Definition
Hemoglobin concentration or red cell mass >2 standard deviations below age and sex mean.
Physiologic state defined by tissue hypoxia secondary to inadequate oxygen-carrying capacity.
Etiologic Classification
Nutritional Deficiency
Decreased dietary intake: Excessive cow milk (iron deficiency); vegan diet (vitamin B12 deficiency).
Increased demand: Rapid growth (iron); hemolysis (folic acid).
Decreased absorption: Intrinsic factor deficiency (B12); malabsorption syndromes (iron, folate).
Specific nutrient deficiencies: Iron, folate, vitamin B12, vitamin C, protein, vitamin B6, thyroxine.
Bone Marrow Failure
Single cell line failure:
Red cell precursors: Congenital red cell aplasia (Diamond-Blackfan anemia), acquired red cell aplasia (Transient erythroblastopenia of childhood [TEC]).
Megakaryocytes: Amegakaryocytic thrombocytopenic purpura, thrombocytopenia-absent radii (TAR).
White cell precursors: Congenital neutropenias.
Trilineage failure (Pancytopenia):
Congenital: Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome.
Acquired: Idiopathic, secondary to drugs, radiation, toxins, viral infections (parvovirus B19, HIV).
Bone Marrow Infiltration
Benign: Osteopetrosis, storage diseases.
Malignant: Primary (leukemia, myelofibrosis), secondary (neuroblastoma, lymphoma).
Dyshematopoietic Anemias
Anemia of chronic disease.
Renal failure, hepatic disease.
Disseminated malignancy, connective tissue diseases.
Sideroblastic anemias.
Blood Loss
Overt or occult hemorrhage.
Perinatal: Fetomaternal, intraplacental, retroplacental, twin-to-twin transfusion.
Gastrointestinal: Cow milk protein allergy, Meckel diverticulum, inflammatory bowel disease, polyps, parasites.
Menstrual: Heavy menstrual bleeding.
Hemolytic Anemia
Corpuscular (Intrinsic) Defects
Membrane defects: Hereditary spherocytosis, elliptocytosis, stomatocytosis, pyknocytosis.
Enzymatic defects: Pyruvate kinase deficiency, Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Hemoglobin defects: Thalassemia syndromes, sickle cell disease, unstable hemoglobins.
Immune: Alloimmunization (Rh, ABO), autoimmune (warm/cold antibodies), drug-induced.
Non-immune: Infection (malaria, sepsis, CMV), microangiopathic (HUS, TTP, DIC, Kasabach-Merritt syndrome), hypersplenism.
Diagnostic Investigations
Clinical Evaluation
History
Age of onset: Physiological anemia (2 months); Thalassemia major (9-12 months); Diamond-Blackfan anemia (newborn/infancy).
Dietary history: Formula, cow milk, weaning foods, pica.
Prematurity, perinatal blood loss, neonatal jaundice.
Family history: Inherited bone marrow failure, sickle cell disease, thalassemia, gallstones, splenectomy.
Medications, toxic exposures, chronic illnesses.
Physical Examination
General: Pallor, tachypnea, tachycardia, flow murmurs, heart failure signs.
Dysmorphic features: Radial limb abnormalities (bone marrow failure syndromes like TAR or Fanconi).
Organomegaly: Splenomegaly (hemolysis, storage disease), hepatomegaly, lymphadenopathy (malignancy, infection).
Skin: Petechiae, purpura, jaundice, leg ulcers.
Primary Laboratory Studies
Hemoglobin, hematocrit, erythrocyte count.
Red cell indices: Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW).
Reticulocyte count (absolute and relative).
Peripheral blood smear.
Leukocyte count, differential count, platelet count.
Algorithmic Approach Based on MCV
MCV Category Common Etiologies Microcytic (Low MCV)Iron deficiency, Thalassemia trait/major, Lead toxicity, Anemia of chronic disease, Sideroblastic anemia, Copper deficiency. Normocytic (Normal MCV)Acute blood loss, Infection, Renal failure, Liver disease, Malignancy, Aplastic anemia, Transient erythroblastopenia of childhood (TEC), Bone marrow infiltration, Hemolysis (RBC enzyme/membrane defects). Macrocytic (High MCV)Normal newborn, B12/Folate deficiency, Diamond-Blackfan anemia, Fanconi anemia, Liver disease, Hypothyroidism, Down syndrome, Increased erythropoiesis (reticulocytosis), Drugs.
Algorithmic Approach Based on Reticulocyte Count
Reticulocyte Index >3% (High): Indicates appropriate marrow response to destruction or loss. Causes include hemolysis, hemorrhage, splenic sequestration, recovery from nutritional deficiency.Reticulocyte Index <3% (Low/Normal): Indicates impaired red cell formation. Causes include nutritional deficiency (Iron, B12, Folate), aplastic anemia, pure red cell aplasia, parvovirus B19 infection, bone marrow infiltration.
Peripheral Blood Smear Findings
Morphologic Finding Associated Diagnostic Conditions Spherocytes Hereditary spherocytosis, immune hemolytic anemia, hypersplenism. Target Cells Thalassemia, Hemoglobin C/E disease, liver disease, postsplenectomy, severe iron deficiency. Schistocytes Hemolytic-uremic syndrome, TTP, DIC, Kasabach-Merritt syndrome. Sickled Cells Sickle cell anemias (SS, SC, Sβ Elliptocytes Hereditary elliptocytosis, iron deficiency, megaloblastic anemia. Dacrocytes (Teardrop) Myelodysplasia, leukemia, neuroblastoma, marrow infiltration. Howell-Jolly Bodies Asplenia, hyposplenia, severe iron deficiency. Heinz Bodies Normal newborn, thalassemia, asplenia, chronic liver disease, Heinz body hemolytic anemia.
Second-Tier Specific Investigations
Suspected Iron Deficiency
Serum iron, total iron-binding capacity (TIBC), transferrin saturation.
Serum ferritin (reflects body iron stores; <15 ng/mL diagnostic of iron deficiency).
Stool for occult blood, Meckel diverticulum scan, gastrointestinal endoscopy.
Suspected Megaloblastic Anemia
Serum vitamin B12, RBC and serum folate levels.
Serum methylmalonic acid, serum homocysteine levels.
Bone marrow aspiration (megaloblastic appearance, hypersegmented neutrophils).
Suspected Hemolytic Anemia
Evidence of Hemolysis: Unconjugated hyperbilirubinemia, low/absent serum haptoglobin, elevated lactate dehydrogenase (LDH), hemoglobinuria, hemosiderinuria, increased urinary urobilinogen.Immune Evaluation: Direct antiglobulin test (DAT/Coombs test) for IgG or complement C3.Membrane Defects: Osmotic fragility test, osmotic gradient ektacytometry, eosin-5-maleimide (EMA) binding test, flow cytometric analysis for PNH (CD55, CD59).Hemoglobin Defects: Hemoglobin electrophoresis, High-performance liquid chromatography (HPLC), quantitative HbF, heat-stability test, globin gene analysis.Enzyme Defects: Specific enzyme assays (G6PD, pyruvate kinase), Heinz body preparation, genetic testing.
Suspected Bone Marrow Failure / Infiltration
Bone Marrow Aspirate and Biopsy: Evaluates cellularity, morphology (normoblastic, megaloblastic, sideroblastic), abnormal infiltrates (blasts, storage cells), and dyserythropoiesis.Cytogenetics: Conventional karyotyping, fluorescence in situ hybridization (FISH), chromosomal breakage studies (Fanconi anemia).Viral PCR: Parvovirus B19, CMV, EBV, HIV.Specific Assays: Erythrocyte adenosine deaminase activity (elevated in Diamond-Blackfan anemia), telomere length (Dyskeratosis congenita). 🌱 This is a Digital Garden. Notes are always growing and changing.
These notes are intended for educational purposes only and reflect my personal understanding of the subject. Please cross-reference with standard textbooks and current clinical guidelines.
Authored by Dr. Rubanbalaji 2026