Anemia — Classification and Approach

Mechanism 1: Decreased Red Cell Production

• Bone marrow failure from intrinsic defects (aplastic anemia, myelodysplasia, pure red cell aplasia) or extrinsic suppression (chemotherapy, radiation, drugs, infection)
• Nutritional deficiencies affecting erythropoiesis: iron (cofactor for heme synthesis and electron transport), vitamin B₁₂ (DNA synthesis, myelin formation), folate (DNA synthesis and cell division), vitamin C (iron absorption and metabolism), copper (cytochrome c oxidase)
• Impaired erythropoietin (EPO) production: chronic kidney disease accounts for ~90% of EPO deficiency; EPO gene mutations; EPO resistance in chronic inflammatory states
• Defective hemoglobin synthesis: thalassemias (β-globin gene mutations) and sideroblastic anemias (impaired heme synthesis due to ALAS2 mutations or acquired mitochondrial dysfunction)
• Abnormal erythroid maturation: megaloblastic changes in B₁₂/folate deficiency, dysmyelopoiesis in MDS, ineffective erythropoiesis

Mechanism 2: Increased Red Cell Destruction (Hemolysis)

• Intrinsic RBC defects: hereditary spherocytosis and elliptocytosis (membrane protein mutations), glucose-6-phosphate dehydrogenase deficiency and other enzyme disorders (impaired antioxidant defenses), hemoglobinopathies (HbS polymerization in sickle cell disease, HbC, HbE)
• Extrinsic RBC destruction: immune hemolytic anemia (warm antibody IgG-mediated via complement and Fc receptors; cold agglutinin disease from IgM pentamers; drug-induced; transfusion reactions), microangiopathic hemolytic anemia from mechanical fragmentation (schistocytes in TTP, HUS, DIC, prosthetic valves), parasitic infections (malaria, babesiosis)
• Hypersplenism: portal hypertension, myeloproliferative disease with extramedullary hematopoiesis
• Complement-mediated destruction in paroxysmal nocturnal hemoglobinuria (PNH) from PIG-A gene mutations causing loss of GPI-anchored complement regulatory proteins (CD55, CD59)

Mechanism 3: Blood Loss

• Acute hemorrhage: trauma, ruptured viscus, massive GI bleed
• Chronic blood loss: GI bleeding (peptic ulcer, malignancy, angiodysplasia), gynecologic bleeding (menorrhagia), parasitic infections (hookworm), pulmonary hemosiderosis
• Phlebotomy or hemodialysis: iatrogenic losses in hospitalized or dialysis patients

Pathophysiological Classification by RBC Indices and Reticulocyte Response

• Mechanism: impaired hemoglobinization; reduced heme or globin synthesis
• Hypochromic microcytic pattern on blood smear; low MCH and MCHC

• Elevated reticulocyte count (>2%) indicates appropriate bone marrow response (hemolysis, acute blood loss)
• Low/normal reticulocyte count (<2%) indicates bone marrow failure or inadequate response

• Megaloblastic changes: immature nuclear chromatin relative to cytoplasmic maturation, nuclear-cytoplasmic asynchrony; hypersegmented neutrophils (≥6 lobes); increased MCV and MCH

Decreased Production Anemias

Nutritional Deficiencies

• Iron deficiency: chronic GI blood loss (peptic ulcer disease, malignancy, inflammatory bowel disease, diverticulosis, angiodysplasia), menorrhagia, inadequate dietary intake (vegans, restrictive diets), malabsorption (celiac disease, post-gastrectomy), increased demands (pregnancy, lactation, growth in children); worldwide most common cause of anemia
• Vitamin B₁₂ (cobalamin) deficiency: pernicious anemia (autoimmune atrophic gastritis, anti-intrinsic factor antibodies), post-gastrectomy or ileal resection, dietary insufficiency (strict vegans), bacterial overgrowth, Diphyllobothrium latum (fish tapeworm), chronic pancreatitis, medications (metformin, proton pump inhibitors)
• Folate deficiency: inadequate dietary intake (alcoholics, elderly), malabsorption (celiac disease, tropical sprue, whipple's disease), increased demands (pregnancy, hemolysis, hyperproliferative states), medications (methotrexate, trimethoprim, sulfasalazine)
• Vitamin C deficiency (scurvy): dietary insufficiency, impaired collagen synthesis
• Copper deficiency: malabsorption, prolonged parenteral nutrition, zinc supplementation (competitive inhibition)

Impaired Erythropoietin Production or Function

• Chronic kidney disease: reduced GFR <45 mL/min/1.73 m², loss of peritubular fibroblasts that produce EPO
• Anemia of chronic disease/inflammation: cytokine-mediated (IL-6, TNF-α, hepcidin) suppression of EPO production and iron availability; seen in infections (TB, endocarditis, osteomyelitis), malignancy, autoimmune disease (RA, SLE), chronic inflammation
• Endocrine deficiencies: hypothyroidism (reduced metabolic rate and EPO production), hypogonadism (testosterone stimulates erythropoiesis)

Bone Marrow Failure

• Aplastic anemia: idiopathic (immune-mediated T-cell destruction of HSC), drug-induced (chemotherapy, chloramphenicol, NSAIDs, antiepileptics), radiation, viral (EBV, hepatitis A/C, HIV), inherited (Fanconi anemia, dyskeratosis congenita)
• Myelodysplastic syndromes: acquired clonal stem cell disorder with cytopenia, dysplasia, and increased blasts; older patients; del(5q), trisomy 8, monosomy 7 common cytogenetics
• Bone marrow infiltration: leukemia, lymphoma, metastatic carcinoma, myelofibrosis, granulomatous disease (TB, fungal infection, sarcoidosis)
• Pure red cell aplasia: selective absence of erythroid precursors; idiopathic, drug-induced (chloramphenicol), paraneoplastic, viral (parvovirus B19)
• Parvovirus B19 infection: direct infection of erythroid progenitors, particularly symptomatic in hemolytic anemias

Hemoglobin Synthesis Defects

• Beta-thalassemia: mutations in β-globin gene (point mutations, deletions) → reduced or absent β-globin chains; phenotype ranges from thalassemia trait (heterozygous, mild) to thalassemia major (homozygous, severe transfusion-dependent); Mediterranean, Middle Eastern, and Asian ancestry
• Alpha-thalassemia: deletions of α-globin genes (--/-α = Hb Bart's hydrops, incompatible with life; --/αα = HbH disease; -α/αα = thalassemia trait; αα/αα = normal); 4 genes on chromosome 16, deletions progressively more severe
• Sideroblastic anemia: impaired heme synthesis from ALAS2 mutations (X-linked, most common hereditary form), acquired mitochondrial dysfunction, myelodysplasia; ringed sideroblasts on Prussian blue stain (iron-laden mitochondria in erythroid ring around nucleus)

Increased Destruction Anemias (Hemolytic)

Intrinsic RBC Defects

• Hereditary spherocytosis: spectrin, ankyrin, band 3, or protein 4.2 mutations → loss of membrane deformability, osmotic fragility, splenic sequestration; spherocytes (dense, hyperchromic, reduced surface area) on smear; positive osmotic fragility test
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: X-linked; impaired pentose phosphate pathway → reduced NADPH → inability to neutralize oxidative stress; hemolytic episodes triggered by oxidant drugs (antimalarials, sulfonamides, aspirin, NSAIDs), infection, fava beans; Heinz bodies (precipitated denatured hemoglobin) visible with supravital staining
• Pyruvate kinase deficiency: autosomal recessive; impaired ATP generation → reduced membrane pump function; hemolysis is chronic and non-immune
• Sickle cell disease: point mutation (GAG→GTG) in β-globin codon 6 (Glu→Val) → HbS polymerization under low oxygen tension → sickling (characteristic crescent shape); hemolytic anemia with painful vaso-occlusive crises, acute chest syndrome, stroke, splenic infarction; African ancestry; also seen in sickle-β-thalassemia
• Hemoglobin C disease: Lys substitution in β-globin; crystal formation; mild hemolysis; West African ancestry

Extrinsic RBC Destruction

• Warm autoimmune hemolytic anemia (AIHA): IgG autoantibodies against RBC surface antigens (often Rh-related); complement activation; splenic destruction via FcγR-mediated recognition; idiopathic, associated with SLE, lymphoproliferative disease, drugs (methyldopa, penicillin); positive direct antiglobulin test (DAT/Coombs) with IgG coating RBCs
• Cold agglutinin disease: IgM pentameric antibodies (usually anti-I antigen) with high thermal amplitude → complement activation (C3 deposition on RBCs) and intravascular hemolysis; associated with Mycoplasma, EBV, lymphoproliferative disorders; polychromasia and spherocytes on smear; positive DAT with C3 (cold-reacting antibody)
• Drug-induced hemolytic anemia: penicillin (hapten mechanism; IgG binds penicillin-RBC complex), quinine (immune complex deposition), methyldopa (immune tolerance loss); positive DAT
• Microangiopathic hemolytic anemia (MAHA): mechanical trauma from abnormal microvascular environment; schistocytes (helmet cells, fragmented RBCs) on smear; seen in TTP (thrombotic thrombocytopenic purpura from ADAMTS13 deficiency), HUS (hemolytic uremic syndrome from Shiga toxin), DIC, disseminated malignancy, prosthetic cardiac valves, preeclampsia/HELLP syndrome
• Transfusion reactions: acute (ABO incompatibility → intravascular hemolysis, hemoglobinuria) versus delayed (non-ABO alloimmunization → extravascular hemolysis days later)
• Paroxysmal nocturnal hemoglobinuria (PNH): acquired somatic PIG-A mutation in hematopoietic stem cell → loss of GPI-anchored proteins (CD55 DAF, CD59 membrane inhibitor of reactive lysis) → complement-mediated intravascular hemolysis; hemoglobinuria, thrombosis, bone marrow failure; positive flow cytometry showing absent GPI-anchored proteins
• Infections: malaria (parasitized RBCs destroyed; anemia exacerbated by hemozoin-induced oxidative stress), babesiosis (Babesia species in RBCs), bartonellosis
• Hypersplenism: any cause of splenomegaly (cirrhosis, myelofibrosis, lymphoma, sarcoidosis, TB) → increased sequestration and destruction of RBCs, WBCs, platelets; splenic pooling accounts for ~25% of RBC mass

Hemoglobinopathies with Hemolysis

• Thalassemia major: severe hemolysis from imbalanced globin chain synthesis (excess α chains precipitate as inclusion bodies); extramedullary hematopoiesis; hepatosplenomegaly; facial bony deformities
• Unstable hemoglobins: point mutations affecting heme pocket stability → hemoglobin precipitation and hemolysis

Blood Loss Anemias

• Mechanism: hypovolemia, compensatory tachycardia, increased cardiac output
• Laboratory: initially normal Hb (hemodilution not yet occurred); elevated lactate, tachycardia, hypotension

• Results in iron deficiency if iron stores depleted
• Fecal occult blood testing, colonoscopy, upper endoscopy, gynecologic evaluation

Cardinal Symptoms

• Acute severe anemia (hemoglobin drop from 14 to 7 g/dL acutely) causes marked fatigue and dyspnea
• Chronic anemia (gradual decline to 7-8 g/dL) may be asymptomatic due to compensatory mechanisms (increased 2,3-DPG, increased cardiac output)

• Conjunctival pallor (Hb <7 g/dL) is a classic sign; present in mucous membranes more reliably than skin due to lack of carotenoid pigment
• Palmar crease pallor: useful in non-anemic individuals as baseline comparison

Physical Examination Findings

Cardiovascular signs

• Tachycardia: compensatory response to maintain cardiac output (CO = HR × SV); high-output cardiac state

Step 1 — confirm and define the anemia

• CBC with RBC indices: the initial test. The World Health Organization defines anemia as hemoglobin <13 g/dL in men and <12 g/dL in non-pregnant women (lower thresholds apply in pregnancy and childhood). MCV then sorts the case into microcytic (<80 fL), normocytic (80–100 fL), or macrocytic (>100 fL).
• RDW: reflects anisocytosis. Elevated RDW with low MCV favors iron deficiency; a normal RDW with low MCV and a high RBC count favors thalassemia trait. The Mentzer index (MCV ÷ RBC count) <13 suggests thalassemia trait, >13 suggests iron deficiency.

Step 2 — assess marrow response

• Reticulocyte count / reticulocyte production index (RPI): the single most useful discriminator in normocytic anemia. RPI corrects the raw percentage for the degree of anemia and for premature marrow release. RPI >2 (hyperproliferative) points to hemolysis or blood loss; RPI <2 (hypoproliferative) points to marrow failure, nutrient deficiency, CKD, or inflammation.
• Peripheral smear: schistocytes (MAHA), spherocytes (hereditary spherocytosis or warm AIHA), bite cells and Heinz bodies (G6PD), hypersegmented neutrophils (megaloblastic), teardrop cells with leukoerythroblastosis (marrow infiltration/myelofibrosis).

Step 3 — targeted confirmatory testing

• Iron studies: low ferritin with low transferrin saturation and high TIBC confirms iron deficiency; ferritin is an acute-phase reactant, so in inflammation rely on transferrin saturation or soluble transferrin receptor.
• Hemolysis panel: elevated LDH and indirect bilirubin with low/undetectable haptoglobin; then direct antiglobulin (Coombs) test to separate immune from non-immune hemolysis.
• B₁₂/folate with metabolites: methylmalonic acid is elevated in B₁₂ deficiency only, homocysteine in both — the discriminating test.
• Hemoglobin electrophoresis/HPLC for hemoglobinopathy; flow cytometry for GPI-anchored proteins for PNH; bone marrow aspirate and biopsy is the gold standard for aplastic anemia, MDS, and infiltrative disease.
• GI evaluation: the American College of Gastroenterology recommends bidirectional endoscopy in adult men and postmenopausal women with iron deficiency anemia.

Immediate stabilization

• Active hemorrhage or hemodynamic instability: ABCs, large-bore IV access, control the bleeding source, and transfuse. In massive hemorrhage a balanced ratio of red cells, plasma, and platelets is used per institutional massive transfusion protocol.
• RBC transfusion thresholds: AABB recommends a restrictive strategy — transfuse at hemoglobin <7 g/dL in most hospitalized hemodynamically stable adults, and <8 g/dL in patients undergoing cardiac or orthopedic surgery or with preexisting cardiovascular disease. Transfuse one unit at a time and reassess. Hemoglobin number alone does not justify transfusion in stable chronic anemia.

Etiology-directed first-line therapy

• Oral iron salts (representative agent: ferrous sulfate) for iron deficiency; alternate-day or once-daily dosing improves fractional absorption by avoiding hepcidin induction. Vitamin C or an acidic environment aids absorption; PPIs impair it. Expect reticulocytosis within about a week.
• Parenteral iron (e.g., ferric carboxymaltose) when there is malabsorption, intolerance, ongoing losses outpacing oral repletion, inflammatory bowel disease, or CKD.
• Cobalamin (IM or high-dose oral) for B₁₂ deficiency, and folic acid for folate deficiency.
• Erythropoiesis-stimulating agents in anemia of CKD: KDIGO advises against normalizing hemoglobin and against initiating ESAs at near-normal levels because of stroke, thrombosis, and tumor-progression risk; correct iron deficiency first.

Escalation and definitive therapy

• Warm autoimmune hemolytic anemia: corticosteroids (prednisone) first-line, then rituximab; splenectomy is a definitive option in refractory disease.
• Cold agglutinin disease: avoidance of cold and rituximab-based therapy; steroids are relatively ineffective.
• PNH: complement C5 inhibition (eculizumab/ravulizumab) with prior meningococcal vaccination.
• Severe aplastic anemia: allogeneic HSCT in young patients; otherwise immunosuppression with ATG plus cyclosporine.

Contraindicated / avoid

• Folate alone in unrecognized B₁₂ deficiency — corrects the anemia while subacute combined degeneration progresses.
• Iron supplementation without documented deficiency, particularly in thalassemia or transfusion-dependent patients (iron overload).
• Oxidant drugs (sulfonamides, dapsone, primaquine, nitrofurantoin) in G6PD deficiency.

Complications of the anemia itself

• High-output heart failure: chronic severe anemia lowers viscosity and systemic vascular resistance, raising stroke volume and heart rate; signals include a wide pulse pressure, flow murmur, and new edema/orthopnea.
• Demand ischemia and myocardial infarction (emergency): reduced oxygen content plus tachycardia raises myocardial oxygen demand while shortening diastolic coronary filling — chest pain with ST depression and rising troponin in a patient with a falling hemoglobin.
• Hemorrhagic shock (emergency): in acute blood loss the hemoglobin is initially normal because plasma and red cells are lost together; tachycardia, narrow pulse pressure, and rising lactate precede the drop.
• Neurodevelopmental impairment in infants with iron deficiency, and adverse obstetric outcomes (preterm birth, low birth weight) — the basis for the AAP's recommendation for hemoglobin screening in infancy and ACOG's attention to anemia in pregnancy.
• Pigment gallstones from chronic hemolysis (unconjugated bilirubin load); aplastic crisis (emergency) when parvovirus B19 infects erythroid progenitors in a patient with shortened red cell survival — abrupt hemoglobin fall with reticulocytopenia.
• Untreated TTP (emergency): schistocytes, thrombocytopenia, and neurologic or renal signs require urgent plasma exchange.

Complications of treatment

• Transfusion reactions: acute hemolytic (ABO mismatch) reaction is an emergency — fever, flank pain, hemoglobinuria; stop the transfusion immediately. Also TRALI (hypoxia with bilateral infiltrates and normal filling pressures), TACO (volume overload), febrile non-hemolytic reactions, and alloimmunization causing delayed hemolysis.
• Transfusional iron overload: cardiomyopathy, cirrhosis, and endocrinopathy after repeated transfusions; managed with chelation (deferasirox).
• Oral iron: constipation, dark stools, epigastric distress limiting adherence; IV iron carries a small risk of hypersensitivity.
• B₁₂ repletion: brisk erythropoiesis can drive hypokalemia.
• ESAs: hypertension, thrombosis, and stroke when hemoglobin is over-corrected.
• Post-splenectomy sepsis (emergency): overwhelming encapsulated-organism infection; vaccinate before elective splenectomy.

• Reticulocyte count is the single best next step in a normocytic anemia: it separates a marrow that is responding (hemolysis, blood loss) from one that is not (marrow failure, CKD, inflammation). Always index it to the hematocrit (RPI).
• RDW is the fastest way to split microcytosis: high RDW with low MCV = iron deficiency; normal RDW, low MCV, and a high RBC count = thalassemia trait. The Mentzer index formalizes this.
• Ferritin is an acute-phase reactant: a "normal" ferritin does not exclude iron deficiency in inflammation, infection, or malignancy — check transferrin saturation or soluble transferrin receptor. This is the classic distractor separating iron deficiency from anemia of chronic disease.
• Methylmalonic acid is elevated in B₁₂ deficiency but not folate deficiency — the discriminating metabolite when both hypersegmented neutrophils and a high MCV are present. Give B₁₂ before folate; folate alone masks the anemia while subacute combined degeneration of the dorsal columns and corticospinal tracts advances.
• Iron deficiency anemia in an adult man or a postmenopausal woman is GI malignancy until proven otherwise — bidirectional endoscopy per the American College of Gastroenterology. The tested association: Streptococcus gallolyticus (formerly S. bovis) bacteremia plus iron deficiency points to colon cancer.
• Intravascular versus extravascular hemolysis: an undetectable haptoglobin with hemoglobinuria and a very high LDH indicates intravascular hemolysis (PNH, ABO mismatch, MAHA); spherocytes with splenomegaly and jaundice indicate extravascular destruction.
• Schistocytes + thrombocytopenia + neurologic changes = TTP: urgent plasma exchange; do not give platelet transfusions, which can worsen microthrombosis.
• In acute hemorrhage the initial hemoglobin is normal — whole blood is lost isotonically, and the value falls only after fluid shifts or resuscitation. Resuscitate on vital signs, not on the CBC.