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Topics Covered

RBC (Hematology)

1. Hemolytic Anemia - Classification (intravascular vs extravascular), types, lab findings
2. Sickle Cell Anemia - Genetics, pathophysiology, crises, complications, lab
3. Thalassemia - α vs β, major vs minor, comparison table, complications
4. Iron Deficiency Anemia - Stages, causes, clinical features, lab (ferritin, TIBC, transferrin saturation)
5. Megaloblastic Anemia - B12 vs folate, pernicious anemia, subacute combined degeneration, lab
6. Aplastic Anemia - Causes, bone marrow findings, treatment

WBC (Hematology)

1. Chronic Myeloid Leukemia - Philadelphia chromosome, BCR-ABL, lab, phases, imatinib
2. Leukemia vs Leukemoid Reaction - Comparison table (LAP score is key differentiator)
3. Acute Myeloid Leukemia - APL with Auer rods, t(15;17), ATRA treatment

Platelets

1. DIC - Pathogenesis, causes, ISTH scoring, lab (D-dimers, schistocytes)
2. ITP - Acute vs chronic, treatment
3. Hemophilia A - Factor VIII deficiency, prolonged aPTT, treatment
4. Pancytopenia - Causes overview

Lymph Node & Spleen

1. Splenomegaly - Causes, complications
2. Hodgkin Lymphoma - RS cells (owl-eye, CD15/CD30+), subtypes table, Ann Arbor staging, ABVD
3. Non-Hodgkin Lymphoma - Key types (DLBCL, Follicular, Burkitt, Mantle Cell)
4. Multiple Myeloma - CRAB criteria, Bence Jones protein, M-spike, Rouleaux formation

CVS

1. Acute MI - Morphological changes over time (key exam table), biomarkers, complications
2. Rheumatic Heart Disease - Aschoff bodies, Jones criteria, valve involvement
3. Infective Endocarditis - Organisms, Duke criteria, Osler/Janeway/Roth spots

Respiratory

1. Lobar Pneumonia - 4 stages (congestion, red hepatization, grey hepatization, resolution), S. pneumoniae
2. COPD - Chronic bronchitis vs emphysema, Reid index

GIT

1. Crohn's vs Ulcerative Colitis - Detailed comparison table
2. Pleomorphic Adenoma - Most common salivary gland tumor, mixed tumor, malignant transformation risk
3. Gastric/Colorectal Carcinoma, PUD - Key exam points

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1. HEMOLYTIC ANEMIA

Definition

• Anemia + low tissue O2 → stimulates erythropoietin from kidneys → marrow erythroid hyperplasia + peripheral reticulocytosis
• In severe cases: extramedullary hematopoiesis in liver, spleen, lymph nodes

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Classification

By Site of Defect:

By Site of Hemolysis (More Clinically Important):

Key Point: Decreased serum haptoglobin is a feature of both types because macrophages regurgitate enough hemoglobin even in extravascular hemolysis.

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Common Types of Hemolytic Anemia

A. Hereditary Spherocytosis

• Genetics: Usually autosomal dominant; rare severe autosomal recessive form
• Pathogenesis: Inherited defects in membrane skeleton proteins (spectrin, ankyrin, band 3, band 4.1, band 4.2) → weaken the link between the membrane skeleton and lipid bilayer → RBCs shed membrane vesicles → surface area-to-volume ratio decreases → cells become spherical
• Consequence: Spherocytes are rigid and non-deformable → trapped in splenic cords → phagocytosed by macrophages (extravascular hemolysis)
• Morphology:
  • Peripheral smear: spherocytes - dark red, lack central pallor, small
  • Splenomegaly (often 500-1000 g; normal 150-200 g)
  • Reticulocytosis, pigment gallstones (40-50% of patients)
• Clinical: Anemia, jaundice, splenomegaly
• Diagnosis: Osmotic fragility test (spherocytes lyse in hypotonic solution); eosin-5-maleimide (EMA) binding test
• Treatment: Splenectomy (corrects anemia; spherocytes persist)

B. G6PD Deficiency

• Genetics: X-linked recessive - affects males primarily
• Pathogenesis: Mutations destabilize G6PD enzyme → RBCs cannot regenerate NADPH → cannot neutralize oxidative damage → Hb precipitates as Heinz bodies → membrane damage → acute intravascular and extravascular hemolysis
• Triggers: Drugs (primaquine, dapsone, nitrofurantoin), infections, fava beans
• Smear: Heinz bodies (with supravital stain); bite cells (after Heinz bodies are removed by splenic macrophages)
• Course: Self-limited; reticulocytes (which have higher G6PD) replace damaged cells

C. Autoimmune Hemolytic Anemia (AIHA)

• IgG (warm-type, 37°C) or IgM (cold-type, <4°C) antibodies against RBC surface antigens
• Warm AIHA: Extravascular hemolysis in spleen; associated with SLE, CLL, drugs (methyldopa, penicillin)
• Cold AIHA: IgM + complement → intravascular hemolysis; associated with Mycoplasma pneumoniae, EBV
• Diagnosis: Direct Coombs (DAT) test positive (antibodies/complement on RBC surface)

D. Microangiopathic Hemolytic Anemia (MAHA)

• Mechanical fragmentation of RBCs in abnormal microvasculature (fibrin strands in DIC, TTP, HUS, malignant hypertension)
• Smear: Schistocytes (fragmented RBCs), helmet cells
• Not immune-mediated; DAT negative

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General Lab Findings in Hemolytic Anemia

• Decreased Hb
• Elevated reticulocyte count
• Decreased serum haptoglobin
• Elevated indirect (unconjugated) bilirubin
• Elevated serum LDH (released from lysed RBCs)
• Peripheral smear: specific morphology depending on type
• Bone marrow: erythroid hyperplasia

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2. SICKLE CELL ANEMIA

Definition & Genetics

• Autosomal recessive hemoglobinopathy
• Point mutation in β-globin gene: Glutamic acid → Valine at position 6 (codon 6, GAG→GTG)
• This creates Sickle Hemoglobin (HbS)

• Most common familial hemolytic anemia
• Prevalent where malaria is/was endemic (equatorial Africa, parts of India, Middle East, southern Europe) - HbS confers protection against falciparum malaria
• In the USA: ~8% of African-Americans are heterozygous HbS carriers; ~1 in 600 have sickle cell anemia

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Normal vs. Abnormal Hemoglobin

• Normal adult: HbA (α2β2) = 96%, HbA2 = 3%, HbF = 1%
• Sickle cell disease (homozygous HbSS): HbA completely replaced by HbS
• Sickle cell trait (heterozygous HbAS): ~40% HbS, ~60% HbA - minimal sickling in vivo because HbA retards HbS polymerization

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Pathogenesis

1. Deoxygenation of HbS → conformational change in β-globin
2. Deoxygenated HbS molecules self-associate via the abnormal valine residue → form long rigid polymers
3. These polymers distort the RBC → elongated crescentic/sickle shape (Fig. 10.3 in Robbins)
4. Initially reversible on reoxygenation
5. Repeated sickling → calcium influx, loss of K+ and water, membrane skeleton damage → irreversibly sickled cells → prone to hemolysis

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Pathologic Consequences

1. Chronic Hemolytic Anemia

• Mean RBC life span: ~20 days (1/6 of normal 120 days)
• Severity correlates with number of irreversibly sickled cells
• Hematocrit: 18-30% (normal 38-48%)

2. Vascular Obstruction (Vasoocclusive Crisis)

• NOT related to number of irreversibly sickled cells
• Triggered by: infection, inflammation, dehydration, acidosis
• Sickled cells obstruct microvasculature → ischemia, infarction, pain

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Morphology (Gross & Microscopic)

• Peripheral smear: Elongated, spindled, boat-shaped irreversibly sickled cells; target cells; reticulocytes
• Bone marrow: Erythroid hyperplasia (compensatory)
• Skeleton: Bone resorption + secondary new bone formation → "crewcut" skull X-ray, prominent cheekbones (similar to thalassemia)
• Spleen:
  • Children: Moderate splenomegaly (up to 500 g) - red pulp congestion from trapped sickled cells
  • Adults: Autosplenectomy - repeated infarcts → fibrotic, small, useless spleen
• Multiple organs: Vascular congestion, thrombosis, infarction affecting bones, liver, kidneys, retina, brain, lung, skin
• Priapism (frequent): penile vascular congestion → fibrosis and erectile dysfunction
• Pigment gallstones (from chronic hemolysis)

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Clinical Features

• Chronic hemolytic anemia
• Jaundice, pallor, fatigue
• Elevated bilirubin → pigment gallstones

• Hand-foot syndrome (dactylitis): Most common presenting symptom in young children - infarction of small bones of hands and feet → painful swelling
• Acute Chest Syndrome: Sickled cells in hypoxemic pulmonary vasculature → creates vicious cycle of worsening hypoxia + more sickling → can be fatal. Also triggered by fat emboli from infarcted bone. Leading cause of death along with stroke.
• Stroke: Cerebral vasoocclusion; especially in children
• Proliferative Retinopathy: Vasoocclusion in retina → visual loss, blindness
• Aplastic Crisis: Parvovirus B19 infects erythroblasts → sudden ↓ in RBC production → severe acute anemia (self-limited)
• Splenic Sequestration Crisis: Children - sudden pooling of blood in spleen → rapid fall in Hb, hypovolemic shock

• Functional asplenia (autosplenectomy in adults; congestion-related dysfunction in children) → susceptible to encapsulated bacteria: Streptococcus pneumoniae, H. influenzae
• Also: gram-negative bacteria (E. coli), Salmonella osteomyelitis (bone infarction provides seeding site)

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Diagnosis

• Newborn screening: Mandatory in the USA - hemoglobin gel electrophoresis from heel-stick
• Peripheral smear: Sickle cells (in homozygous); sickling induced in vitro by hypoxia (in trait)
• Hb electrophoresis: HbS band, absence of HbA (in HbSS)
• Sickle solubility test (Sickling test): Positive in both SS and AS
• Prenatal diagnosis: Fetal DNA from amniocentesis or chorionic villus biopsy

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Treatment

• Hydroxyurea (mainstay): Inhibits DNA synthesis; reduces crises by:
  1. Increasing HbF levels (HbF inhibits HbS polymerization)
  2. Anti-inflammatory effect (inhibits WBC production)
  3. Increases RBC size → lowers intracellular Hb concentration
  4. Metabolized to NO → vasodilation + inhibits platelet aggregation
• Prophylactic penicillin + pneumococcal vaccine (especially in children <5 years)
• Blood transfusions (for crises, stroke prevention)
• Allogeneic bone marrow transplantation (potentially curative)
• Gene therapy (promising, potentially curative)

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3. THALASSEMIA

Definition

1. Deficiency of Hb → microcytic hypochromic anemia
2. Excess of the unpaired normal globin chain → precipitates → red cell damage and hemolysis

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Genetics

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β-THALASSEMIA

Molecular Basis

• Caused mainly by point mutations (>100 different mutations known)
• β0: No β-globin produced (complete absence)
• β+: Reduced (but detectable) β-globin production
• Mutations disrupt: abnormal RNA splicing (most common), promoter mutations (↓ transcription), coding region mutations (↓ translation)
• Gene deletions are rare in β-thalassemia (unlike α-thalassemia)

Clinical Genotype Classification:

Pathogenesis of β-Thalassemia Major (Two mechanisms):

• ↓ β-globin → small, poorly hemoglobinized (microcytic, hypochromic) RBCs

• α-chains form toxic precipitates → damage RBC and erythroid precursor membranes → apoptosis of erythroblasts in bone marrow = Ineffective erythropoiesis (large fraction never reach circulation)
• The few RBCs that are released have a shortened lifespan

• Low hepcidin (due to erythroferrone secreted by expanded erythroblast pool) → ↑ intestinal iron absorption → iron overload (even without transfusions)
• Massive erythroid hyperplasia → marrow expansion → bone deformities

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Morphology of β-Thalassemia Major

• Marked microcytosis and hypochromia
• Poikilocytosis (variation in shape)
• Anisocytosis (variation in size)
• Target cells (increased surface area-to-volume ratio)
• Nucleated red cells (normoblasts) - reflect erythropoietic drive
• Basophilic stippling

• Striking hyperplasia of erythroid progenitors, shifted toward early forms
• Expanded erythropoietic marrow fills intramedullary space → invades cortex → impairs bone growth

• "Crew-cut" skull X-ray (hair-on-end appearance)
• Frontal bossing, prominent cheekbones ("chipmunk face")
• Maxillary overgrowth with malocclusion

• Massive hepatosplenomegaly (extramedullary hematopoiesis + hyperplasia of mononuclear phagocytes)
• Lymphadenopathy

• From repeated transfusions + inappropriate gut iron absorption
• Deposition in: Heart (cardiomyopathy - major cause of death), liver (cirrhosis), endocrine glands (diabetes, hypogonadism, hypothyroidism)

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Clinical Features of β-Thalassemia Major

• Manifests postnatally as HbF synthesis diminishes (after ~3-6 months)
• Growth retardation starting in infancy
• Severe anemia → pallor, fatigue, failure to thrive
• Skeletal deformities (bone expansion)
• Massive hepatosplenomegaly
• With transfusions alone: survival into 2nd-3rd decade
• Without iron chelation: cardiac dysfunction (secondary hemochromatosis) → fatal in 2nd-3rd decade
• Treatment of choice: Hematopoietic stem cell transplantation at early age (curative)

Clinical Features of β-Thalassemia Minor (Trait)

• Usually asymptomatic
• Mild microcytic hypochromic anemia (may be mistaken for IDA)
• Normal life expectancy
• Diagnosis: HbA2 elevated (>3.5%) on electrophoresis; HbF mildly elevated
• Important for genetic counseling: two carriers → 25% chance of thal major in offspring

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α-THALASSEMIA

Molecular Basis

• Caused mainly by gene deletions (unlike β-thalassemia which is due to point mutations)
• Since there are 4 α-globin genes (2 per chromosome 16), severity is proportional to number of genes deleted:

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Diagnosis of Thalassemias

• Both show microcytic hypochromic anemia
• IDA: low ferritin, low serum iron, high TIBC
• β-thal trait: normal/elevated ferritin, elevated HbA2 on electrophoresis

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Sources: Robbins & Kumar Basic Pathology (Elsevier), retrieved from the medical textbook library - directly from the Hemolytic Anemia, Sickle Cell, and Thalassemia chapters.