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PATHOLOGY - MUHS 2nd MBBS EXAM NOTES

Haemodynamic Disorders: Complete Reference

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SAQ ANSWERS

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1. INFARCT - Definition and Types

Definition

"An infarct is an area of ischemic necrosis caused by occlusion of either arterial supply or the venous drainage." - Robbins Basic Pathology

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Types of Infarcts

A. Based on COLOR (Gross Appearance)

1. Venous occlusions (e.g., ovarian torsion)
2. Loose/spongy tissues (e.g., lung) where blood can collect
3. Dual blood supply (e.g., lung - pulmonary + bronchial)
4. Re-perfusion of previously ischemic tissue
5. Previously congested tissues

1. End-artery supply (heart, kidney, spleen)
2. Dense solid tissues that limit hemorrhagic seepage

B. Based on PRESENCE OF BACTERIA

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Gross Morphology of Infarct

EARLY (6-12 hrs): Poorly defined, soft, congested area
                  Coagulative necrosis not yet apparent

24-48 hrs:       Well-defined, pale yellow/white (or red)
                  Wedge-shaped with base at periphery
                  Tip pointing toward occluded vessel

OLD INFARCT:     Contracted, firm scar
                  Pale grey-white color
                  Depressed surface (fibrosis)

     Surface of kidney
    ___________________
   |    /\    /\       |
   |   /  \  /  \      |
   |  /    \/    \     |
   | (wedge-shaped)    |
   |   base at cortex  |
   |___________________|

Microscopic Features of Infarct

• Early: Coagulative necrosis - ghost outlines of cells, pyknotic nuclei, eosinophilic cytoplasm
• 24-48 hrs: Neutrophilic infiltration at margins
• 1 week: Macrophage infiltration, phagocytosis of debris
• 2 weeks+: Granulation tissue formation (angiogenesis + fibroblasts)
• Final: Fibrous scar replacing infarcted tissue

Factors Affecting Infarct Development

1. Nature of vascular supply (dual vs. end artery)
2. Rate of occlusion (slow = collaterals can develop)
3. Vulnerability of tissue to hypoxia
   • Neurons: 3-5 min
   • Myocardium: 20-30 min
   • Skeletal muscle: hours
4. Oxygen content of blood
5. Collateral circulation

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2. OEDEMA - Definition, Classification, Transudate vs Exudate

Definition

• Anasarca - severe generalized oedema with profound subcutaneous tissue swelling
• Hydrothorax - fluid in pleural cavity
• Hydropericardium - fluid in pericardial cavity
• Ascites - fluid in peritoneal cavity

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Classification of Oedema

A. By Distribution

1. Localized oedema - limited to a particular organ/region (e.g., pulmonary, cerebral, dependent)
2. Generalized oedema (Anasarca) - widespread, involves subcutaneous tissue, serous cavities

B. By Mechanism / Pathogenesis

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Pathogenesis of Oedema (Starling Forces)

NORMAL BALANCE (Starling's Law):
                                         
  Capillary      Interstitium
  Arteriolar end:
  ┌──────────┐   
  │ HP=35    │ ──────────────► Filtration OUT
  │ OP=25    │
  │ Net=10   │   (Fluid leaves)
  
  Venular end:
  ┌──────────┐   
  │ HP=15    │ ◄────────────── Reabsorption IN
  │ OP=25    │
  │ Net=-10  │   (Fluid returns)
  
  HP = Hydrostatic Pressure
  OP = Oncotic Pressure

1. ↑ Hydrostatic pressure → More fluid forced out → Heart failure, venous obstruction
2. ↓ Plasma oncotic pressure → Less fluid drawn back → Hypoproteinemia, nephrotic syndrome
3. ↑ Vascular permeability → Proteins leak out → Inflammation, burns
4. Lymphatic obstruction → Fluid not drained → Filariasis
5. Na+ and water retention → Increased plasma volume → Renal failure, aldosterone excess

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TRANSUDATE vs EXUDATE

Memory Trick: Transudate = "Thin/Transparent" = Low protein. Exudate = "Exit of proteins" = High protein.

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3. VIRCHOW'S TRIAD - Role in Thrombus Formation; Thrombus - Gross and Microscopic Features

Virchow's Triad

         ┌─────────────────────────────────────┐
         │         VIRCHOW'S TRIAD             │
         │                                     │
         │    1. Endothelial Injury             │
         │    2. Abnormal Blood Flow            │
         │    3. Hypercoagulability             │
         └──────────────┬──────────────────────┘
                        │
                        ▼
                  THROMBUS FORMATION

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1. Endothelial Injury (Most Important)

• Key factor for thrombus formation in heart and arteries
• Causes: Atherosclerosis, hypertension, turbulent flow, toxins, inflammation, hypercholesterolemia, homocystinemia, cigarette smoke

• Loss of anticoagulant surface → exposes subendothelial collagen + von Willebrand factor (vWF)
• Platelet adhesion via vWF (Gp Ib receptor) → activation → aggregation
• Tissue factor (TF) released → extrinsic pathway activated
• Decreased production of prostacyclin (PGI₂) and NO (vasodilators/platelet inhibitors)
• Decreased thrombomodulin expression → less protein C activation

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2. Abnormal Blood Flow (Stasis / Turbulence)

• Normal laminar flow: platelets kept central, separated from endothelium by plasma layer
• Turbulence (arterial/cardiac): disrupts laminar flow, causes endothelial injury
• Stasis (venous): platelets and coagulation factors accumulate; endothelium becomes hypoxic → prothrombotic gene expression

• Stasis → DVT (deep vein thrombosis), post-operative, immobilization
• Turbulence → cardiac thrombi in MI, aneurysms, stenotic valves

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3. Hypercoagulability

• Factor V Leiden mutation (most common) - resistant to activated Protein C
• Prothrombin G20210A mutation - elevated prothrombin
• Protein C or S deficiency - cannot inactivate Va, VIIIa
• Antithrombin III deficiency - cannot inactivate thrombin, Xa
• Hyperhomocysteinemia - endothelial injury + platelet activation

• Prolonged bed rest / immobilization
• Myocardial infarction
• Oral contraceptive pills (estrogen → ↑ clotting factors, ↓ antithrombin III)
• Malignancy (Trousseau syndrome - migratory thrombophlebitis)
• Pregnancy (↑ clotting factors, venous stasis)
• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia (HIT)
• Disseminated intravascular coagulation (DIC)

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Thrombus - Gross Features

GROSS APPEARANCE:

1. ARTERIAL THROMBUS:
   - Grey-white, firm
   - Laminated appearance
   - Lines of Zahn visible macroscopically
   - Adherent to vessel wall
   - Dry, friable

2. VENOUS THROMBUS:
   - Red-blue (gelatinous)
   - Soft, coagulated
   - Poorly attached, can break off
   - Shows lines of Zahn at proximal end only
   - Resembles "currant jelly" appearance (post-mortem clot is different)
   
3. CARDIAC MURAL THROMBUS:
   - Overlies infarcted myocardium
   - Grey-white, laminated
   
POST-MORTEM CLOT vs THROMBUS (distinguish in exams!):
┌──────────────┬────────────────────────────────────┐
│ Feature      │ Post-mortem clot  │ Ante-mortem     │
│              │                   │ thrombus        │
├──────────────┼───────────────────┼─────────────────┤
│ Consistency  │ Gelatinous        │ Firm, dry       │
│ Attachment   │ Not adherent      │ Adherent        │
│ Lines Zahn   │ Absent            │ Present         │
│ Color        │ Yellow + red      │ Grey-white      │
│              │ (chicken fat)     │ (or red)        │
└──────────────┴───────────────────┴─────────────────┘

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Thrombus - Microscopic Features

LINES OF ZAHN (Pathognomonic feature of thrombus)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

  ┌─────────────────────────────────────────┐
  │ PALE BAND (Platelets + Fibrin)          │
  ├─────────────────────────────────────────┤
  │ RED BAND (RBCs + WBCs)                  │
  ├─────────────────────────────────────────┤
  │ PALE BAND (Platelets + Fibrin)          │
  ├─────────────────────────────────────────┤
  │ RED BAND (RBCs + WBCs)                  │
  └─────────────────────────────────────────┘
  = Alternating pale and dark laminations
  = LINES OF ZAHN

1. Platelet aggregates - pale, granular clusters (lines of Zahn - pale component)
2. Fibrin mesh - eosinophilic threads entrapping cells
3. Red blood cells - dark component of Lines of Zahn
4. WBCs (mainly neutrophils) - scattered throughout
5. Vessel wall - thrombus is ATTACHED to wall (unlike post-mortem clot)

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Fate of Thrombus (Important for Exam)

FATE OF THROMBUS
      │
      ├──→ 1. PROPAGATION: Growth by continued platelet/fibrin accretion
      │
      ├──→ 2. EMBOLIZATION: Part/all breaks off → travels downstream
      │
      ├──→ 3. DISSOLUTION: Fibrinolysis → complete lysis (best outcome)
      │                     (basis of tPA/streptokinase therapy)
      │
      ├──→ 4. ORGANIZATION and RECANALIZATION:
      │       - Macrophages + fibroblasts → granulation tissue
      │       - Endothelial cells grow in → new channels form
      │       - May restore partial blood flow
      │       - Seen as fibrous tissue with vascular channels
      │
      └──→ 5. CALCIFICATION: "Phleboliths" (venous) or arterial calcification

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4. Pathways Leading to Systemic Oedema from Primary Heart Failure

PRIMARY HEART FAILURE
         │
         ▼
┌─────────────────────────┐
│ ↓ Cardiac Output        │
│ (Forward Failure)       │
└─────────┬───────────────┘
          │
          ├──────────────────────────────────────┐
          │                                      │
          ▼                                      ▼
┌──────────────────┐                  ┌───────────────────────┐
│ ↓ Renal Perfusion│                  │ ↑ Venous Pressure      │
│ (GFR falls)      │                  │ (Backward Failure)     │
└────────┬─────────┘                  └──────────┬────────────┘
         │                                       │
         ▼                                       ▼
┌──────────────────────┐              ┌───────────────────────┐
│ Activation of RAAS   │              │ ↑ Capillary Hydrostatic│
│ (Renin-Angiotensin-  │              │ Pressure              │
│  Aldosterone System) │              └──────────┬────────────┘
└──────────┬───────────┘                         │
           │                                     │
           ▼                                     ▼
┌──────────────────────┐              ┌───────────────────────┐
│ ↑ Na+ & H₂O retention│              │ Fluid forced into     │
│ ↑ ADH secretion      │              │ interstitium          │
└──────────┬───────────┘              └──────────┬────────────┘
           │                                     │
           └───────────────┬─────────────────────┘
                           │
                           ▼
                  ┌─────────────────┐
                  │ SYSTEMIC OEDEMA │
                  │ (Dependent      │
                  │  oedema, ascites│
                  │  anasarca)      │
                  └─────────────────┘

NOTE: Right-sided heart failure → systemic oedema
      Left-sided heart failure → pulmonary oedema (initially)

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5. EMBOLISM - Definition; Pulmonary Thromboembolism

Definition of Embolism

~99% of all emboli arise from thrombi = Thromboembolism

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Pulmonary Thromboembolism (PTE)

Source

• ~95% arise from deep vein thrombosis (DVT) of lower limbs (femoral, popliteal, iliac veins)
• Detached thrombus → right side of heart → pulmonary artery

Classification by Size

Clinical Features

• Sudden onset dyspnea (most common)
• Pleuritic chest pain
• Hemoptysis
• Tachycardia, hypoxemia
• Massive PE: sudden death (saddle embolus)
• Small PE: may cause pulmonary infarction - wedge-shaped, hemorrhagic infarct in lung

Gross Features of Pulmonary Embolism/Infarct

• Embolus visible in pulmonary artery or branch
• Pulmonary infarct - hemorrhagic, wedge-shaped, base at pleural surface, tip toward hilus
• Overlying pleural fibrinous exudate (pleurisy)
• Red-brown, consolidated area

Microscopic Features

• Coagulative necrosis with ghost outlines of alveoli
• Hemorrhage filling alveolar spaces
• Inflammatory infiltrate at margins (neutrophils → macrophages)
• Hemosiderin-laden macrophages in older lesions ("heart failure cells")
• Fibrin thrombus in involved vessels

Paradoxical Embolism

• Thrombus in venous system passes to arterial system through patent foramen ovale (PFO)
• Causes arterial (systemic) complications despite venous origin

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6. Liver and Spleen in Right-Sided Heart Failure

LIVER (Cardiac Liver / "Nutmeg Liver")

Mechanism

Gross Features

NUTMEG LIVER (Chronic Passive Congestion)

Cross-section appearance:
  
  ┌─────────────────────────────────────┐
  │  .  RED   .  TAN  .  RED  . TAN  . │
  │  (congested (fatty) (congested)     │
  │   center)  areas    center)         │
  │                                     │
  │  Alternating RED and YELLOW areas   │
  │  resembling a CUT NUTMEG!           │
  └─────────────────────────────────────┘
  
- Enlarged liver (hepatomegaly)
- Tense, capsule under pressure
- Cut surface: RED centers (centrilobular) + TAN/YELLOW periphery (fatty)
- Resembles cut surface of nutmeg
- CARDIAC CIRRHOSIS (late stage): firm, fibrosed

Microscopic Features

CENTRILOBULAR NECROSIS (Zone 3 necrosis)

    Portal Triad         Central vein (CV)
         ↓                     ↓
    Zone 1 (periportal)   Zone 3 (centrilobular)
    - Normal              - CONGESTED
    - Fatty change        - NECROTIC hepatocytes
                          - RBCs in sinusoids
                          - Hemosiderin
    
    "Blood lake" appearance around central veins

1. Centrilobular congestion - dilated sinusoids filled with RBCs (zone 3)
2. Centrilobular hepatocyte necrosis - hepatocytes around central vein undergo necrosis/atrophy (ischemia + congestion)
3. Periportal hepatocytes relatively preserved (closer to blood supply)
4. Fatty change - in periportal hepatocytes (zone 1)
5. Chronic cases: Cardiac cirrhosis - perivenular fibrosis extending out
6. Hemosiderin-laden Kupffer cells

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SPLEEN (Congestive Splenomegaly)

Mechanism

Gross Features

• Enlarged, firm spleen (moderate splenomegaly ~500-1000g; normal ~150g)
• Cut surface: dark red-blue (congested)
• Tense capsule, may be thickened
• Follicles may be compressed/inconspicuous
• Gamna-Gandy bodies (hemosiderin deposits = "tobacco speck" foci) in chronic cases

Microscopic Features

CONGESTED SPLEEN:

  ┌────────────────────────────────────────┐
  │ • Sinusoids MARKEDLY DILATED           │
  │ • Packed with RBCs                     │
  │ • White pulp (lymphoid follicles)      │
  │   ATROPHIED / compressed               │
  │ • Fibrosis of red pulp (chronic)       │
  │ • GAMNA-GANDY BODIES:                  │
  │   - Hemosiderin + calcium deposits     │
  │   - Within fibrotic foci               │
  │   - Appear as brown, iron-positive     │
  │     deposits on Prussian blue stain    │
  └────────────────────────────────────────┘

• Fibrotic thickening of sinusoidal walls
• Deposition of hemosiderin and calcium in the walls
• "Perisplenitis" - fibrous capsular thickening

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LAQ ANSWERS

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LAQ 1. OEDEMA - Complete Answer

Definition

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Types / Classification

1. Localised oedema
2. Generalised oedema (Anasarca)

1. Transudate (non-inflammatory) - protein < 3g/dL
2. Exudate (inflammatory) - protein > 3g/dL

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Pathogenesis of Oedema

Net Fluid Movement = Kf [(Pc - Pi) - σ(πc - πi)]

Pc = Capillary hydrostatic pressure
Pi = Interstitial hydrostatic pressure
πc = Plasma oncotic pressure  
πi = Interstitial oncotic pressure
Kf = Filtration coefficient
σ = Reflection coefficient for proteins

PATHOGENESIS OF OEDEMA
══════════════════════

1. ↑ HYDROSTATIC PRESSURE
   │
   ├─ Arterial: Arteriolar dilatation (inflammation, heat)
   └─ Venous: Heart failure, venous thrombosis, portal HTN
   → Excess fluid forced into interstitium

2. ↓ PLASMA ONCOTIC PRESSURE (HYPOPROTEINEMIA)
   │
   ├─ ↓ Synthesis: Liver failure (↓ albumin), starvation
   └─ ↑ Loss: Nephrotic syndrome (proteinuria), burns
   → Less fluid drawn back into capillaries

3. ↑ VASCULAR PERMEABILITY (Inflammatory)
   │
   ├─ Mediators: Histamine, bradykinin, IL-1, TNF, VEGF
   └─ Proteins + fluid leak into interstitium
   → Draws more fluid out (↑ interstitial oncotic pressure)

4. LYMPHATIC OBSTRUCTION
   │
   ├─ Filariasis (most common in tropics)
   ├─ Post-mastectomy
   └─ Malignant infiltration
   → Interstitial fluid not drained

5. Na+ AND WATER RETENTION
   │
   ├─ ↓ GFR (heart failure, renal failure)
   ├─ ↑ Aldosterone (RAAS activation)
   └─ ↑ ADH
   → ↑ Plasma volume → ↑ hydrostatic pressure

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Pulmonary Oedema

Pathophysiologic Mechanism

PULMONARY OEDEMA PATHOGENESIS
══════════════════════════════

LEFT VENTRICULAR FAILURE (Most common)
         │
         ▼
↑ Left atrial pressure
         │
         ▼
↑ Pulmonary venous pressure
         │
         ▼
↑ Pulmonary capillary hydrostatic pressure
(exceeds 18-25 mmHg)
         │
         ▼
Fluid transudates into alveolar interstitium
         │
         ▼
Overwhelms lymphatic drainage capacity
         │
         ▼
Fluid fills alveoli (airspace oedema)
         │
         ▼
PULMONARY OEDEMA
(↓ gas exchange, hypoxemia, dyspnoea)

OTHER CAUSES:
- ARDS (↑ permeability oedema)
- Hypoalbuminemia
- High altitude oedema
- Neurogenic oedema (brain injury)
- Toxin inhalation

Gross Features of Pulmonary Oedema

• Heavy, wet lungs (normal ~400g; oedematous >700-1000g)
• Frothy, pink fluid oozes from cut surface and airways
• Congested, dark red-pink colour
• Waterlogged consistency
• In chronic cases: brown induration (firm, brown - due to hemosiderin + fibrosis)

Microscopic Features of Pulmonary Oedema

HISTOLOGY OF PULMONARY OEDEMA:

Normal alveolus:      Oedematous alveolus:
    ┌──┐                  ┌─────────────┐
    │  │ Air              │░░░░░░░░░░░░░│ Pink fluid
    │  │                  │░░ FLUID ░░░│ (transudate)
    └──┘                  └─────────────┘
 Thin walls            Thickened alveolar walls
                       Fluid = pink, homogeneous
                       Few RBCs in fluid

1. Alveoli filled with homogeneous pink fluid (transudate) - pale eosinophilic material
2. Alveolar capillaries dilated and congested
3. Alveolar walls thickened
4. Hyaline membranes in acute cases (ARDS) - fibrin + protein lining alveolar walls
5. Chronic pulmonary oedema:
   • Heart failure cells - hemosiderin-laden alveolar macrophages (ingest extravasated RBCs)
   • Hemosiderin deposits (iron-positive on Prussian blue stain)
   • Fibrosis of alveolar septa (brown induration)

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LAQ 2. EMBOLISM - Complete Answer

Definition

---

Types with Examples

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Pathogenesis of Embolism

FORMATION → DETACHMENT → TRANSPORT → IMPACTION

1. FORMATION:
   - Thrombus forms due to Virchow's triad
   - Fat released from bone marrow/adipocytes (trauma)
   - Air introduced via catheter/surgery

2. DETACHMENT:
   - Part or all of thrombus breaks off
   - Physical trauma, sudden movement, Valsalva

3. TRANSPORT:
   - Carried in bloodstream
   - Venous → right heart → pulmonary circulation
   - Arterial → systemic circulation (brain, kidney, limbs)

4. IMPACTION:
   - Lodges where vessel diameter < embolus size
   - Causes obstruction → ischemia/infarction downstream

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Pulmonary Thromboembolism (PTE) - Morphological Appearance

Main pulmonary artery
          │
    ┌─────┴──────┐
    │ (embolus   │
    │  straddles │
    │  bifurc.)  │
    └────────────┘
    → Sudden death (acute cor pulmonale)

• Coiled, red-brown thrombus in pulmonary artery (or branches)
• Lines of Zahn visible (confirms ante-mortem origin)
• Wedge-shaped hemorrhagic infarct (if small artery occluded)
• Pleural fibrinous exudate

• Organizing thrombus in vessel lumen
• Coagulative necrosis in infarcted area
• Hemorrhage filling alveoli
• Fibrin in alveolar spaces
• "Heart failure cells" (hemosiderin macrophages) in older lesions

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Fate of Emboli

FATE OF EMBOLUS
     │
     ├──→ Sudden death (massive PTE)
     ├──→ Infarction (small/medium vessels)
     ├──→ Organization and recanalization
     ├──→ Complete lysis (fibrinolysis)
     └──→ Chronic pulmonary hypertension (recurrent micro-emboli)

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Air Embolism

1. IV line insertion/disconnection (>100 mL air needed to be fatal)
2. Neck surgery (large veins open to atmosphere)
3. Obstetric procedures
4. Decompression sickness ("the bends") - Nitrogen bubbles form when divers ascend too quickly

Air bubble enters vein
      ↓
Passes to right heart
      ↓
"Frothy blood" - cannot be pumped efficiently
      ↓
Pulmonary obstruction → hypoxia
      ↓
If air passes to left side: cerebral/coronary air embolism
      ↓
Rapid death (>300 mL air in adults)

• Nitrogen dissolves in blood/tissues at high pressure
• Rapid ascent → nitrogen comes out of solution as bubbles
• Gas emboli in joints (bends - pain), lungs (chokes - dyspnoea), brain (staggers - neurological)
• Tx: Recompression in hyperbaric chamber

• After fractures of long bones (femur) or orthopedic surgery
• Fat embolism syndrome (24-72 hrs later): dyspnoea, neurological symptoms, petechial rash
• Mechanism: fat globules + free fatty acids → inflammatory mediators → ARDS-like picture
• Micro: Oil red O/Sudan stain shows fat globules in pulmonary vessels

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LAQ 3. THROMBUS - Definition, Pathogenesis, Types, Fate, Complications

Definition

---

Pathogenesis (Virchow's Triad - see SAQ 3 above for detail)

Vascular injury
      ↓
Collagen + vWF exposed
      ↓
Platelet adhesion (Gp Ib - vWF interaction)
      ↓
Platelet activation (shape change, granule release)
   - ADP, TXA₂ released
   - GpIIb/IIIa expressed
      ↓
Platelet aggregation (fibrinogen bridges GpIIb/IIIa)
      ↓
Coagulation cascade activated (tissue factor pathway)
      ↓
Thrombin generated
   - Converts fibrinogen → fibrin
   - Further activates platelets
   - Activates factor XIII (cross-links fibrin)
      ↓
STABLE THROMBUS
(Platelets + fibrin + entrapped RBCs/WBCs)

---

Types of Thrombus

---

Fate of Thrombus (5 fates - Important!)

1. Propagation - grows larger; may occlude vessel completely
2. Embolization - breaks off, travels to distant site
3. Dissolution - fibrinolysis by plasmin; most favourable outcome
4. Organization and recanalization - fibroblasts + endothelial cells invade → fibrous tissue + new vascular channels; restores partial flow
5. Calcification - rarely; "phleboliths" in veins

---

Complications of Thrombus

1. Obstruction - ischemia/infarction downstream
2. Embolism - PE (from venous), stroke/MI (from arterial)
3. Infection - septic thrombus/embolism
4. Heart failure - from coronary/cardiac thrombi
5. Pulmonary hypertension - recurrent micro-emboli
6. Paradoxical embolism - through PFO

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LAQ 4. NORMAL HAEMOSTASIS AND THROMBOSIS

Normal Haemostasis

HAEMOSTASIS IN 3 PHASES:

PHASE 1: PRIMARY HAEMOSTASIS (Platelet plug)
══════════════════════════════════════════════
Vascular injury
      ↓
① VASOCONSTRICTION (immediate, transient)
   - Neurogenic reflex
   - Endothelin released from endothelium
      ↓
② PLATELET ADHESION
   - Collagen + vWF exposed
   - Platelet GpIb binds vWF → adhesion
      ↓
③ PLATELET ACTIVATION (Shape change)
   - ADP + TXA₂ released (amplify activation)
   - GpIIb/IIIa expressed on surface
   - Phosphatidylserine exposed (for coag.)
      ↓
④ PLATELET AGGREGATION
   - GpIIb/IIIa binds fibrinogen
   - Fibrinogen bridges platelets
   → LOOSE PLATELET PLUG (primary plug)

PHASE 2: SECONDARY HAEMOSTASIS (Coagulation)
══════════════════════════════════════════════
Tissue factor (TF) released by subendothelium
      ↓
EXTRINSIC PATHWAY:
TF + VIIa → Xa (+ Va) → Prothrombin → Thrombin
      ↓
INTRINSIC PATHWAY (amplification):
XII → XI → IX → (with VIIIa) → Xa
      ↓
COMMON PATHWAY:
Thrombin → cleaves Fibrinogen → Fibrin monomers
         → activates Factor XIII
         → Cross-linked Fibrin
         → STABLE FIBRIN CLOT
         → entraps RBCs + WBCs

PHASE 3: FIBRINOLYSIS (Limiting the clot)
══════════════════════════════════════════
t-PA released from endothelium
      ↓
Plasminogen → Plasmin
      ↓
Plasmin digests fibrin → Fibrin degradation products
(D-dimer = marker of fibrinolysis/thrombosis)

---

Coagulation Cascade Diagram

INTRINSIC PATHWAY          EXTRINSIC PATHWAY
(Contact activation)       (Tissue factor)

XII → XIIa                 TF + VII → VIIa
      ↓                           ↓
XI → XIa                           ↓
      ↓                           ↓
IX → IXa ─────────────────────────┘
      ↓ (with VIIIa, Ca²⁺, PL)
      X → Xa
           ↓ (with Va, Ca²⁺, PL)
     Prothrombin → THROMBIN
                       ↓
              Fibrinogen → FIBRIN
                               ↓ (Factor XIII)
                       CROSS-LINKED FIBRIN CLOT

Ca²⁺ required for factors II, VII, IX, X (vitamin K dependent)
Warfarin blocks vitamin K → inhibits II, VII, IX, X
Heparin activates antithrombin III → inhibits thrombin + Xa

---

Antithrombotic Mechanisms of Normal Endothelium

NORMAL ENDOTHELIUM: ANTI-THROMBOTIC SURFACE
═════════════════════════════════════════════

1. PGI₂ (Prostacyclin) → inhibits platelet aggregation + vasodilator
2. NO → inhibits platelet aggregation + vasodilator
3. ADPase (CD39) → degrades ADP (platelet activator)
4. Thrombomodulin → binds thrombin → activates Protein C
5. Protein C + S → inactivate factors Va + VIIIa
6. Heparin-like molecules → activate Antithrombin III
7. Antithrombin III → inhibits thrombin, Xa, IXa, XIa
8. TFPI (Tissue Factor Pathway Inhibitor) → inhibits TF/VIIa
9. t-PA → converts plasminogen to plasmin → fibrinolysis

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Thrombosis - Factors Causing (MUHS Exam - Important)

VIRCHOW'S TRIAD
┌────────────────────┬────────────────────┬────────────────────┐
│ ENDOTHELIAL INJURY │ ABNORMAL FLOW      │ HYPERCOAGULABILITY │
├────────────────────┼────────────────────┼────────────────────┤
│ • Atherosclerosis  │ • Stasis (DVT)     │ PRIMARY:           │
│ • Hypertension     │ • Turbulence       │ • Factor V Leiden  │
│ • Toxins/smoking   │   (aneurysm, MI)   │ • Protein C/S def  │
│ • Inflammation     │ • Cardiac AF       │ • AT III def       │
│ • Homocysteinemia  │ • Immobilization   │ SECONDARY:         │
│ • Irradiation      │ • Obesity          │ • OCP              │
│                    │                    │ • Malignancy       │
│                    │                    │ • Pregnancy        │
│                    │                    │ • Nephrotic synd.  │
│                    │                    │ • Antiphospholipid │
└────────────────────┴────────────────────┴────────────────────┘
        ↓                    ↓                     ↓
                     THROMBOSIS

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HISTOPATHOLOGY DIAGRAMS FOR EXAM

1. Lines of Zahn (Microscopic feature of thrombus - easy to draw)

   ╔════════════════════════════════════════╗
   ║ [PALE - Platelets + Fibrin mesh]      ║
   ╠════════════════════════════════════════╣
   ║ [DARK - RBCs + WBCs]                  ║
   ╠════════════════════════════════════════╣
   ║ [PALE - Platelets + Fibrin mesh]      ║
   ╠════════════════════════════════════════╣
   ║ [DARK - RBCs + WBCs]                  ║
   ╚════════════════════════════════════════╝
        Vessel wall (attached)

2. Nutmeg Liver (Microscopic)

   Portal triad                Central vein
       (PT)                        (CV)
        *                           ●
       / \                         
  Zone 1   Zone 2   Zone 3
  (FATTY)           (CONGESTED + NECROTIC)
  Normal            • Sinusoids dilated
                    • RBCs in sinusoids
                    • Hepatocyte necrosis
                    • Hemosiderin in Kupffer cells

3. Pulmonary Oedema (Microscopic)

   ALVEOLAR WALL
   ─────────────────────────────────────
   Alveolar space:
   ░░░░░░░ PINK FLUID ░░░░░░░░░░░░░░░░
   ░ (homogeneous, eosinophilic) ░░░░░
   ░░ Few RBCs scattered ░░░░░░░░░░░░░
   ─────────────────────────────────────
   
   CHRONIC: Heart failure cells (macrophages with brown hemosiderin granules) visible
   ■ ■ ■ = hemosiderin-laden macrophages

4. Spleen in CHF (Microscopic)

   WHITE PULP (lymphoid follicles):
   [○] [○] SMALL, ATROPHIED
   
   RED PULP (sinusoids):
   ════════════════════
   │▓▓▓▓ RBCs ▓▓▓▓▓▓│   ← Dilated sinusoids
   │▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓│      packed with blood
   ════════════════════
   ■ = Gamna-Gandy bodies (hemosiderin + calcium)

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QUICK REVISION MNEMONICS

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IMPORTANT DEFINITIONS (One-Liners for Exam)

• Infarct = area of ischemic coagulative necrosis due to vessel occlusion
• Oedema = excess interstitial fluid accumulation
• Anasarca = severe generalized oedema with subcutaneous swelling
• Thrombus = solid mass formed in cardiovascular system from blood constituents during life
• Thrombosis = pathological formation of thrombus in intact vessels
• Embolism = transport of intravascular material to a distant site
• Embolus = detached intravascular mass transported by blood
• Transudate = non-inflammatory fluid; protein < 3g/dL; sp. gravity < 1.012
• Exudate = inflammatory fluid; protein > 3g/dL; sp. gravity > 1.020
• Lines of Zahn = alternating pale (platelet-fibrin) and dark (RBC) laminations in thrombus
• Nutmeg liver = gross appearance of liver in chronic passive venous congestion
• Heart failure cells = hemosiderin-laden macrophages in lung in chronic left heart failure
• Saddle embolus = large pulmonary embolus straddling main pulmonary artery bifurcation
• Virchow's triad = endothelial injury + stasis/turbulence + hypercoagulability

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