemia (MCV >100 fL):

• Vitamin B12 deficiency 1, 2
• Folate deficiency 1, 2
• Myelodysplastic syndrome 1, 2
• Hypothyroidism 1, 2
• Medication-induced (e.g., azathioprine) 1, 2
• Alcoholism 2

Kinetic Classification (Based on Reticulocyte Response)

Low/Normal Reticulocytes (Hypoproliferative):

• Indicates impaired red blood cell production 1
• Includes iron deficiency, nutritional deficiencies, chronic disease, renal failure, bone marrow disorders 1

Elevated Reticulocytes (Hyperproliferative):

• Indicates appropriate bone marrow response to anemia 1
• Suggests hemolysis or acute blood loss 1
• Excludes all deficiency states 1

Diagnostic Workup

Essential Initial Laboratory Tests

Complete Blood Count with Indices:

• Hemoglobin and hematocrit confirm severity 3, 4
• MCV provides morphologic classification 1, 4
• Red cell distribution width (RDW) >15% suggests iron deficiency or mixed deficiencies 4
• Red blood cell count helps distinguish thalassemia (elevated) from iron deficiency (decreased) 4

Reticulocyte Count:

• Assesses bone marrow response to anemia 1, 3
• Distinguishes hypoproliferative from hyperproliferative anemia 1

Iron Studies (Essential for All Anemia Evaluations):

• Serum ferritin is the most powerful single test for iron deficiency 4
  • <30 μg/L confirms iron deficiency without inflammation 1, 3, 2
  • <100 μg/L may indicate iron deficiency with inflammation present 1
• Transferrin saturation <16-20% suggests iron deficiency 3, 4
• Total iron-binding capacity and serum iron interpreted alongside ferritin 3, 4

Inflammatory Markers:

• C-reactive protein (CRP) assesses inflammation affecting iron study interpretation 3, 4
• Elevated CRP raises ferritin threshold for diagnosing iron deficiency 1

Additional Testing Based on Initial Classification

For Microcytic Anemia:

• Hemoglobin electrophoresis to exclude thalassemia and hemoglobinopathies, especially in appropriate ethnic backgrounds 1, 4
• Stool guaiac test for occult gastrointestinal bleeding 3
• In men and postmenopausal women with iron deficiency, gastrointestinal evaluation with upper endoscopy and colonoscopy is mandatory to rule out malignancy 4

For Normocytic Anemia:

• Serum creatinine/eGFR to evaluate chronic kidney disease 3, 4
• Vitamin B12 and folate levels to exclude deficiencies that may mask microcytosis 3, 4
• Thyroid function tests to rule out hypothyroidism 3, 4
• Hemolysis workup if reticulocytes elevated: Coombs test, haptoglobin, indirect bilirubin, LDH 1

For Macrocytic Anemia:

• Vitamin B12 level <150 pmol/L indicates deficiency; if equivocal, methylmalonic acid >271 nmol/L confirms B12 deficiency 1, 2
• Folate level: serum folate <10 nmol/L or RBC folate <305 nmol/L indicates deficiency 1
• Thyroid function tests 1
• Consider bone marrow biopsy for suspected myelodysplastic syndrome 1

For Chronic Kidney Disease Patients:

• Serum bicarbonate to evaluate metabolic acidosis 3, 4
• Calcium, phosphorus, and intact parathyroid hormone 3, 4
• Hemoglobin monitoring every 3 months if GFR <30 mL/min/1.73 m² 3, 4

Critical Diagnostic Pitfalls to Avoid

• Never assume normocytic anemia excludes iron deficiency—early iron deficiency presents with normal MCV but elevated RDW 4
• Don't overlook mixed deficiencies—concurrent B12/folate and iron deficiency can result in normocytic indices despite significant abnormalities 4
• In inflammatory states, ferritin up to 100 μg/L may still represent iron deficiency 1
• Always evaluate for chronic kidney disease in normocytic anemia, as CKD-related anemia becomes more prevalent as GFR declines 4

Clinical Features

Acute Anemia Presentation

• Symptoms more pronounced due to rapid onset 1
• Tachycardia, hypotension, orthostatic changes 1
• Dyspnea, chest pain, altered mental status 1
• Requires immediate assessment for hemodynamic stability 1

Chronic Anemia Presentation

• Often well-tolerated due to physiologic compensation 1
• Progressive fatigue, weakness 1
• Exertional dyspnea 1
• Lightheadedness 1
• Worsening of preexisting cardiovascular, pulmonary, or cerebrovascular disease 1

Compensatory Mechanisms

• Heightened cardiac output 1
• Increased coronary flow 1
• Altered blood viscosity 1
• Changes in oxygen consumption and extraction 1

Management

Iron Deficiency Anemia

Oral Iron Supplementation:

• First-line treatment for mild-moderate iron deficiency anemia 2
• A hemoglobin rise ≥10 g/L within 2 weeks strongly confirms iron deficiency 3

Intravenous Iron:

• Consider when oral iron fails, intolerance occurs, or rapid repletion needed 1
• Particularly important in inflammatory bowel disease and chronic kidney disease 1

Vitamin B12/Folate Deficiency

• Supplementation with appropriate vitamin 2
• Address underlying cause (pernicious anemia, malabsorption, dietary insufficiency) 2
• Folate deficiency: serum folate <10 nmol/L requires replacement 1
• B12 deficiency: parenteral B12 if malabsorption present 1

Anemia of Chronic Disease/Inflammation

• Primary therapy targets the underlying inflammatory condition 2
• Functional iron deficiency may require intravenous iron despite normal/elevated ferritin 1
• Erythropoiesis-stimulating agents (ESAs) considered in specific contexts (CKD, cancer chemotherapy) with caution due to thrombotic and mortality risks 5

Chronic Kidney Disease-Related Anemia

• Evaluate and correct iron deficiency first 1
• ESAs may be considered when hemoglobin remains low despite iron repletion 1, 5
• ESAs carry black box warnings for increased risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor progression 5
• Target hemoglobin should not exceed levels that increase cardiovascular risk 1

Red Blood Cell Transfusion

Transfusion Decision-Making:

• Transfusion decisions must not be based solely on hemoglobin thresholds but on individual patient characteristics, symptom severity, comorbidities, and clinical judgment 1, 2

Three Clinical Categories:

1. Asymptomatic without significant comorbidities: Observation and periodic reevaluation 1
2. Asymptomatic with comorbidities or high risk: Consider transfusion 1
3. Symptomatic: Transfusion indicated 1

Transfusion Strategy:

• Restrictive strategy (hemoglobin 7-9 g/dL) preferred for hemodynamically stable patients without acute coronary syndrome 2
• One unit of packed red blood cells increases hemoglobin by approximately 1 g/dL 1
• Provides rapid correction—the only intervention for patients requiring immediate hemoglobin increase 1

Special Considerations:

• Preexisting cardiovascular, pulmonary, or cerebrovascular disease compromises tolerance to anemia 1
• Progressive decline in hemoglobin after anticancer treatment may warrant transfusion even without symptoms 1

Anemia in Cancer Patients

• Evaluate for iron deficiency, vitamin deficiencies, hemorrhage, hemolysis, kidney disease before attributing to cancer or chemotherapy 1
• Treat reversible causes first 1
• ESAs carry significant risks in cancer patients and require careful risk-benefit assessment 5

Monitoring

• Hemoglobin monitoring preferred over hematocrit due to greater accuracy and less variability 4
• CKD patients with GFR <30 mL/min/1.73 m² require hemoglobin monitoring at least every 3 months 3, 4
• Reassess iron studies during treatment to detect functional iron deficiency 1