What are the different types of anemia and their respective causes and treatments?

Types of Anemia: Classification, Causes, and Treatment

Primary Classification Systems

Anemia is most effectively classified using two complementary approaches: morphologic (based on mean corpuscular volume) and kinetic (based on reticulocyte response), with both systems essential for comprehensive evaluation. 1

Morphologic Classification by MCV

The initial classification uses mean corpuscular volume from the complete blood count:

Microcytic Anemia (MCV < 80 fL)

• Iron deficiency anemia is the most common cause globally and the primary etiology of microcytic anemia 1, 2
• Thalassemia presents with microcytosis, diagnosed through hemoglobin electrophoresis 1
• Anemia of chronic disease can present as microcytic, though more commonly normocytic 1
• Sideroblastic anemia identified by sideroblasts on bone marrow biopsy 1
• Lead poisoning (rare cause) 1

Normocytic Anemia (MCV 80-100 fL)

• Acute hemorrhage with initially normal reticulocytes that may later elevate 1
• Hemolysis with elevated reticulocyte response 1
• Anemia of chronic inflammation associated with malignancy, infection, or chronic disease 1
• Renal insufficiency with inappropriately low endogenous erythropoietin levels (GFR < 60 mL/min/1.73 m²) 1
• Bone marrow failure including aplastic anemia, pure red cell aplasia, leukemias, and myelodysplastic syndrome 1
• Bone marrow infiltration by metastatic cancer (prostate, breast) 1

Macrocytic Anemia (MCV > 100 fL)

• Vitamin B12 deficiency from pernicious anemia, H. pylori gastritis, antacid use, or vegan diet 1
• Folate deficiency from increased requirements (pregnancy, hemolysis, chronic myeloid leukemia) or dietary insufficiency 1
• Myelodysplastic syndrome requiring bone marrow evaluation 1, 3
• Medication-induced: hydroxyurea, methotrexate, azathioprine, anticonvulsants 1, 3
• Hypothyroidism 1
• Alcoholism (may cause isolated macrocytosis without anemia) 1

Kinetic Classification by Reticulocyte Index

The reticulocyte index (RI) distinguishes production versus destruction/loss mechanisms:

Low Reticulocyte Index (< 1.0-2.0)

Indicates decreased red blood cell production: 1

• Iron deficiency anemia 1
• Vitamin B12/folate deficiency 1
• Aplastic anemia 1
• Bone marrow dysfunction from cancer, radiation, or myelosuppressive chemotherapy 1
• Anemia of chronic disease/inflammation 1

High Reticulocyte Index (> 2.0)

Indicates normal or increased red blood cell production, suggesting compensatory response: 1

• Acute or chronic blood loss 1
• Hemolytic anemia (immune or non-immune) 1

Diagnostic Approach Algorithm

Initial Laboratory Evaluation

Begin with complete blood count including hemoglobin, MCV, white blood cell differential, platelet count, and absolute reticulocyte count. 4, 2

Essential Follow-up Tests Based on MCV

For Microcytic Anemia:

• Serum ferritin (most specific test for iron deficiency; < 30 ng/mL diagnostic in absence of inflammation) 1, 4
• Transferrin saturation (< 15% supports iron deficiency) 1, 2
• Total iron binding capacity 1
• Critical caveat: Ferritin is an acute phase reactant and can be falsely elevated by inflammation, chronic disease, malignancy, or liver disease 1, 2
• In inflammatory bowel disease patients, ferritin up to 100 μg/L may still indicate iron deficiency when inflammation is present 1

For Normocytic Anemia:

• Reticulocyte count to differentiate production versus destruction 1, 2
• If low reticulocyte count: evaluate for renal insufficiency (creatinine, GFR), bone marrow disorders 1
• If high reticulocyte count: evaluate for hemorrhage (stool guaiac, endoscopy) or hemolysis 1
• Hemolysis workup: Coombs test, haptoglobin (low), indirect bilirubin (elevated), LDH 1

For Macrocytic Anemia:

• Vitamin B12 and folate levels 1, 3, 4
• Methylmalonic acid (greater sensitivity than serum B12 alone when B12 deficiency suspected but levels equivocal) 3
• Thyroid stimulating hormone 3
• Liver function tests 3
• Peripheral blood smear for megaloblastic changes (macro-ovalocytes, hypersegmented neutrophils) 3
• Medication history for causative drugs 3
• Bone marrow aspiration and biopsy when initial workup unrevealing or additional cytopenias present 3, 2

Red Flag Indicators Requiring Urgent Evaluation

• Abnormalities in two or more cell lines (warrants hematology consultation) 4, 2
• Severe anemia without obvious cause 4
• Suspected hemolysis 4
• Unexplained anemia after extended workup 4

Treatment Principles by Anemia Type

Iron Deficiency Anemia

Identify and treat the underlying cause, especially gastrointestinal blood loss in adult men and postmenopausal women. 4, 2

• Oral iron supplementation: 100-200 mg elemental iron daily (first-line for mild-moderate anemia), though 3-6 months often required to normalize hemoglobin and replenish stores 5
• Lower dose if side effects occur 5
• Intravenous iron: reserved for oral treatment failure, intolerance, intestinal malabsorption, or prolonged inflammation 1, 5
• IV iron has superior efficacy compared to oral iron 1

Vitamin B12/Folate Deficiency

• Vitamin supplementation for confirmed deficiencies 3, 4
• Treat underlying cause (pernicious anemia, malabsorption, dietary insufficiency) 1

Anemia of Chronic Disease/Inflammation

Treat the underlying inflammatory condition as primary therapy. 2

• Hepcidin upregulation from inflammatory cytokines reduces iron export from macrophages, creating functional iron deficiency 1
• Inflammatory cytokines also reduce erythropoietin production and inhibit erythropoiesis 1
• Erythropoietin therapy may be considered in specific situations such as chronic kidney disease 2

Chronic Kidney Disease-Associated Anemia

Use the lowest erythropoiesis-stimulating agent (ESA) dose sufficient to reduce red blood cell transfusion need; targeting hemoglobin > 11 g/dL increases mortality, cardiovascular events, and stroke risk. 6

• Correct nutritional deficiencies (iron, B12, folate) before initiating ESA therapy 1, 4
• Specialized interstitial cells in kidney cortex produce erythropoietin in response to tissue hypoxia 1
• ESA dosing for CKD: initial 50-100 Units/kg three times weekly (adults), individualize maintenance dose 6
• Intravenous route recommended for hemodialysis patients 6

Cancer and Chemotherapy-Induced Anemia

ESAs are indicated only for anemia from myelosuppressive chemotherapy in patients not receiving curative-intent treatment; they increase mortality and tumor progression risk. 1, 6

• ESAs shortened overall survival and/or increased tumor progression in breast, non-small cell lung, head and neck, lymphoid, and cervical cancers 6
• Consider ESA therapy when hemoglobin ≤ 10 g/dL to prevent red blood cell transfusions 1
• Discontinue ESAs following completion of chemotherapy course 1
• ESA dosing: 40,000 Units weekly or 150 Units/kg three times weekly (adults); 600 Units/kg IV weekly (pediatric ≥ 5 years) 6

Transfusion Thresholds

Transfusion decisions should not be based solely on hemoglobin thresholds but on individual patient characteristics, symptom severity, and comorbidities. 1

• Asymptomatic without comorbidities: observation with periodic reevaluation 1
• Asymptomatic with comorbidities: consider transfusion 1
• Symptomatic patients: transfuse 1
• Restrictive strategy (hemoglobin 7-9 g/dL) for hemodynamically stable chronic anemia without acute coronary syndrome 1
• Symptomatic anemia (hemoglobin < 10 g/dL): transfusion goal 8-10 g/dL to prevent symptoms 1
• Acute coronary syndrome/myocardial infarction: transfusion goal 10 g/dL 1
• Restrictive transfusion strategy (hemoglobin < 6-8 g/dL) associated with better outcomes than liberal strategy 7

Hemolytic Anemia

• Coombs test positive for immune-mediated hemolysis 1
• Consider in chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and autoimmune disease history 1
• Treat underlying cause (immune suppression, discontinue offending drugs) 1

Inherited Anemias

• Diagnosis based on personal and family history 1
• Hemoglobin electrophoresis for thalassemia and hemoglobinopathies 1
• Specialized hematology management required 4

Common Pitfalls and Caveats

• Do not empirically treat anemia of uncertain etiology with nutritional supplements without proper diagnostic workup 7
• Ferritin interpretation requires clinical context: chronic inflammation, malignancy, and liver disease falsely elevate levels despite true iron deficiency 1, 2
• Acute blood loss may initially present with normocytic anemia and normal reticulocyte count before compensatory erythropoiesis begins 1
• Combination deficiencies (iron plus B12/folate) can present as normocytic anemia, masking individual deficiencies 1
• ESA therapy in cancer patients requires informed consent under REMS guidelines due to increased mortality and tumor progression risks 1, 6
• Evaluate iron status before and during ESA treatment; functional iron deficiency (ferritin < 800 ng/mL and transferrin saturation < 20%) may develop during therapy 1