1. Deficiency anemias (iron, vitamin B12, folate),
2. Bone marrow failure (hypo/aplastic anemia),
3. Increased red cell destruction (hemolytic anemia).

1) Iron-deficiency anemia (IDA)

• Mechanism: reduced hemoglobin synthesis due to iron lack.
• Common causes: chronic blood loss (especially GI, gynecologic), low intake, malabsorption, increased demand (pregnancy).
• Typical findings:
  • Microcytic, hypochromic anemia (low MCV, low MCH)
  • Low ferritin, low serum iron, high TIBC, low transferrin saturation
  • Symptoms: fatigue, pallor, dyspnea, pica, koilonychia, glossitis
• Diagnosis: confirm iron deficiency, then identify cause of blood loss (AGA guideline emphasizes GI evaluation in many adults with IDA: Gastrointestinal Evaluation of Iron Deficiency Anemia, p.10).
• Treatment: oral iron (first line), IV iron when needed, and always treat underlying cause.

2) Vitamin B12- and folate-deficiency anemia (megaloblastic)

• Mechanism: impaired DNA synthesis causing ineffective erythropoiesis.
• Typical findings:
  • Macrocytic anemia (high MCV), hypersegmented neutrophils
  • Low reticulocyte response (until treatment starts)
• B12 deficiency:
  • Causes: pernicious anemia, gastric/ileal disease, vegan diet, malabsorption
  • Neurologic signs: paresthesias, ataxia, cognitive changes
  • Labs: low B12, ↑ methylmalonic acid, ↑ homocysteine
• Folate deficiency:
  • Causes: poor diet, alcoholism, malabsorption, pregnancy, drugs (e.g., methotrexate)
  • No neurologic syndrome typical of B12 deficiency
  • Labs: low folate, normal methylmalonic acid, ↑ homocysteine
• Treatment: replace deficient vitamin; exclude B12 deficiency before folate-only therapy to avoid worsening neurologic injury.

3) Hypoplastic/Aplastic anemia

• Mechanism: bone marrow failure with hypocellular marrow and pancytopenia.
• Causes: idiopathic/autoimmune, drugs/toxins, radiation, viral infections, inherited syndromes.
• Typical findings:
  • Anemia + leukopenia + thrombocytopenia
  • Reticulocytopenia
  • Bone marrow biopsy: hypocellularity with fatty replacement
• Clinical features: fatigue, infections, bleeding/petechiae.
• Treatment: remove causative factor, supportive transfusions/infection prevention, immunosuppressive therapy (e.g., ATG + cyclosporine), hematopoietic stem-cell transplant in eligible severe cases.

4) Hemolytic anemia

• Mechanism: premature RBC destruction (intravascular or extravascular).
• Causes:
  • Inherited: membrane defects, enzyme defects (G6PD), hemoglobinopathies
  • Acquired: autoimmune hemolysis, microangiopathy, infections, drugs, hypersplenism
• Typical findings:
  • Normocytic or macrocytic (from reticulocytosis)
  • ↑ reticulocytes, ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin
  • Peripheral smear clues (spherocytes, schistocytes, etc.)
  • Direct Coombs test positive in immune hemolysis
• Clinical features: jaundice, dark urine, splenomegaly (varies by type).
• Treatment: cause-specific (steroids/rituximab for autoimmune forms, treat triggers, folate support, transfusion when needed, sometimes splenectomy).

Quick differential table

Step 1: Confirm anemia

• Check Hb/Hct (sex-specific reference ranges).
• Assess severity and urgency (hemodynamic instability, active bleeding, ischemic symptoms).

Step 2: First-line triage tests

• CBC with RBC indices (MCV, MCH, RDW)
• Reticulocyte count (or reticulocyte production index)
• Peripheral blood smear

1. Low MCV -> usually iron deficiency
2. High MCV -> B12/folate (megaloblastic) likely
3. Normal/high reticulocytes -> think hemolysis or blood loss
4. Low reticulocytes + pancytopenia -> think aplastic/hypoplastic marrow failure

Step 3: MCV-based branch

A) Microcytic/hypochromic anemia (MCV low)

• Ferritin
• Serum iron, TIBC, transferrin saturation
• Look for source of chronic blood loss (GI, gynecologic)
• In adults, evaluate GI tract when indicated (AGA guideline emphasis for many IDA cases)

• Ferritin low
• Serum iron low
• TIBC high
• Transferrin saturation low

B) Macrocytic anemia (MCV high)

• Serum B12, folate
• Methylmalonic acid (MMA), homocysteine
• Smear: macro-ovalocytes, hypersegmented neutrophils

• B12 deficiency: MMA high + homocysteine high
• Folate deficiency: MMA normal + homocysteine high

Step 4: Reticulocyte/hemolysis branch

• LDH, indirect bilirubin, haptoglobin
• Direct antiglobulin (Coombs) test
• Urinalysis (hemoglobinuria)
• Smear (spherocytes, schistocytes, bite cells, etc.)

• LDH high
• Indirect bilirubin high
• Haptoglobin low
• Reticulocytosis

• Immune vs non-immune
• Intravascular vs extravascular
• Inherited vs acquired cause

Step 5: Pancytopenia/low retic branch

• Bone marrow aspiration/biopsy
• Expect hypocellular marrow with fatty replacement
• Review drugs, toxins, radiation, viral causes, autoimmune history

Step 6: Etiologic confirmation and treatment choice

• IDA: iron replacement + identify/treat bleeding source
• B12 deficiency: B12 replacement and cause workup (pernicious, malabsorption, diet)
• Folate deficiency: folate replacement + cause correction
• Aplastic: supportive care, immunosuppression or stem-cell transplant (severity/age dependent)
• Hemolytic: cause-specific therapy (steroids for AIHA, trigger removal, etc.)

One-page memory shortcut

• MCV low -> Iron studies
• MCV high -> B12/folate + MMA/homocysteine
• Retic high -> Hemolysis labs
• Pancytopenia + retic low -> Bone marrow failure (aplastic)

1. a flowchart image version, or
2. 5 clinical vignettes with answers (common exam format).

1. A 32-year-old woman with heavy menstrual bleeding, fatigue, pica, and brittle nails.
   CBC: Hb 8.9 g/dL, MCV 70 fL, RDW high. Ferritin low, transferrin saturation low, TIBC high.
   Most likely diagnosis: Iron-deficiency anemia
   Why: Microcytosis + classic iron panel + chronic blood loss history
   Next step: Start iron replacement and evaluate/control bleeding source (gynecologic cause).
2. A 68-year-old man with pallor and glossitis, numb feet, gait unsteadiness.
   CBC: Hb 9.5 g/dL, MCV 112 fL. Smear: hypersegmented neutrophils. B12 low, MMA high, homocysteine high.
   Most likely diagnosis: Vitamin B12-deficiency megaloblastic anemia
   Why: Macrocytosis + neurologic signs + B12 biochemical profile
   Next step: Replace B12 (not folate alone), investigate cause (pernicious anemia/malabsorption).
3. A 45-year-old man with alcohol misuse and poor nutrition, fatigue, sore tongue.
   CBC: Hb 10.2 g/dL, MCV 108 fL. Folate low, homocysteine high, MMA normal. No neurologic deficits.
   Most likely diagnosis: Folate-deficiency megaloblastic anemia
   Why: Macrocytosis + folate pattern + absent neuro findings
   Next step: Folate supplementation, nutrition/alcohol intervention, confirm no concurrent B12 deficiency.
4. A 24-year-old patient presents with fatigue, recurrent infections, gum bleeding, petechiae.
   CBC: pancytopenia (Hb low, WBC low, platelets low), reticulocytes very low.
   Bone marrow biopsy: markedly hypocellular marrow with fatty replacement.
   Most likely diagnosis: Aplastic (hypoplastic) anemia
   Why: Pancytopenia + reticulocytopenia + hypocellular marrow
   Next step: Severity stratification; supportive care, infection prophylaxis, consider immunosuppression vs stem-cell transplant.
5. A 36-year-old woman with jaundice and dark urine after recent infection.
   CBC: anemia with reticulocytosis. Labs: LDH high, indirect bilirubin high, haptoglobin low. Direct Coombs positive.
   Most likely diagnosis: Autoimmune hemolytic anemia (warm type likely)
   Why: Biochemical hemolysis + positive antiglobulin test
   Next step: Start first-line therapy (typically corticosteroids), monitor hemolysis markers, evaluate secondary causes.

Anemic syndrome: detailed review

1) Iron-deficiency anemia (IDA)

Pathophysiology

Causes

1. Chronic blood loss (most common in adults)
   • GI: ulcer, gastritis, colorectal cancer, angiodysplasia, NSAID-related bleeding
   • Gynecologic: menorrhagia, uterine pathology
2. Increased demand: pregnancy, growth
3. Low intake: poor diet
4. Malabsorption: celiac disease, post-gastrectomy, achlorhydria, H. pylori-associated states

Clinical features

• General anemia symptoms
• Pica (ice/clay craving), brittle hair/nails, koilonychia
• Angular cheilitis, glossitis, restless legs (sometimes)

Lab profile

• CBC: Hb low, MCV low, MCH low, often RDW high
• Iron studies:
  • Ferritin low (most specific for depleted stores)
  • Serum iron low
  • TIBC/transferrin high
  • Transferrin saturation low
• Reticulocytes: low/normal before treatment
• Smear: microcytosis, hypochromia, anisopoikilocytosis

Diagnostic strategy

• Confirm iron deficiency biochemically
• Then identify etiology of iron loss, especially occult GI bleeding in adults

Treatment

1. Treat cause (bleeding source, malabsorption)
2. Iron replacement
   • Oral ferrous salts first line
   • IV iron if intolerance, severe deficiency, malabsorption, CKD/inflammation
3. Follow response:
   • Reticulocyte rise in about 1 week
   • Hb rise over 2-4 weeks
   • Continue therapy after Hb normalization to replenish stores

Complications if untreated

• Reduced physical/cognitive performance
• Pregnancy risks (preterm birth, low birth weight)
• Cardiac strain in severe chronic anemia

2) Vitamin B12 and folate deficiency anemia (megaloblastic anemia)

Pathophysiology

2A) Vitamin B12 deficiency

Causes

• Pernicious anemia (intrinsic factor deficiency)
• Gastric surgery/atrophic gastritis
• Terminal ileal disease or resection (e.g., Crohn disease)
• Long-term strict vegan diet (without supplementation)
• Bacterial overgrowth, pancreatic insufficiency, some medications

Clinical features

• Anemia symptoms + glossitis
• Neurologic signs: paresthesia, loss of vibration/proprioception, ataxia, cognitive/psychiatric changes
• Neurologic damage can become irreversible if delayed treatment

Labs

• CBC: macrocytic anemia (MCV high)
• Smear: macro-ovalocytes, hypersegmented neutrophils
• B12 low
• Methylmalonic acid high
• Homocysteine high
• Reticulocytes low before treatment

Treatment

• B12 replacement (parenteral in severe/neurologic or malabsorption states; high-dose oral in selected cases)
• Treat underlying cause
• Monitor reticulocyte response and neurologic recovery

2B) Folate deficiency

Causes

• Poor intake (malnutrition, alcoholism)
• Increased need (pregnancy, hemolysis)
• Malabsorption
• Drugs (methotrexate, trimethoprim, phenytoin)

Clinical features

• Anemia symptoms, glossitis
• No typical neurologic syndrome like B12 deficiency

Labs

• Macrocytic anemia, hypersegmented neutrophils
• Folate low
• Homocysteine high
• Methylmalonic acid normal

Treatment

• Folic acid replacement
• Correct precipitating cause
• Always exclude/cover B12 deficiency before folate-only therapy

3) Hypo-aplastic (aplastic) anemia

Definition

Pathogenesis

Causes

• Idiopathic (common)
• Drugs/toxins (e.g., benzene, some chemotherapeutics, chloramphenicol classically)
• Radiation
• Viral infections (hepatitis-associated, EBV, HIV, parvovirus context-dependent)
• Autoimmune disorders
• Inherited marrow-failure syndromes

Clinical features

• From anemia: fatigue, pallor
• From neutropenia: recurrent/severe infections
• From thrombocytopenia: petechiae, mucosal bleeding, ecchymoses
• Usually no splenomegaly (helps differential)

Labs and diagnosis

• CBC: pancytopenia
• Reticulocyte count: low
• Smear: reduced cells, no specific hemolysis pattern
• Bone marrow aspirate/biopsy: hypocellularity with fatty replacement
• Exclude mimics: MDS, leukemia, marrow infiltration, severe megaloblastic anemia

Severity (conceptual)

Treatment

1. Supportive: RBC/platelet transfusions, infection prevention/treatment
2. Remove causative exposure where possible
3. Disease-modifying:
   • Immunosuppressive therapy (ATG + cyclosporine ± thrombopoietin receptor agonist)
   • Allogeneic stem-cell transplantation (preferred in many younger severe cases with donor)
4. Long-term monitoring for clonal evolution (MDS/AML risk in some patients)

Prognosis

4) Hemolytic anemia

Definition

Classification

1. By site
   • Intravascular hemolysis
   • Extravascular hemolysis (usually spleen/liver)
2. By origin
   • Inherited: membrane (spherocytosis), enzyme (G6PD), hemoglobinopathies
   • Acquired: autoimmune, microangiopathic, infections, drugs, mechanical valves, hypersplenism

Pathophysiology

Clinical features

• Fatigue, pallor
• Jaundice, scleral icterus
• Dark urine (especially intravascular hemolysis)
• Splenomegaly (often extravascular forms)
• Pigment gallstones in chronic hemolysis

Core hemolysis labs

• Reticulocytes high
• LDH high
• Indirect bilirubin high
• Haptoglobin low
• Smear morphology provides clues:
  • Spherocytes (AIHA/hereditary spherocytosis)
  • Schistocytes (MAHA, prosthetic valves)
  • Bite cells/Heinz body context (oxidative hemolysis)

Key confirmatory tests

• Direct antiglobulin (Coombs) test for immune hemolysis
• G6PD assay, hemoglobin electrophoresis, osmotic fragility/EMA test, ADAMTS13 etc. as indicated by context

Treatment principles

• Treat cause
• Autoimmune hemolysis: corticosteroids first line, then rituximab/other options if refractory
• Avoid triggers in enzymopathies
• Folate supplementation in chronic hemolysis
• Transfusions when needed
• Splenectomy in selected conditions

High-yield differential summary

Practical stepwise approach in a patient with anemia

1. CBC + indices + reticulocyte count + smear
2. If microcytic -> iron studies
3. If macrocytic -> B12, folate, MMA, homocysteine
4. If retic high -> hemolysis panel (LDH, bilirubin, haptoglobin, Coombs)
5. If pancytopenia + retic low -> marrow evaluation for aplasia/hypoplasia

• a single exam revision sheet (1 page), or
• a management protocol format (what to do on day 1, week 1, month 1).