Note: The library does not contain Harsh Mohan's textbook, but it has Robbins & Kumar Basic Pathology - the international gold standard from which Harsh Mohan draws heavily. All answers below are sourced from Robbins (equivalent content, same exam answers).

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PATHOLOGY PAPER I - COMPLETE ANSWERS

(Source: Robbins & Kumar Basic Pathology)

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GENERAL PATHOLOGY

Introduction to Pathology

SN 1. Telepathology (Pg. 7)

• Static telepathology - pre-selected digital images sent for consultation
• Dynamic (live) telepathology - real-time video transmission with remote control of the microscope stage
• Whole-slide imaging (WSI) - entire slide digitized at high resolution and viewed remotely

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Injury, Cellular Adaptations and Cellular Aging

SN 1. Calcification - Types; Dystrophic Calcification; Dystrophic vs. Metastatic - Differences

1. Dystrophic calcification - calcium deposition in dead or dying tissue; serum calcium is NORMAL
2. Metastatic calcification - calcium deposition in normal viable tissue; serum calcium is ELEVATED (hypercalcaemia)

• Occurs in necrotic tissue, atheromatous plaques, old tuberculous lesions, dead parasites, necrotic tumours
• Mechanism: Cell death → loss of membrane integrity → intracellular calcium rises → phospholipids of dead membranes bind calcium → hydroxyapatite crystal formation
• Gross: Chalky-white, gritty deposits
• Micro: Granular blue deposits (H&E), amorphous or crystalline

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SN 2. Apoptosis - Definition, Examples, Morphological Changes, Mechanisms, Causes

1. Cell shrinkage (cytoplasm condenses, organelles pack tightly)
2. Chromatin condensation (pyknosis) - chromatin aggregates under nuclear membrane
3. Nuclear fragmentation (karyorrhexis)
4. Formation of apoptotic bodies - membrane blebs pinch off containing nuclear fragments and organelles
5. Phagocytosis by adjacent cells or macrophages - NO inflammation

1. Mitochondrial (intrinsic) pathway:
   • Triggered by DNA damage, oxidative stress, loss of growth factors
   • Pro-apoptotic signals → decrease Bcl-2, Bcl-XL → cytochrome c released from mitochondria → forms apoptosome with Apaf-1 → activates caspase-9 → activates effector caspases (3, 6, 7)
2. Death receptor (extrinsic) pathway:
   • Fas ligand binds Fas (CD95) or TNF binds TNFR1
   • FADD recruited → activates caspase-8 → effector caspases activated

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SN 3. Endogenous Pigments

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SN 4. Necrosis - Types, Examples, Mechanisms; Caseous, Coagulative, Liquefactive

1. Coagulative Necrosis
   • Protein denaturation predominates over enzymatic digestion
   • Architecture of dead tissue is preserved (ghost outline)
   • Cause: Ischemia/infarction (except brain)
   • Example: MI (pale infarct in heart, kidney, spleen)
   • Gross: Firm, pale, chalky
   • Micro: Anucleate cells with eosinophilic cytoplasm, preserved cell outlines
2. Liquefactive Necrosis
   • Enzymatic digestion predominates → tissue liquefies
   • Cause: Bacterial/fungal infections (pus = dead neutrophils + bacteria + liquefied tissue); brain infarcts (rich in lipids and water)
   • Example: Brain abscess, cerebral infarct, lung abscess
   • Gross: Creamy-yellow fluid (pus) or cystic cavity
   • Micro: Debris, neutrophils, liquid
3. Caseous Necrosis
   • Combination of coagulative + liquefactive - unique to tuberculosis (and some fungi)
   • Gross: Friable, white-yellow, "cheesy" (cheese-like) material
   • Micro: Amorphous granular debris surrounded by granulomatous inflammation (epithelioid macrophages + Langhans giant cells + lymphocytes); NO preserved cell architecture
   • Sites: Lung, lymph nodes (TB)
4. Fat Necrosis
   • Lipase action on adipose tissue
   • Cause: Acute pancreatitis (enzymatic), trauma to breast
   • Gross: Chalky white deposits (calcium soaps = saponification)
   • Micro: Shadowy fat cell outlines with basophilic calcium deposits
5. Gangrenous Necrosis
   • Not a distinct pattern; usually coagulative (dry gangrene) + superimposed liquefactive (wet gangrene)
   • Common in limb ischemia
6. Fibrinoid Necrosis
   • Vascular walls - immune complex deposition + plasma protein leak
   • Micro: Bright pink, homogeneous deposits in vessel walls (H&E)
   • Seen in: Malignant hypertension, polyarteritis nodosa

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SN 5. Reperfusion Injury - Definition, Mechanism

1. ROS burst - reoxygenation generates massive reactive oxygen species (superoxide, H2O2, OH•) via xanthine oxidase and mitochondria; antioxidant defenses are depleted during ischemia
2. Neutrophil influx - complement activation and cytokines attract neutrophils → further ROS + proteases
3. Calcium overload - damaged membranes allow massive Ca2+ influx → activates destructive enzymes
4. Mitochondrial permeability transition - MPT pore opens on reperfusion → cytochrome c release → apoptosis

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SN 6. Metaplasia, Hypertrophy/Hyperplasia, Atrophy - Definitions with Examples

• Squamous metaplasia: columnar → squamous in bronchus (smokers), bladder (Schistosoma), cervix (ectropion)
• Glandular/intestinal metaplasia: squamous → glandular in Barrett esophagus (chronic GERD)
• Significance: Predisposes to dysplasia/carcinoma if stimulus persists

• Examples: Cardiac hypertrophy in hypertension, skeletal muscle in athletes, pregnant uterus

• Examples: Endometrial hyperplasia (excess estrogen), nodular hyperplasia of prostate, compensatory liver hyperplasia post-hepatectomy, thyroid hyperplasia in iodine deficiency

• Physiologic: Thymus in adulthood, uterus post-partum
• Pathologic causes: Disuse (immobilization), denervation, ischemia, malnutrition, loss of endocrine stimulation, pressure

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SN 7. Atrophy - Brown Atrophy of Heart

• Seen in elderly persons, severe malnutrition, cancer cachexia
• Gross: Small, shrunken heart; epicardial fat replaced by serous atrophy (gelatinous, watery); coronary arteries appear tortuous (serpentine) due to shrunken myocardium
• Micro: Cardiac myocytes shrunken; prominent brown lipofuscin granules at both poles of nucleus (residual bodies from autophagic vacuoles = "wear-and-tear" pigment)
• Causes: Old age, cachexia, malnutrition

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LAQ 1. Necrosis - Definition, Types with Examples

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LAQ 2. Fatty Change - Etiopathogenesis; Fatty Liver - Morphology

1. Excess FFA delivery (obesity, DM, starvation - mobilization of peripheral fat)
2. Decreased oxidation (hypoxia, alcohol - NADH excess shifts away from oxidation)
3. Increased esterification (excess glucose → acetyl CoA → FFA synthesis; alcohol promotes)
4. Decreased apoprotein synthesis → impaired VLDL export (protein malnutrition, CCl4 toxicity, alcohol)
5. Impaired secretion of lipoproteins

• Gross: Liver enlarged (may reach 3-6 kg), pale yellow, greasy, soft, edges rounded
• Micro: Microvesicular steatosis: small fat droplets in cytoplasm, nucleus central (seen in acute fatty liver of pregnancy, Reye syndrome); Macrovesicular steatosis: single large fat vacuole displaces nucleus to periphery (alcoholic/NASH)
• Stains: Fat droplets stain with Oil Red O on frozen sections (dissolved in formalin-fixed paraffin sections)

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LAQ 3. Free Radicals and Free Radical-Induced Cell Injury

• Superoxide (O2•-) - generated by mitochondria
• Hydrogen peroxide (H2O2) - from dismutation of O2•-
• Hydroxyl radical (OH•) - most reactive; formed by Fenton reaction (Fe2+ + H2O2)

• Normal metabolism (mitochondrial electron transport)
• Reperfusion after ischemia (xanthine oxidase)
• Ionizing radiation
• Metabolism of drugs/chemicals (CCl4 → CCl3•)
• Activated macrophages (respiratory burst - NADPH oxidase)

• Superoxide dismutase (SOD) → H2O2
• Catalase → H2O + O2
• Glutathione peroxidase
• Antioxidants: vitamin E, vitamin C, beta-carotene

1. Lipid peroxidation - chain reaction destroying cell and organelle membranes
2. Protein oxidation - fragmentation, cross-linking, enzyme inactivation
3. DNA damage - strand breaks, base modifications (8-OH-deoxyguanosine), mutations → cancer, aging

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LAQ 4. Pigments - Classification; Disorders of Hemoprotein-derived Pigments

• Exogenous: Carbon (anthracosis), silica, tattoo pigments
• Endogenous: Hemosiderin, bilirubin, melanin, lipofuscin, haematin

• Derived from degradation of Hb (heme → ferritin → hemosiderin)
• Stain: Prussian blue (Perls' stain)
• Local: Bruising, pulmonary haemosiderosis (heart failure cells = siderophages in lung)
• Systemic hemosiderosis: Iron overload without tissue damage (multiple transfusions, dietary excess)
• Hemochromatosis: Iron overload WITH organ damage - liver cirrhosis, pancreatic fibrosis (bronze diabetes), skin pigmentation, cardiomyopathy, hypogonadism

• Hb → biliverdin → bilirubin → conjugated in liver → excreted in bile
• Accumulation = jaundice/icterus (yellow discoloration of skin, sclera, mucosae)
• Types: Pre-hepatic (haemolytic), hepatic (hepatocellular), post-hepatic (obstructive/cholestatic)
• Kernicterus: Unconjugated bilirubin deposits in basal ganglia of neonates

• Hb digestion by Plasmodium → haematin deposited in brain, spleen, liver
• Gross: Black discoloration of spleen, liver; "slate-grey" brain

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Immunopathology Including Amyloidosis

SN 1. Hypersensitivity Reactions - Definition, Classification; Type I in Detail

1. Sensitization phase: First exposure to allergen → Th2 cell activation → IL-4, IL-5 production → B-cell class switching to IgE → IgE binds high-affinity FcεRI receptors on mast cells/basophils
2. Effector phase (re-exposure): Allergen cross-links IgE on mast cells → mast cell degranulation

• Pre-formed (immediate - within minutes): Histamine (vasodilation, bronchoconstriction, increased permeability), heparin, eosinophil/neutrophil chemotactic factors
• Newly synthesised (late - 2-24 hrs): Leukotrienes (LTC4, LTD4 - potent bronchoconstrictors, > histamine), PGD2, thromboxane, PAF; cytokines (IL-4, IL-5, TNF)

• Local: Allergic rhinitis, asthma, eczema, urticaria, food allergy
• Systemic (anaphylaxis): Massive mast cell degranulation → vasodilatory shock, bronchospasm, laryngeal oedema - life-threatening; treat with epinephrine

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SN 2. Amyloid - Definition, Classification, Molecular Structure, Special Stains, Physicochemical Properties

• Beta-pleated sheet (antiparallel) - the defining feature shared by all amyloids
• Fibrils ~7.5-10 nm diameter; 4-6 fibrils wound around each other
• P component (SAP - serum amyloid P) - non-fibrillar glycoprotein present in all amyloid deposits
• Apolipoprotein E (ApoE) - promotes fibrillogenesis

• Beta-pleated sheet → resistance to proteolysis
• Insoluble in physiologic conditions
• Apple-green birefringence with Congo red under polarized light (diagnostic)
• Negative charge

• Congo red - salmon-pink/orange color (light microscopy); apple-green birefringence under polarized light (PATHOGNOMONIC)
• PAS - positive
• Metachromatic with crystal violet/methyl violet
• Thioflavin T/S - fluorescence
• EM - 7.5-10 nm non-branching fibrils

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SN 3. Sago Spleen; Amyloidosis of Spleen - Gross and Microscopic Features

• Early amyloid deposition in the Malpighian corpuscles (white pulp - lymphoid follicles)
• Gross: Spleen normal or slightly enlarged; white pulp appears as small, discrete, translucent, grey, tapioca/sago grain-like nodules against red background → "Sago spleen"
• Micro: Amyloid deposited in and around central arterioles and lymphoid follicles; Congo red positive deposits

• Later stage - amyloid deposits extend into red pulp sinusoids
• Gross: Spleen markedly enlarged, firm, waxy, lard-like appearance ("lardaceous spleen")
• Micro: Diffuse sheets of amyloid in red pulp replacing normal architecture

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SN 4. Autoimmune Disorders - Mechanisms

1. Failure of central tolerance - self-reactive T and B cells normally deleted in thymus/bone marrow; defects in AIRE (autoimmune regulator) gene allow escape
2. Failure of peripheral tolerance:
   • Defective clonal anergy (self-reactive cells not silenced)
   • Defective regulatory T cells (Tregs)
   • Activation of anergic self-reactive lymphocytes by co-stimulation
3. Molecular mimicry: Foreign antigens (microbial) share epitopes with self antigens → antibody cross-reacts (e.g., post-streptococcal rheumatic fever - M protein vs. cardiac myosin)
4. Bystander activation: Inflammation releases cytokines that activate quiescent self-reactive lymphocytes
5. Polyclonal lymphocyte activation: EBV, LPS activate B cells non-specifically
6. Exposure of sequestered antigens: Lens proteins, sperm antigens, myelin → exposed after trauma
7. Altered antigen: Drug-modified self proteins (e.g., methyldopa-modified RBCs → AIHA)
8. Genetic factors: HLA associations (HLA-DR2, DR3, DR4, B27)

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SN 5. Neoplasms in HIV/AIDS Patients

1. Kaposi Sarcoma (KS) - most common AIDS-defining malignancy; caused by HHV-8; spindle cell tumour of endothelium; cutaneous, oral, GI, pulmonary
2. Non-Hodgkin Lymphoma - aggressive B-cell lymphomas (Burkitt, large B-cell); EBV-associated; CNS lymphoma pathognomonic of AIDS
3. Primary CNS Lymphoma - EBV-driven; highly aggressive; seen only with severe immunosuppression
4. Invasive Cervical Carcinoma - HPV-related; AIDS-defining
5. Anal Carcinoma - HPV-related
6. Hodgkin Lymphoma - increased risk (mixed cellularity type)
7. Leiomyosarcoma in children with AIDS (EBV-associated)

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LAQ 1. Autoimmunity - Definition, Pathogenesis

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LAQ 2. AIDS - Etiology, Transmission, Natural History, Diagnosis

1. Sexual contact (most common worldwide) - vaginal, anal intercourse
2. Parenteral - IV drug use (shared needles), blood transfusion, needlestick injury
3. Vertical (mother to child) - transplacental, at birth (most common), breastfeeding

1. Early/Acute HIV syndrome (2-4 weeks post-exposure): Flu-like illness (fever, lymphadenopathy, pharyngitis, rash, myalgia); CD4 drops transiently; high viraemia; seroconversion occurs
2. Chronic latent phase (clinical latency, years - up to 10): Asymptomatic; ongoing viral replication in lymph nodes; CD4 gradually falls (500-200 cells/µL); Persistent Generalized Lymphadenopathy (PGL)
3. AIDS (CD4 < 200 cells/µL OR AIDS-defining illness): Opportunistic infections (PCP, CMV retinitis, Cryptococcal meningitis, Toxoplasmosis), AIDS-defining cancers (KS, NHL), wasting, dementia

• Screening: ELISA for anti-HIV antibodies (sensitivity >99.5%)
• Confirmatory: Western blot
• 4th generation tests: HIV p24 antigen + antibody detection (detects earlier)
• HIV RNA PCR (viral load): Monitoring treatment response; diagnosis in neonates
• CD4 count: Stages disease; CD4 < 200 = AIDS; CD4 < 50 = severe immunodeficiency

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Derangements of Homeostasis and Haemodynamics

SN 1. Infarct - Definition, Types

1. White (pale/anaemic) infarct:
   • Arterial occlusion in solid organs (heart, kidney, spleen)
   • No collateral circulation; end-arteries
   • Gross: Wedge-shaped, pale, firm
   • Coagulative necrosis
2. Red (haemorrhagic) infarct:
   • Venous occlusion, dual blood supply (lung, small intestine), loose tissue, reperfusion
   • Gross: Wedge-shaped, red/haemorrhagic
   • Examples: Pulmonary infarct, intestinal infarct, brain infarct (if reperfused), testicular torsion

• Bland infarct - sterile
• Septic infarct - infected embolus seeds infarct → abscess formation

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SN 2. Oedema - Definition, Classification; Transudate vs. Exudate Differences

1. Increased hydrostatic pressure - heart failure, venous obstruction
2. Decreased oncotic pressure (hypoproteinaemia) - nephrotic syndrome, cirrhosis, malnutrition
3. Lymphatic obstruction (lymphoedema) - filariasis, post-mastectomy, tumour
4. Sodium and water retention - renal failure, hyperaldosteronism
5. Increased vascular permeability (inflammation) - histamine, kinins, cytokines

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SN 3. Virchow's Triad; Thrombus - Gross and Microscopic Features

1. Endothelial injury - most important; exposes subendothelial collagen + tissue factor; trauma, hypertension, atherosclerosis, inflammation; directly activates coagulation cascade
2. Abnormal blood flow (stasis or turbulence) - stasis in heart failure/atrial fibrillation/venous stasis; turbulence in aneurysms/arterial plaques; disrupts laminar flow, brings platelets in contact with endothelium, prevents dilution of activated clotting factors
3. Hypercoagulability (thrombophilia) - primary (genetic - factor V Leiden, prothrombin mutation, antithrombin III deficiency, protein C/S deficiency); secondary (acquired - malignancy, pregnancy, OCP, antiphospholipid syndrome, smoking)

• Gross: Lines of Zahn = alternating pale (platelet/fibrin) and dark red (RBC) layers - pathognomonic of ante-mortem clot (distinguishes from post-mortem clot which is homogeneous)
• Micro: Fibrin meshwork trapping RBCs, platelets, leukocytes; lines of Zahn; organized thrombus shows ingrowth of smooth muscle and endothelial cells (recanalisation)

1. Propagation
2. Embolisation
3. Dissolution (fibrinolysis)
4. Organisation and recanalisation

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SN 4. Pathways Leading to Systemic Oedema from Primary Heart Failure - Figure

Left Heart Failure
        ↓
↓ Cardiac output → ↓ Renal perfusion
        ↓
Activation of RAAS + ADH secretion
        ↓
Na+ and H2O retention
        ↓
↑ Plasma volume + ↑ Venous pressure
        ↓
↑ Capillary hydrostatic pressure
        ↓
Fluid transudation into interstitium
        ↓
SYSTEMIC OEDEMA (peripheral, dependent)

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SN 5. Embolism - Definition; Pulmonary Thromboembolism

• Source: 95% from deep vein thrombosis (DVT) of lower limbs (femoral, popliteal, iliac veins)
• Risk factors: Virchow's triad (immobilization, surgery, pregnancy, malignancy, OCP)

1. Massive PTE (>60% pulmonary circulation blocked): Sudden death, acute cor pulmonale, cardiovascular collapse
2. Moderate PTE (subsegmental): Pulmonary infarction (lung infarct = red/haemorrhagic, wedge-shaped, pleural surface)
3. Small/microemboli: Often asymptomatic; pulmonary hypertension if recurrent

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SN 6. Liver and Spleen in Right-Sided Heart Failure

• Gross: Enlarged, tense, dark-red; cut surface shows mottled red-yellow pattern like nutmeg (centrilobular congestion = dark red, peripheral fatty change = pale yellow)
• Micro: Centrilobular (zone 3) congestion and necrosis - sinusoids dilated and filled with RBCs; hepatocytes around central veins atrophied/necrotic; peripheral hepatocytes may show fatty change
• Chronic: "Cardiac cirrhosis" (fibrosis extending from central veins)

• Gross: Enlarged (up to 500 g), tense, firm, dark-red; cut surface seeps blood
• Micro: Dilated sinusoids filled with RBCs; occasional infarcts; long-standing congestion → fibrous thickening of sinusoidal walls and trabeculae → "Gamna-Gandy bodies" (foci of old haemorrhage with haemosiderin and calcium deposits - visible on MRI)

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LAQ 1. Oedema - Full Discussion

• Causes: Left heart failure (most common), mitral stenosis, ARDS, hypoalbuminaemia, high-altitude
• Pathophysiology:
  • Left heart failure → ↑ pulmonary venous pressure → ↑ capillary hydrostatic pressure → fluid transudation into alveolar walls (interstitial oedema) → then into alveoli (alveolar oedema)
• Gross: Lungs heavy (>1000g), wet, boggy; frothy pink fluid in airways
• Micro: Alveolar septa widened by fluid; alveoli filled with pink proteinaceous fluid; red blood cells (haemorrhage); macrophages with haemosiderin ("heart failure cells" / siderophages)

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LAQ 2. Embolism - Full Discussion

1. Thromboembolism (most common - 99%) - venous or arterial
2. Fat embolism - long bone fractures, liposuction; fat globules enter veins; lungs → brain, kidneys; Fat Embolism Syndrome: dyspnoea, petechiae, neurological signs 24-72h post-fracture
3. Air/Gas embolism - IV injection, thoracocentesis, diving (caisson disease/decompression sickness); nitrogen gas bubbles in joints, bones, CNS ("bends")
4. Amniotic fluid embolism - obstetric emergency; amniotic contents enter uterine veins; DIC, respiratory failure
5. Tumour embolism - metastasis mechanism
6. Septic embolism - infected thrombus/endocarditis vegetations
7. Atheromatous embolism - cholesterol crystal embolism (blue-toe syndrome)

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LAQ 3. Thrombus - Full Discussion

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LAQ 4. Normal Haemostasis

1. Primary haemostasis (platelet plug):
   • Injury → vasoconstriction (reflex + endothelin)
   • Von Willebrand factor (vWF) bridges subendothelial collagen to GPIb on platelets (adhesion)
   • Platelets activated → shape change, degranulation (ADP, TXA2, serotonin) → platelet aggregation (GPIIb/IIIa + fibrinogen) → loose platelet plug
2. Secondary haemostasis (coagulation cascade):
   • Extrinsic pathway: Tissue factor (TF/Factor III) + Factor VII → Factor X activation
   • Intrinsic pathway: Contact activation (XII → XI → IX) → Factor X
   • Common pathway: Xa + Va (prothrombinase complex) → thrombin (IIa); thrombin cleaves fibrinogen → fibrin; XIIIa cross-links fibrin → stable clot
   • Thrombin amplifies itself by activating V, VIII, XI, XIII
3. Clot limitation (natural anticoagulants):
   • Antithrombin III (inhibits thrombin, Xa, IXa)
   • Protein C + Protein S (inactivate Va and VIIIa)
   • Tissue Factor Pathway Inhibitor (TFPI)
   • Prostacyclin (PGI2) + Nitric oxide from intact endothelium
4. Fibrinolysis: tPA → plasminogen → plasmin → degrades fibrin; D-dimer released

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Inflammation and Healing

SN 1. Factors Affecting Wound Healing - Enumerate; Complications

1. Wound size and depth
2. Blood supply (ischaemia impairs healing)
3. Infection (most common cause of delayed healing)
4. Foreign bodies
5. Wound edges (apposition, tension)
6. Radiation (impairs vascularity)

1. Nutrition - protein deficiency, vitamin C deficiency (collagen synthesis impaired), zinc deficiency
2. Metabolic disease - diabetes mellitus (impaired neutrophil function, vascular disease)
3. Glucocorticoids/steroids (anti-inflammatory, inhibit fibroblast proliferation and collagen synthesis)
4. Immunosuppression
5. Old age
6. Anaemia
7. Uraemia

1. Infection
2. Dehiscence (wound breakdown) - obesity, infection
3. Hernia
4. Keloid - excess collagen deposition beyond wound margins; more common in dark skin
5. Hypertrophic scar - excess collagen within wound
6. Contracture - excess myofibroblast activity → joint deformity, restricted movement
7. Excessive granulation tissue ("proud flesh")
8. Pigmentation changes
9. Malignant transformation (Marjolin's ulcer - squamous carcinoma in chronic scar/burn)

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SN 2. Chemotaxis and Phagocytosis

• Directed migration of leukocytes along a chemical gradient toward site of injury
• Chemotactic agents (exogenous and endogenous): Bacterial products (fMLP - N-formyl-methionyl peptides), complement fragments (C5a), leukotriene B4 (LTB4), IL-8 (CXCL8), TGF-β
• Mechanism: Chemoattractant binds G-protein-coupled receptors → activates phospholipases, Rho GTPases → actin polymerization at leading edge → cell crawls towards stimulus

1. Recognition and attachment - Opsonization (coating of microbe with IgG Fc or C3b) enhances phagocytosis via Fc receptors and complement receptors (CR3) on phagocytes
2. Engulfment - pseudopod extension → phagosome formation
3. Killing and degradation:
   • Oxygen-dependent (ROS) - NADPH oxidase generates superoxide → H2O2 → HOCl (hypochlorous acid via MPO) - most bactericidal
   • Oxygen-independent - bactericidal permeability-increasing protein (BPI), defensins, lysozyme, lactoferrin, cathepsins

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SN 3. Lepromatous Leprosy - Gross and Microscopic Findings

• Caused by Mycobacterium leprae; occurs in patients with poor cell-mediated immunity (anergic)
• Th2 response (anti-inflammatory); high antibody levels but ineffective

• Widespread symmetric skin lesions - macules, papules, nodules (lepromas)
• Leonine facies (loss of eyebrows/eyelashes - madarosis, thickened skin of face)
• Saddle nose deformity (nasal septum destruction)
• Nerve thickening (ulnar, common peroneal, great auricular)
• Orchitis → testicular atrophy
• Involvement of viscera (liver, spleen, lymph nodes, marrow)

• Granulomatous inflammation with foamy (Virchow) macrophages (lepra cells) packed with acid-fast bacilli
• NO epithelioid granulomas (poor CMI)
• Grenz zone (subepidermal clear zone between epidermis and inflammatory infiltrate)
• Abundant bacilli demonstrable on Fite-Faraco (modified ZN) stain = high bacterial index
• Lymphocytes sparse

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SN 4. Primary Tuberculosis - Pathogenesis

1. Inhalation of droplet nuclei containing M. tuberculosis
2. Bacteria deposit in lower part of upper lobe or upper part of lower lobe (area of greatest airflow) → phagocytosed by alveolar macrophages
3. Bacteria survive within macrophages by inhibiting phagolysosome fusion
4. Primary (Ghon) focus forms - initially non-specific pneumonic consolidation
5. Bacteria spread via lymphatics to hilar lymph nodes → Ghon complex = Ghon focus + lymphangitis + hilar lymphadenopathy
6. Sensitization (3-8 weeks): T cells activate macrophages (via IFN-γ) → epithelioid granuloma formation (delayed hypersensitivity, Type IV) → central caseous necrosis
7. Outcomes of primary TB in immunocompetent host:
   • 90-95%: Healing - fibrosis, calcification → Ranke complex (calcified Ghon complex)
   • 5-10%: Progressive primary TB (especially children, immunocompromised)

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SN 5. Inflammation - Chemical Mediators

• Histamine - mast cells, basophils; early response; vasodilation, ↑ permeability
• Serotonin - platelets; vasoconstriction at high doses
• Bradykinin - from kinin system; vasodilation, ↑ permeability, pain
• Nitric oxide (NO) - vasodilation, anti-platelet

• Prostaglandins (PGE2, PGI2) - vasodilation, fever, pain (via COX pathway)
• Leukotrienes: LTB4 - chemotaxis; LTC4/D4/E4 - bronchoconstriction, ↑ permeability (SRSA)
• PAF (Platelet activating factor) - bronchoconstriction, vasodilation

• Complement - C3a, C5a (anaphylatoxins - mast cell degranulation, chemotaxis); C5b-9 (MAC)
• Coagulation/Kinin system - XIIa → bradykinin, plasmin, thrombin

• TNF, IL-1 - fever, acute phase reaction, vascular changes, leukocyte adhesion
• IL-8 (CXCL8) - potent neutrophil chemotactic factor
• IL-6 - acute phase protein synthesis (CRP, fibrinogen, complement)

• Lysosomal enzymes - from neutrophils/macrophages
• ROS - bactericidal; tissue damage
• Neuropeptides - substance P (pain, vascular permeability)

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SN 6. Ridley and Jopling Classification of Leprosy

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SN 7. Acute Inflammation - Cellular Events; Definition, Vascular Events, Types

1. Transient vasoconstriction (seconds)
2. Vasodilation (arterioles, venules) → increased blood flow → redness (rubor) and heat (calor)
3. Increased vascular permeability → protein-rich exudate leaks into interstitium → swelling (tumor); mechanisms:
   • Endothelial cell contraction (histamine, bradykinin - immediate transient, venules)
   • Endothelial injury (direct injury - all vessels)
   • Leukocyte-mediated endothelial injury (late prolonged)
   • Transcytosis (VEGF)
4. Stasis of blood flow → rouleaux formation

1. Margination - leukocytes move from axial flow to periphery (stasis)
2. Rolling - loose adhesion via selectins (P-selectin on endothelium + PSGL-1 on leukocyte; L-selectin; E-selectin)
3. Adhesion - firm adhesion via integrins (LFA-1/MAC-1 on leukocytes + ICAM-1 on endothelium); upregulated by TNF, IL-1
4. Transmigration (diapedesis) - migration through endothelial junctions (PECAM-1/CD31)
5. Chemotaxis - directional migration to site of injury (see SN 2)
6. Phagocytosis - killing of microbes (see SN 2)

• Rubor (redness), Calor (heat), Tumor (swelling), Dolor (pain), Functio laesa (loss of function)

1. Serous - thin watery fluid; skin blisters, peritoneal exudate
2. Fibrinous - fibrin-rich exudate; pericarditis ("bread and butter"), pleuritis
3. Suppurative (purulent) - neutrophilic exudate with pus; abscess (localised), empyema
4. Ulcerative - necrosis of surface epithelium + acute inflammatory exudate

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SN 8. Granulation Tissue; Delayed Wound Healing

• Gross: Pink-red, granular, soft; bleeds easily; fills wound from day 3-5
• Micro (key features):
  1. Proliferating capillary buds/loops (angiogenesis - VEGF, bFGF driven)
  2. Proliferating fibroblasts → collagen synthesis (TGF-β driven)
  3. Myofibroblasts (wound contraction - α-SMA positive)
  4. Loose ECM (hyaluronic acid, fibronectin early; collagen later)
  5. Inflammatory cells (macrophages, lymphocytes - scant)
  6. Edematous stroma

• Infection (most important)
• Foreign body
• Ischaemia/poor blood supply
• Diabetes mellitus
• Malnutrition (protein, vitamin C, zinc deficiency)
• Glucocorticoids
• Anaemia
• Uremia
• Old age
• Excessive wound tension/movement
• Radiation

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SN 9. Wound Healing by Primary and Secondary Intention

• Clean surgical wound with apposed edges; minimal tissue loss
• Day 1-3: Clot fills incision; neutrophil influx; basal cells of epidermis migrate across wound within 24-48 hrs; thin layer of epidermis bridges wound
• Day 3-5: Granulation tissue appears; macrophages replace neutrophils; fibroblasts migrate + collagen deposition begins; neovascularization
• Week 1-2: Collagen bridges incision; inflammatory infiltrate recedes; adnexal structures regenerate
• Month+: Scar remodelling - type III collagen → type I collagen; tensile strength increases; 70-80% of original strength by 3 months; never 100%

• Large wound, infected wound, tissue loss; edges NOT apposed
• Key differences from primary intention:
  • Larger amounts of granulation tissue (fills cavity)
  • Wound contraction by myofibroblasts (up to 10% of original size) - important feature
  • More extensive scar formation
  • Slower, more fibrous repair
  • Greater risk of keloid/hypertrophic scar

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SN 10 & 11. Primary Tuberculosis Complex (Ghon's Complex)

• Site: Subpleural, lower part of upper lobe or upper part of lower lobe (right > left)
• Gross: 1-2 cm grey-white focus of consolidation → central caseation
• Micro: Granuloma with central caseous necrosis, epithelioid macrophages, Langhans giant cells, lymphocytic cuff, peripheral fibroblasts

1. Exudative stage - non-specific pneumonic consolidation (neutrophils, macrophages)
2. Productive stage (3-8 weeks post-sensitization) - epithelioid granuloma with Langhans cells
3. Caseous stage - central caseous necrosis (from necrotic macrophages releasing enzymes)
4. Healing - fibrosis → calcification → Ranke complex

• Most common: Healing (fibrosis + calcification = Ranke complex) - immune-competent
• Liquefaction → cavity formation → bronchial spread
• Progressive primary TB (uncommon - young children, immunocompromised)
• Miliary TB (haematogenous dissemination)
• Lymph node disease > pulmonary focus in children

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Neoplasia

SN 1. Precancerous Lesions

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SN 2. Tumour Markers - Role in Diagnosis

1. Screening (limited - PSA for prostate)
2. Diagnosis (AFP in hepatocellular carcinoma + yolk sac tumour)
3. Staging and prognosis
4. Monitoring response to treatment
5. Detecting recurrence

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SN 3. Anaplastic Tumour Cells - Morphology

1. Pleomorphism - variation in size and shape of cells and nuclei
2. Nuclear changes:
   • Hyperchromatism (dark-staining due to excess DNA)
   • Increased nuclear-cytoplasmic (N:C) ratio (normally 1:4 to 1:6; in anaplasia may be 1:1)
   • Prominent, enlarged nucleoli (irregular, multiple)
   • Coarse, irregularly clumped chromatin
   • Abnormal mitoses - tripolar, multipolar
3. Loss of polarity - disorganized architecture, no recognizable glandular/squamous pattern
4. Tumour giant cells - mono or multinucleated, bizarre shape
5. Atypical mitoses
6. Stromal changes - neoangiogenesis, desmoplasia

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SN 4. Oncogenic Viruses - Enumerate with Cancer Caused

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SN 5. Laboratory Diagnosis of Cancer

1. Histopathology (gold standard) - excision biopsy, incision biopsy, punch biopsy
2. Cytology - FNAC, exfoliative cytology (Pap smear, sputum, CSF, urine)
3. Frozen section - intraoperative diagnosis for surgical margins
4. Immunohistochemistry (IHC) - tumour markers, receptor status (ER/PR/HER2 in breast), lineage determination
5. Flow cytometry - cell surface markers, DNA ploidy, in haematological malignancies
6. Molecular/genetic tests - FISH, PCR, NGS - gene mutations (EGFR, KRAS, BRCA), translocations (BCR-ABL in CML), microsatellite instability
7. Electron microscopy - rarely used; Birbeck granules (Langerhans), neurosecretory granules
8. Tumour markers in blood - AFP, CEA, PSA etc. (see SN 2)
9. Imaging - CT, MRI, PET for staging

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SN 6. Paraneoplastic Syndromes - Examples

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SN 7. Chemical Carcinogenesis - Process with Examples

• Irreversible DNA mutation by carcinogen (or its reactive electrophilic metabolite)
• Carcinogen must be activated (procarcinogen → ultimate carcinogen) by cellular enzymes (CYP450)
• Initiated cell: Permanently mutated but not yet transformed; requires promotion to become cancer
• Examples: Alkylating agents (cyclophosphamide), polycyclic hydrocarbons (DMBA, benzo[a]pyrene), aromatic amines (β-naphthylamine), nitrosamines, aflatoxin B1

• Reversible; requires repeated/sustained exposure
• Promoter not mutagenic alone; stimulates proliferation of initiated cell
• Examples: Phorbol esters (TPA), saccharin, hormones (oestrogen in breast), bile salts (in colon)
• Promoters stimulate transcription, cell growth, and inhibit apoptosis

• Additional mutations accumulate → malignant phenotype (invasion, metastasis)
• Genomic instability accelerates this phase

• Polycyclic aromatic hydrocarbons (cigarette smoke, coal tar) → lung, skin
• Aromatic amines (aniline dyes, β-naphthylamine) → bladder cancer
• Aflatoxin B1 (Aspergillus flavus on grain) → HCC; causes G→T mutation in p53 codon 249
• Vinyl chloride → angiosarcoma of liver
• Asbestos → mesothelioma (chrysotile + amphiboles), bronchogenic carcinoma
• Nitrosamines (tobacco, preserved meats) → gastric/oesophageal
• Alkylating agents (cyclophosphamide) → leukaemia

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Genetic and Paediatric Diseases

SN 1 & 2. Down Syndrome / Trisomy 21

• Most common chromosomal disorder (1:700 live births); risk increases with maternal age
• Karyotype: Trisomy 21 (94%), Robertsonian translocation (5%), Mosaicism (1%)
• Mechanism: Maternal non-disjunction during meiosis I (90%)

• Intellectual disability (IQ 25-50)
• Flat facies, epicanthal folds, oblique palpebral fissures
• Small ears, single palmar (simian) crease
• Protruding tongue (relative macroglossia), small mouth
• Hypotonia at birth
• Short stature, short neck

• Congenital heart disease (40-50%) - AV canal defect (most characteristic), VSD, ASD
• Duodenal atresia ("double bubble")
• Hirschsprung disease
• Increased risk of ALL (10-20x), AML (especially M7)
• Alzheimer disease (nearly 100% after age 40)
• Hypothyroidism
• Atlantoaxial instability

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SN 3. Klinefelter Syndrome

• Karyotype: 47,XXY (most common); also 48,XXXY, 46XY/47XXY mosaics
• Most common cause of male hypogonadism
• Mechanism: Non-disjunction - extra X chromosome (usually maternal in origin)

• Tall stature (long legs), eunuchoid body habitus
• Small testes (hyalinisation and fibrosis of seminiferous tubules) → azoospermia → infertility
• Gynaecomastia
• Sparse body/facial hair
• Low testosterone; elevated FSH, LH
• Mild intellectual disability (variable)
• Barr body (inactive X) present in somatic cells

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HAEMATOLOGY

Introduction to Haematopoietic System and Disorders of Erythroid Series

SN 1 & 2. Megaloblastic Anaemia - Haematological Findings; Megaloblast

1. Macro-ovalocytes (large oval RBCs) - most characteristic finding
2. Hypersegmented neutrophils (>5 lobes in >5% = pathognomonic; or any cell with ≥6 lobes)
3. Anisocytosis and poikilocytosis (marked)
4. Leucopenia, thrombocytopenia (in severe cases)
5. MCV > 100 fL (macrocytic anaemia)

• Megaloblasts = enlarged erythroid precursors; abundant cytoplasm (normal haemoglobin maturation) but immature, open-lace (fine) chromatin nucleus = nuclear-cytoplasmic asynchrony
• Giant metamyelocytes and band forms
• Hypercellular marrow (ineffective erythropoiesis → cell death in marrow)
• Giant megakaryocytes

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SN 3. Sickle Cell Anaemia - Etiopathogenesis, Lab Investigations, Peripheral Smear

• Autosomal recessive; HbS = Hb with glutamate → valine substitution at position 6 of β-globin chain (GAG → GTG mutation)
• Homozygous (SS) = disease; Heterozygous (SA) = trait (usually asymptomatic)
• Under low O2 tension, HbS polymerizes → rigid, elongated, sickled RBCs
• Consequences: Haemolysis, vaso-occlusion

• Deoxygenation → HbS polymerizes → RBC sickles
• Sickled cells: rigid, block small vessels → vaso-occlusive crises → ischaemia/infarction
• Repeated sickling → membrane damage → irreversibly sickled cells → haemolytic anaemia (extravascular + intravascular)
• Protective factors (slow sickling): HbF (inhibits polymerization), low MCHC, short transit time

• Hb: Low (6-9 g/dL)
• PBS: Sickle cells, target cells, polychromasia, nucleated RBCs, Howell-Jolly bodies (functional asplenia)
• Sickling test: Sodium metabisulphite → positive
• Haemoglobin electrophoresis: HbS predominant band (no HbA); confirms diagnosis
• Solubility test (Sickledex)
• High reticulocyte count (haemolysis)
• Elevated bilirubin (unconjugated)
• High LDH

• Sickle cells (drepanocytes)
• Target cells (codocytes)
• Polychromasia
• Nucleated RBCs
• Howell-Jolly bodies
• Poikilocytosis, anisocytosis

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LAQ 1. Megaloblastic Anaemia - Lab Investigations, PBS, Bone Marrow

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LAQ 2. Anaemia - Definition, Classification; Iron Deficiency Anaemia (IDA)

• Adult men: < 13 g/dL
• Adult women: < 12 g/dL
• Pregnant women: < 11 g/dL

1. Blood loss (acute/chronic)
2. Decreased production (IDA, megaloblastic, aplastic, ACD)
3. Increased destruction (haemolytic - intrinsic/extrinsic)

1. Pre-latent iron deficiency - depleted stores (↓ serum ferritin), Hb normal
2. Latent iron deficiency - ↓ serum iron, ↑ TIBC; Hb still normal
3. Iron deficiency anaemia - ↓ Hb, microcytic hypochromic anaemia

• PBS: Microcytosis (low MCV), hypochromia (low MCH/MCHC), anisocytosis, poikilocytosis, pencil (cigar) cells (elongated elliptocytes), target cells
• Serum ferritin: DECREASED (earliest marker of iron depletion; best single test)
• Serum iron: Decreased
• TIBC (Total Iron Binding Capacity): INCREASED
• Transferrin saturation: Decreased (<16%)
• Serum soluble transferrin receptor (sTfR): Increased
• Bone marrow: Absent iron stores (Perls' stain negative); normoblastic hyperplasia
• Reticulocytes: Low (decreased production)
• WBC/Platelets: Mild thrombocytosis may occur

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LAQ 3. Haemolytic Anaemia - Lab Investigations

1. ↑ Reticulocytes (reticulocytosis) - compensatory, most consistent finding
2. ↑ Unconjugated (indirect) bilirubin → jaundice
3. ↑ Urobilinogen in urine
4. ↑ LDH (released from lysed RBCs)
5. ↓ Haptoglobin (binds free Hb; consumed in intravascular haemolysis - most sensitive for intravascular)
6. Haemoglobinaemia (pink plasma in intravascular)
7. Haemoglobinuria (brown/red urine - intravascular)
8. Haemosiderinuria (urine sediment positive for iron - chronic intravascular)
9. Bone marrow: Erythroid hyperplasia (M:E ratio reversal)

• Coombs test (DAT): Positive in immune haemolytic anaemia
• PBS: Spherocytes (HS, AIHA), sickle cells, target cells, fragmented cells (schistocytes in microangiopathic HA)
• Osmotic fragility: Increased in hereditary spherocytosis
• Haemoglobin electrophoresis: Thalassemia, sickle cell
• G6PD assay

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LAQ 4. Macrocytic Anaemia - Causes

1. Megaloblastic:
   • Vitamin B12 deficiency (pernicious anaemia, vegetarian diet, malabsorption, gastrectomy, fish tapeworm)
   • Folate deficiency (malnutrition, pregnancy, malabsorption, drugs - methotrexate, phenytoin, alcohol)
   • Combined B12 + folate deficiency
2. Non-megaloblastic macrocytic:
   • Liver disease (altered lipid composition of RBC membrane → target cells, macro-ovalocytes)
   • Hypothyroidism
   • Alcoholism (direct toxic effect on marrow)
   • Myelodysplastic syndrome (MDS)
   • Aplastic anaemia
   • Reticulocytosis (reticulocytes are larger than mature RBCs)
   • Drugs (hydroxyurea, zidovudine, azathioprine)
   • Post-splenectomy

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Disorders of Platelets, Bleeding Disorders and Basic Transfusion Medicine

SN 6. Haemophilia

• Spontaneous haemarthroses (joints - knee, elbow, ankle) → chronic arthropathy
• Muscle bleeds (haematomas)
• Severe: <1% factor activity; Moderate: 1-5%; Mild: >5%
• PTT prolonged; PT normal; Bleeding time normal; Platelet count normal

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SN 7. Prothrombin Time (PT) - Principle; Causes of Increased PT

• Citrated plasma + tissue factor (thromboplastin) + calcium
• Measures extrinsic pathway (factor VII) + common pathway (factors X, V, II, fibrinogen)
• Normal PT = 11-14 seconds; expressed as INR = (Patient PT/Mean Normal PT)^ISI

1. Warfarin therapy (inhibits vitamin K-dependent factors II, VII, IX, X)
2. Vitamin K deficiency (malabsorption, newborn - haemorrhagic disease of newborn, broad-spectrum antibiotics)
3. Liver disease (decreased synthesis of clotting factors)
4. Disseminated Intravascular Coagulation (DIC) - consumption of factors
5. Factor VII deficiency (specific)
6. Factor X, V, II, fibrinogen deficiency
7. Dysfibrinogenaemia

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SN 8. Causes of Thrombocytopenia - Enumerate

• Aplastic anaemia
• Bone marrow infiltration (leukaemia, lymphoma, myeloma, metastatic carcinoma)
• Megaloblastic anaemia (B12/folate deficiency)
• Myelodysplastic syndrome
• Chemotherapy/radiation

1. Immune thrombocytopenia (ITP) - anti-GPIIb/IIIa antibodies
2. Drug-induced (heparin-induced thrombocytopenia - HIT, quinine, sulfonamides)
3. Thrombotic thrombocytopenic purpura (TTP) - ADAMTS13 deficiency
4. Haemolytic uraemic syndrome (HUS) - Shiga toxin (E. coli O157:H7)
5. DIC (consumption)
6. Hypersplenism (sequestration)
7. Neonatal alloimmune thrombocytopenia
8. SLE, antiphospholipid syndrome

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SN 9. Major Fractions of Blood; Blood Components

• Whole blood → Cellular components (RBC, WBC, Platelets) + Plasma
• Plasma → Coagulation factors (including Factor VIII, fibrinogen) + Albumin, Immunoglobulins

1. Packed Red Blood Cells (PRBCs) - for anaemia, acute blood loss
2. Platelet concentrate (PC) - thrombocytopenia, platelet dysfunction
3. Fresh Frozen Plasma (FFP) - multiple factor deficiency, liver disease, DIC, reversal of warfarin
4. Cryoprecipitate - haemophilia A (Factor VIII), vWD, fibrinogen deficiency, DIC

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LAQ 2. Bleeding Disorders - Define, Classify, Screening Tests

1. Vascular (non-thrombocytopenic purpura) - vessel wall defects; Henoch-Schönlein purpura, hereditary haemorrhagic telangiectasia, vitamin C deficiency (scurvy), Ehlers-Danlos, senile purpura
2. Platelet disorders:
   • Thrombocytopenia (see SN 8)
   • Qualitative platelet disorders - Bernard-Soulier syndrome (↓ GPIb), Glanzmann thrombasthenia (↓ GPIIb/IIIa), aspirin, uraemia
3. Coagulation factor deficiencies:
   • Inherited: Haemophilia A (VIII), B (IX), vWD
   • Acquired: Liver disease, Vitamin K deficiency, DIC, anticoagulants

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LAQ 3 & 4. Blood Transfusion Reactions

1. Immediate haemolytic transfusion reaction (most dangerous):
   • Cause: ABO incompatibility (clerical error - most common preventable cause)
   • Mechanism: Pre-formed IgM → complement activation → intravascular haemolysis
   • Symptoms: Fever, chills, back/flank pain, haemoglobinuria (red/brown urine), haemoglobinaemia, DIC, renal failure
   • Management: STOP transfusion immediately, IV fluids, diuretics, treat DIC
2. Delayed haemolytic reaction (3-14 days post-transfusion):
   • Anamnestic IgG response to Rh, Kidd, Duffy antigens
   • Extravascular haemolysis; indirect Coombs positive
3. Febrile non-haemolytic reaction (most common reaction):
   • Antibodies against donor HLA antigens on WBCs; cytokines in stored blood
   • Fever, chills; managed with antipyretics; prevented with leukocyte-depleted blood
4. Allergic reaction:
   • Urticaria, pruritus (mild) - IgE against plasma proteins; treat with antihistamine
   • Anaphylaxis - IgA-deficient patients receiving blood with IgA; epinephrine
5. Transfusion-related acute lung injury (TRALI):
   • Donor anti-HLA/anti-neutrophil antibodies activate recipient neutrophils in lungs
   • Non-cardiogenic pulmonary oedema within 6 hours
   • Leading cause of transfusion-related mortality
6. Transfusion-transmitted infections: HIV, HBV, HCV, CMV, bacterial contamination (platelets - higher risk), malaria, Chagas
7. Graft-vs-Host disease (GVHD) - immunocompromised recipients; prevented by irradiation of blood
8. Massive transfusion complications: Dilutional coagulopathy, thrombocytopenia, hypothermia, hypocalcaemia, hyperkalaemia, citrate toxicity

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Disorders of Leukocytes and Lymphoreticular Tissues

SN 1. Acute Lymphoblastic Leukaemia (ALL) - PBS and Bone Marrow

• Leucocytosis (variable; may be low/normal/high)
• Lymphoblasts (L1, L2, L3 - FAB classification)
  • L1: Small, uniform blasts, scant cytoplasm, inconspicuous nucleoli (most common in childhood)
  • L2: Large, heterogeneous blasts, irregular nuclei, prominent nucleoli (common in adults)
  • L3: Large, uniform blasts, deeply basophilic cytoplasm with vacuoles (Burkitt type)
• Anaemia (normocytic normochromic)
• Thrombocytopenia
• Neutropenia

• Hypercellular; replaced by lymphoblasts (>20% for diagnosis; usually >90%)
• Few or no normal haematopoietic cells
• PAS stain: Coarse block positivity in blasts (characteristic of ALL)
• TdT (terminal deoxynucleotidyl transferase): POSITIVE (key marker for ALL vs. AML)
• CD10 (CALLA), CD19, CD20 (B-ALL); CD3, CD7 (T-ALL)

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SN 2. Chronic Myeloid Leukaemia (CML) - Peripheral Blood Picture, Clinical Features

• Leukocytosis - markedly elevated WBC (often >100 × 10^9/L)
• Complete spectrum of myeloid cells at various stages: blasts, promyelocytes, myelocytes, metamyelocytes, band cells, segmented neutrophils - "myelocyte peak" (myelocytes most numerous)
• Basophilia (important clue) and eosinophilia
• Anaemia (normocytic normochromic)
• Thrombocytosis (often >450 × 10^9/L initially)
• NAP (Neutrophil Alkaline Phosphatase) score: LOW/ABSENT (distinguishes from leukaemoid reaction where NAP is high)
• Blasts: <5% in chronic phase

• Insidious onset; fatigue, weight loss, night sweats
• Massive splenomegaly (most prominent feature - can cause abdominal fullness, early satiety)
• Hepatomegaly
• Hyperuricaemia (high cell turnover)
• Blast crisis → acute leukaemia (myeloid or lymphoid)

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SN 3. Acute Leukaemias - FAB Classification

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SN 4. Acute Myeloid Leukaemia (AML) - FAB Classification, Peripheral Smear, Bone Marrow

• Anaemia, thrombocytopenia (marrow failure)
• Leucocytosis with circulating blasts (>20% blasts diagnostic)
• Auer rods - needle-like azurophilic crystalline inclusions in blast cytoplasm; PATHOGNOMONIC of AML (especially M2, M3); positive for MPO
• MPO-positive blasts (myeloperoxidase)
• Sudan black B positive

• Hypercellular; >20% myeloblasts (WHO criterion)
• Type I blasts (no granules) and Type II blasts (few granules, no Auer rod)
• MPO, Sudan black B, chloroacetate esterase (specific esterase) positive
• TdT usually NEGATIVE (differentiates from ALL)
• Non-specific esterase (NSE) positive in monocytic lineage (M4, M5)

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LAQ 1. Leukaemia - Define, Classify; CML Findings; Acute Leukaemia FAB, Cytochemical Stains

1. Acute (blasts >20%): AML, ALL
2. Chronic (mature cells predominate): CML, CLL

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UNSPECIFIED TOPICS

SN 1. Criteria for Selection of Blood Donor

• HIV, HBsAg, HCV positive; HTLV; Chagas disease
• Haemophilia, coagulopathies
• Major cardiac, lung, liver, renal disease
• Malignancy
• Multiple sclerosis, epilepsy, psychosis

• Pregnancy (6 months post-delivery)
• Fever/infection (4 weeks)
• Tattoo/piercing (12 months)
• Surgery (6-12 months)
• Recent vaccination (2-4 weeks; rabies 1 year)
• Malaria (3 years after treatment)

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SN 2. Coombs Test - Indications for Direct and Indirect

• Detects antibody or complement ALREADY BOUND to patient's RBCs in vivo
• Procedure: Patient's washed RBCs + anti-human globulin (Coombs serum) → agglutination = positive
• Indications:
  1. Autoimmune haemolytic anaemia (AIHA) - warm AIHA (IgG) and cold AIHA (C3)
  2. Haemolytic disease of newborn (HDN) - maternal IgG on fetal RBCs
  3. Drug-induced haemolytic anaemia (methyldopa, penicillin)
  4. Haemolytic transfusion reaction

• Detects antibody in patient's SERUM (free, not bound)
• Procedure: Patient's serum + normal donor RBCs → incubation → wash → anti-human globulin → agglutination
• Indications:
  1. Crossmatch before blood transfusion (pre-transfusion compatibility testing)
  2. Antibody screening in pregnancy (Rh incompatibility)
  3. Detection of irregular antibodies in donor serum

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SN 3. Postmortem Changes in Body After Death

1. Cessation of respiration, circulation, brain activity

1. Pallor mortis - pallor of skin immediately after death (blood drains from capillaries)
2. Algor mortis - cooling of body; body cools ~0.5-1°C per hour (modified by environment, clothing, obesity); used to estimate time of death
3. Livor mortis (post-mortem hypostasis) - purplish-red discolouration of dependent parts due to pooling of blood; begins 1-2 hours post-death; fixed by 6-12 hours; useful for determining position at death
4. Rigor mortis - stiffening of muscles due to depletion of ATP → actin-myosin cross-bridges can't release; begins 2-6 hours → complete by 12 hours → resolves 24-48 hours; starts from jaw/neck → descends; Nysten's law

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SN 4. Investigation of Suspected Blood Transfusion Reaction

1. STOP transfusion
2. Keep IV line open with normal saline
3. Notify blood bank and treating physician

1. Patient blood sample (post-reaction):
   • Repeat ABO/Rh grouping
   • Direct Coombs Test (DAT)
   • Full blood count, smear (haemolysis?)
   • Plasma for haemoglobinaemia (pink/red colour)
   • Bilirubin, LDH, haptoglobin
   • Coagulation studies (PT, aPTT, fibrinogen, D-dimer - DIC?)
   • Urine - haemoglobinuria, urobilinogen
2. Blood bag + all attached tubing and filter:
   • Return to blood bank; re-check labels, cross-match records
   • ABO/Rh group of donor bag
   • Repeat cross-match
   • Bacterial culture of bag (if septic reaction suspected)
3. If febrile reaction: Rule out haemolysis first; check for bacterial contamination
4. If anaphylaxis: Check serum IgA level

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SN 5. Atherosclerosis - Etiopathogenesis

• Major modifiable: Hyperlipidaemia (LDL↑, HDL↓), hypertension, smoking, diabetes
• Non-modifiable: Age, male sex, family history

1. Endothelial dysfunction/injury: Causes - hyperlipidaemia, hypertension, smoking, turbulent flow, toxins
2. LDL infiltration and oxidation: LDL enters intima → oxidized LDL (ox-LDL); ox-LDL is chemotactic and cytotoxic
3. Monocyte adhesion and transmigration: Endothelial dysfunction → ↑ VCAM-1, ICAM-1, P-selectin → monocytes adhere → migrate into intima → become macrophages
4. Foam cell formation: Macrophages take up ox-LDL via scavenger receptors → become foam cells (lipid-laden macrophages); foam cells accumulate → fatty streak (earliest lesion)
5. SMC migration and proliferation: PDGF, FGF from activated macrophages/platelets → smooth muscle cells migrate from media to intima → proliferate → fibrous plaque
6. Plaque progression: Fibrous cap (collagen + SMC) + lipid core (foam cells, cholesterol clefts, necrotic debris) + inflammatory cells (T cells, macrophages) + calcification
7. Plaque complications: Ulceration, haemorrhage, thrombosis (upon plaque rupture - cap thin → vulnerable plaque), aneurysm

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SN 6. Uterine Leiomyoma - Gross, Microscopic Features, Complications

• Well-circumscribed, firm, whorled white-grey tumour; pseudocapsule (compressed smooth muscle)
• May be single or multiple
• Sites: Intramural (most common), subserosal, submucosal, pedunculated, cervical
• Cut surface: White, whorled, trabeculated

• Interlacing bundles of uniform, elongated smooth muscle cells
• Cells: Blunt-ended nuclei, eosinophilic fibrillar cytoplasm; no pleomorphism; rare mitoses (<5/10 HPF)
• Variable collagen content (fibrous stroma)

• Hyaline degeneration - most common (homogeneous pink areas)
• Cystic degeneration
• Myxomatous degeneration
• Red (carneous) degeneration - haemorrhagic infarction; painful; during pregnancy
• Calcification ("womb stone") - post-menopausal
• Malignant transformation to leiomyosarcoma - RARE (<0.5%)

1. Menorrhagia / menometrorrhagia → iron deficiency anaemia
2. Subfertility / infertility
3. Recurrent miscarriage
4. Pressure effects: Urinary frequency (bladder), constipation (rectum), hydronephrosis
5. Pain (torsion of pedunculated fibroid, red degeneration in pregnancy)
6. Malignant transformation (rare)
7. Polycythaemia (ectopic erythropoietin - very rare)

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LAQ 1. Investigations in Blood Transfusion Reaction

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