PATHOLOGY

(Study (logos) of suffering (pathos)

Pathology is the “Study of disease”.

It describes the effects, progress and consequences of the disease and attempts to determine the cause (aetiology)
and underlying mechanisms (pathogenesis).

It forms a bridge between basic science and clinical practice.

COMPONENTS OF PATHOLOGY:

1.Predisposing Causes of Disease: Factors which make an individual more susceptible to a disease (damp weather,
poor ventilation, etc.)

2.Etiology: This involves the study of pathogens that cause disease

3.Pathogenesis: The mechanism causing the disease

4.Morphology: The structural features of the disease

5.Clinical Significance: The functional features of the disease.

INFLAMMATION:
Inflammation is a protective complex reaction to injurious agents such as microbes and damaged, usually necrotic
cells that consists of vascular responses, migration and activation of leukocytes, and systemic reactions.

CARDINAL SIGNS OF INFLAMMATION:

-Rubor (redness) and Calor (heat)

Histamine-mediated vasodilation of arterioles

-Tumor (swelling)

Histamine mediated increase in permeability of venules

-Dolor (pain)

Prostaglandin (PG)E2 sensitizes specialized nerve endings to the effects of bradykinin and other pain mediators.

-Functio laesa (Loss of function)

ACUTE VS CHRONIC INFLAMMATION:

SEQUENTIAL VASCULAR EVENTS:

A. Vasoconstriction of arterioles: Neurogenic

reflex that lasts only seconds.

B. Vasodilation of arterioles:(Histamine and

other vasodilators (e.g., nitric oxide) relax
vascular smooth muscle causing increased
blood flow. Increased blood flow increases
intravascular hydrostatic pressure.

C. Increased permeability of venules:

Histamine and other mediators contract
endothelial cells producing endothelial gaps.
Outpouring of protein rich fluid into the
extravascular tissue leads to decreased
intravascular osmotic pressure. Transudate
moves into the interstitial tissue.

D. Swelling of tissue: Net outflow of fluid

surpasses lymphatic ability to remove

fluid.

E. Reduced blood flow: Decrease in hydrostatic pressure caused by outflow of fluid into the interstitial tissue
results in stasis ( dilated blood vessel packed with RBC, with slower blood flow and increased viscosity of the
blood.
SEQUENTIAL CELLULAR EVENTS:

Neutrophils are the primary leukocytes in acute inflammation.

1. Margination
2. Rolling
3. Adhesion
4. Transmigration(Diapedesis)
5. Chemotaxis
6. Phagocytosis

1.MARGINATION:

 RBCs aggregate into rouleaux (stacked coins) in venules

 Neutrophils are pushed from the central axis column to the periphery
(margination).
 Accumulation of leukocytes along the endothelial surface.

2. ROLLING:

 Due to activation of selectin adhesion molecules on the

surface of neutrophils and endothelial cells.
 Neutrophil loosely bind to selectins through their sialylated
forms of oligosachharides (sialylated lewis X) and roll along
the endothelium.

3.ADHESION:

 Adhesion molecules bind neutrophils to endothelial cells by neutrophil adhesion molecules and
endothelial adhesion molecules.
 Neutrophils in the blood are subdivided into circulating pool and marginating pool. (i.e. neutrophils not
adhered to the endothelium and adhered to the endothelium respectively.)
a) Neutrophils adhesion molecules
1-Integrins (CD11a/CD18)
o Adhesion molecule activation is mediated by C5a and
leukotrienes B4 (LTB4). Catecholamines, corticosteroids, and
lithium inhibit activation of adhesion molecules.
o Peripheral blood neutrophil count(neutrophil leukocytosis) is
increased.
o Endotoxins enhance activation of adhesion molecules
o Peripheral blood neutrophil count is decreased (neutropenia)
b) Endothelial adhesion molecules
o Intercellular adhesion molecules (ICAM) and vascular cell
adhesion molecule (VCAM) bind to integrins on the surface of neutrophils.
o ICAM and VCAM activation is mediated by interleukin 1(IL-1) and Tumor necrosis factor (TNF)
4. TRANSMIGRATION(DIAPEDESIS):

 Migration of the leukocytes through the endothelium is called

transmigration (Diapedesis)
 Homophilic adhesion molecules (adhesion molecules that bind to
each other) e.g. PECAM (Platelet endothelial cell activation
molecule) or CD31 present in the intercellular junction of the
endothelium initiate the migration of the leukocytes.
 Neutrophils dissolve the basement membrane and enter interstitial
tissue by the enzyme collagenase that acts on Type IV collagen
present in the basement membrane.
 Fluid rich in proteins and cells (i.e. exudate ) accumulates in
interstitial tissue.

5. CHEMOTAXIS:

 Neutrophils follow chemical gradients that lead to the infection site.

 Chemotactic mediators bind to neutrophil receptors. Mediators include C5a, LTB4, bacterial products and
IL-8 ( CILK: C5a,IL-8,LTB4 and Kallikrein)
 Binding of the mediators leads to the release of calcium, which increases neutrophil motility.

6.PHAGOCYTOSIS:

Comprises of :

a)Opsonization b)Ingestion c)Killing

a) Opsonization:

-Opsonins attach to bacteria (or foreign bodies)

-Opsonins include IgG, C3b fragment of complement and other proteins (e.g. C-reactive protein).

- Neutrophils have membrane receptor for IgG and C3b

-Opsonization enhances neutrophil recognition and attachment to bacteria.

b) Ingestion:

-Neutrophils engulf (phagocytose) and then trap bacteria in phagocytic vacuoles.

-Primary lysosomes empty hydrolytic enzymes into phagocytic vacuoles producing phagolysosomes.

- In Chediak-Higashi syndrome: There is a defect in microtubule function that prevents phagolysosome formation.

c) Bacteria killing:

i. O2-dependent myeloperoxidase system

ii. O2 independent system

i.O2 dependent-myeloperoxidase (MPO) system:

Only present in neutrophils and monocytes (and nonmacrophage).There is –

1)Production of superoxide free radicals (O - ) - NADPH(Reduced nicotinamide adenine dinucleotide2phosphate
(NADPH)phagocyte oxidase converts molecular O2 t o O - that releases energy called the respiratory or oxidative
burst2.

2)Production of H2O2 ( Hydrogen peroxide) : O2 - is converted to H2O2 by Superoxide dismutase.

3)Production of hydroxyl free radicals (OH) : Some H2O2 is converted to OH- free radicals by iron.

4)Production of bleach (HOCL- ) – Myeloperoxidase combines H202 with chloride to form Hypochlorous free
radicals (bleach) that Kills bacteria.

5)Formation of free radical peroxynitrite (OONO-) – NO produced from arginine in the presence of NOS (nitric
oxide synthase) reacts with superoxide to generate OONO-

Figure shows Phagolysosome formation, and killing

of bacteria by lysosomal enzyme and MPO system
in the phagolysosome.

ii.O2 independent system:

 Bacterial killing through the action of substances in leukocyte granules.

 E.g. Bactericidal permeability increasing protein (BPI), lactoferrin, defensins etc
CHEMICAL MEDIATORS OF INFLAMMATION:

CHEMICAL MEDIATORS:

1. Vasoactive amines: Histamine, serotonin

2. Plasma proteins: Complement system, kinin system, Clotting system
3. Arachidonic acid metabolites: Prostaglandins, leukotrienes, and lipoxin
4. Platelet-activating factor (PAF)
5. Cytokines and chemokines : Tumor necrosis factor and interleukin – 1
6. Lysosomal constituents of leukocytes
7. Oxygen-derived free radicals
8. Neuropeptides

IMPORTANT CYTOKINESIS (MNEMONICS):

IL-1: Fever (Hot)

IL-2: Stimulates T cells

IL-3: Stimulates bone marrow

Hot T-Bone stEAk
IL-4: Stimulates IgE production

IL-5: Stimulates IgA production

CHRONIC INFLAMMATION:

Inflammation of prolonged duration (weeks to years) in which active inflammation, tissue destruction and
attempts at repair are proceeding simultaneously is known as chronic inflammation.

CAUSES OF CHRONIC INFLAMMATION:

•Persistent infections by certain microorganisms, such as tubercle bacilli, lepra bacilli, hepatitis C

•Autoimmune disease: It is the development of immune reaction against the individual’s own tissue.

•Prolonged exposure to potentially toxic agents e.g. silica, uric acid, silicone in breast implants.
GRANULOMATOUS INFLAMMATION:

Specialized type of chronic inflammation. Causes:

A) Infectious causes: Tuberculosis, Leprosy, Systemic fungal infections (e.g., Histoplasmosis), Cat- scratch fever

B) Non-infectious causes: Sarcoidosis, Crohn’s disease.

Morphology:

 Nodule with or without central caseation.

 Presence of epithelioid cells (activated macrophages), mononuclear cell infiltrate
 Multinucleated giant cells formed by fusion of epithelioid cells (Nuclei usually located at the periphery)

Pathogenesis:

 By macrophages and T- Helper cells.

ACUTE INFLAMMATION:

OUTCOMES OF ACUTE INFLAMMATION:

THE SYSTEMIC EFFECTS OF INFLMMATION:

The acute phase responses are:

a) Fever: Due to stimulation of PG synthesis in the hypothalamus by inflammatory stimuli E.g. IL-1 and TNF
production in response to bacterial infection.
b) Leukocytosis: Increased number of peripheral white blood cells due to increased production. Abnormally high
leukocyte count is known as “Leukemoid-reaction”

Shift to the left: Increase number of immature forms of neutrophils.

Increase in neutrophils (Neutrophilia): Bacterial infection

Increase in lymphocytes (Lymphocytosis): E.g., Viral infection.

Increase in eosinophils (Eosinophilia): E.g. allergic conditions or parasitic infestation.

c)Increased levels of acute phase proteins: E.g., C-reactive protein, Fibrinogen and serum Amyloid A

d)Others: Increased pulse & BP, chills, anorexia, malaise (because of cytokines).

REMEMBER:

Neither too much of nor too less of inflammatory response is favorable for health.

Too less (Defective) inflammatory response: Leads to poor wound healing and susceptibility to infections.

Too much (Exaggerated) inflammatory response: E.g., allergies, autoimmune diseases etc.

HEALING WITH FIRST INTENTION (WOUNDS WITH OPPOSED EDGES):

 hours: The incision is filled with clotted blood

 3-24 hours: Neutrophils infiltrate the clot
 24-48 hours: Epithelial cells migrate from the edges of the wound depositing Basement membrane;
proliferation is minimal
 Day 3: Neutrophils are replaced by macrophages. Granulation tissue begins to appear
 Day 5: The incision space is filled with granulation tissue., neovascularization and epithelial proliferation is
maximal; collagen fibril begins to appear.
 Week 2: Inflammation, edema, and increased vascularity have waned; fibroblast proliferation
accompanies continued collagen accumulation.
 Month 2: Scar now consists of connective tissue devoid of inflammation covered by intact epidermis.
Tensile strength of the wound will continue to accrue.

HEALING BY SECOND INTENTION (WOUNDS WITH SEPARATED EDGES):

Similar to wound healing by first intention, but in addition will have:

• Seen in surface wounds that create large defects

• Abundant granulation tissue formation

• Intense inflammatory reaction

• Wound contraction by formation of myofibroblasts

DIFFERENCE BETWEEN PRIMARY AND SECONDARY WOUND HEALING:

Primary wound healing

  Seen in sharp, incised wounds.
 Seen in wounds with narrow gaping.
 Seen in wounds with straight apposing edges.
 Seen in clean wounds.
 Seen in uninfected wounds.
 Lesser scab/scar Formation.
 More granulation tissue

Secondary wound healing

 Seen in lacerated wounds.

 Seen in wounds with wide gaping.
 Seen in wounds with zagged margins.
 Seen in dirty wounds.
 Seen in infected wounds.
 More scab/scar formation.
 Lesser granulation tissue formation

FACTORS INFLUENCING WOUND HEALING:

I)Systemic factors

a. Nutrition: Deficiency of Vit.C and protein impairs wound healing (impaired collagen synthesis). Def. of zinc
and copper can also lead to deficient healing.
b. Metabolic status: Diabetes mellitus (microangiopathy +accumulation of glucose inside the macrophages)
c. Circulatory status: Inadequate blood supply
d. Hormones: Glucocorticoids (Anti-inflammatory, interferes with collagen synthesis)

II) Local factors

a. Infection: Results in persistent injury and inflammation. Most common cause- Staphylococcus aureus.
b. Mechanical factors: Wound gaping, compression of the blood vessels.
c. Foreign bodies: e.g., suture, glass fragments.
d. Size, location, and type of wound: Richly vascularized tissue, small incisional wound have better healing
capacity.

ESR (ERYTHROCYTE SEDIMENTATION RATE):

Products of inflammation (e.g. Fibrinogen) coat RBCs and cause aggregation. The aggregated RBCs fall at a faster
rate within the test tube.

 Increased ESR: Infection, Inflammation, Cancer, Pregnancy, SLE, Anemia

 Decreased ESR: Sickle cell (Altered shape), Polycythemia (too many), CHF(Unknown)
 HEMOSTASIS
(Hemo = blood ; Stasis = halting)

Normal hemostasis comprises a series of regulated processes that MAINTAIN blood in a fluid, clot-free state in
normal vessels while rapidly forming a localized hemostatic plug at the site of vascular injury.

SEQUENCE OF RESPONSES THAT STOP BLEEDING:

3 Steps to stop bleeding:

I. Primary Hemostasis
 Vascular spasms
 Platelet plug formation
II. Secondary Hemostasis
 Coagulation, or blood clotting

FIBRINOLYTIC SYSTEM:

Method for removing clots and maintenance of a patent. Vascular system and fibrin deposited during
inflammation and tissue injury must be removed.

 Plasmin (serine protease) primarily responsible for fibrinolysis.

 Produced in the liver and kidney, it circulates in an inactive form (plasminogen).
 While plasminogen is normally found in blood and body fluids, plasmin is usually absent due to numerous
antiplasmins.
 Inactivators of plasmin: antithrombin III, a2-macroglobulin, a1-antitrypsin and C1 inactivator.

THROMBOSIS:
 It is a process by which a thrombus is formed.
 A thrombus is an adherent intravascular coagulation (PATHOLOGICAL clot ) (solid mass of blood
constituents) which develops in intact artery or vein.
 Often causes significant interruption to blood flow.
  It is composed of varying proportions of coagulation factors, RBCs and platelets.

Pathogenesis:Three primary influences predispose to thrombusformation, the

so-called VIRCHOW’S TRIAD:

a. Endothelial injury
b. Stasis or turbulence of blood flow
c. Blood hypercoagulability

a.Endothelial injury:

 This is the dominant influence to thrombus formation.

 Endothelial injury is particularly important in thrombus formation in the heart (E.g. Myocardial infarction)
and arterial circulation (Vasculitis), atherosclerosis, hypertension).
 Overt loss of endothelium exposes subendothelial ECM
 Net effect: Increased prothrombotic effect than the antithrombotic effect.
-E.g. Reduces local production of PGI2 and plasminogen activators
-Increases platelet adhesion molecules, tissue factor, PAI (Plasminogen activator inhibitor)

b.Alteration in normal blood flow:

 Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction as
well as by forming countercurrents and local pockets of stasis.
 Stasis is a major factor in the development of venous thrombi.

Stasis and Turbulence:

 Disrupt laminar flow and bring platelets into contact with the endothelium.
 Prevent dilution by fresh flowing blood of activated clotting factors.
 Retard the inflow of clotting factor inhibitors and permit the build-up of thrombi.
 Promotes endothelial cell activation, predisposing to local thrombosis, leukocyte adhesion and a variety of
other endothelial cell effects.

c.Hypercoagulity:

Hypercoagulability contributes less frequently to thrombotic states.

Can be genetic or acquired;

 Genetic: Mutations in the factor V gene is most common (Leiden mutation),

 Acquired: -Heparin-induced thrombocytopenia and thrombosis syndrome
- Antiphospholipid antibody syndrome

FATE OF THROMBUS:

If the patient survives the thrombotic vascular obstruction thrombi may undergo:

1. Propagation : The thrombus enlarges.

2. Embolization: Part or all of the thrombus is dislodged and transported elsewhere in the vasculature.
3. Dissolution: If a thrombus is newly formed, activation of fibrinolytic factors may lead to its rapid
shrinkage and complete dissolution.
4. Organization And Recanalization: Ingrowth of endothelial cells, smooth muscle cells, and fibroblasts into
the fibrin- rich thrombus. Capillary channels are formed.
THROMBI: CLINICAL CORRElATION:

Can cause -

 Cause obstruction of arteries and veins

 Are possible sources of emboli

The significance of each depends on where the thrombus occurs

VENOUS THROMBOSIS(RED THROMBUS):

 The great preponderance of venous thrombi occur in either the superficial or deep veins of the leg.
 In veins the circulation is sluggish and the thrombi are primarily composed of a dark red mass of fibrin
within which are entrapped RBCS, white blood cells and a few platelets.

ARTERIAL THROMBOSIS(PALE THROMBUS):

 Atherosclerosis is a major initiator of thromboses, related to abnormal vascular flow and loss of
endothelial integrity.
 In arteries there is rapid blood flow and the thrombi are composed of platelets with some fibrin and
appear firm and pale.

MORPHOLOGY OF THROMBI:

Thrombi can have grossly (and microscopically) apparent laminations called LINES OF ZAHN; these represent pale
platelet and fibrin layers alternating with darker red cell–rich layers.

Lines of Zahn are only found in thrombi that form in flowing blood. (Helps to differentiate antemortem thrombus
from postmortem thrombus)

Lines of Zahn are the alternating pale pink bands of platelets with fibrin and red bands of RBCs forming a true
thrombus.
Clot: Formed in injured blood vessels.

Thrombus: Clot which is formed in the uninjured blood vessels and is adherent to its wall.

Embolus: Any mass solid, liquid or gas (mostly thromboembolus) detached from its site of origin and carried to
distant site.

Postmortem clot: Do not have lines of Zahn unlike to thrombus and are not attached to the vessel wall.

EMBOLISM

An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant
from its point of origin.

TYPES OF EMBOLISM:

1. Thromboembolism (Most common) –

A) Pulmonary

B) Systemic

C) Paradoxical emboli

2. Fat embolism
3. Amniotic fluid embolism
4. Air embolism

1.THROMBOEMBOLISM:

A) PULMONARY (VENOUS) EMBOLISM:

 Pulmonary embolism has an incidence of 20/25 per 100,000 hospitalized patients with a death rate of 2%
 In greater than 95% of cases the venous embolus originates from deep leg veins (Femoral veins) above
the knee.

B) SYSTEMIC(ARTERIAL) EMBOLISM:

 Arises from the left heart.

C)PARADOXIAM EMBOLISM:

 Arise in the venous system and pass through an atrial or ventricular septal defect into the systemic
circulation
2.FAT EMBOLISM:

-Most fat emboli occur after fractures of long bones (Particularly the shaft of femur) and pelvis.

-Microglobules of fat from the bone marrow or surrounding fat tissue enter the circulation and lodge in the
microvasculature throughout the body.

-Bone marrow embolus. The embolus is composed of hematopoietic marrow and marrow fat cells.

-Fat embolism syndrome begins 1-3 days after injury with sudden onset of

i. Respiratory symptoms- Tachypnea, dyspnea.

ii. Neurologic symptoms
iii. Rash may occur.

(The above symptoms arise due to impaired perfusion, however rash production is due to thrombocytopenia as a
consequence of platelet adherence to the circulating fat.)

3.AIR EMBOLISM:

-Gas bubbles within the circulation can obstruct vascular flow.

-Usually, an excess of 100cc is required to have a clinical effect.

-A particular form of gas embolism called decompression sickness (Caisson disease) occurs when individuals are
exposed to sudden changes in atmospheric pressure. E.g. Sudden ascent towards the surface by the scuba (deep
sea divers).

-Acutely, the formation of painful gas bubbles within the skeletal muscles and tissues in and around the joints is
responsible for what is called the bends.

-In the lungs, edema, hemorrhages, and focal atelectasis or emphysema may appear leading to respiratory
distress, the so-called chokes.

(Bends” comes from the 1880s fashion statement)

4.AMNIOTIC FLUID EMBOLISM:

-Is a potential complication of difficult labor and delivery.

-The underlying cause is the infusion of amniotic fluid into the maternal circulation via a tear in the placental
membranes and rupture of uterine veins.

-Results in respiratory distress, cardiovascular collapse and bleeding secondary to DIC (The amniotic fluid is rich in
thromboplastin).

ISCHEMIA
-Occurs when the tissue has become deficient in blood from its local arterial supply or when the demand of the
tissue for oxygenated blood exceeds the capacity of the vascular supply.

-May lead to cell death or infarction (ischemic necrosis).

 INFARCTION
An infarct is an area of ischemic necrosis within a tissue or organ, produced by the occlusion of either its arterial
supply or venous drainage.

The majority are associated with thromboembolism and involve arterial occlusions.

TYPES OF INFARCTS:

A.RED INFARTS: occurs

 With venous occlusions.

 In loose tissues which allow blood to collect (lungs)
 In tissues with dual circulations (lung & intestines)
 In tissues that were previously congested.
 When flow is reestablished after infarction (e.g., after angioplasty of an arterial obstruction).

B.WHITE INFARCTS:

 Occur with arterial occlusions

 In solid organs (heart, spleen, kidney) where the solidity of the tissue limits the amount of hemorrhage
than can seep into the damaged area.

IMMUNITY:
Derived from the latin word “ Immunitas” (freedom from services which other citizens had to discharge)

Summary (Definition) of the entire immune system :Kill the pathogen & Don’t harm the host

Antigen Vs Immunogen: Antigen is anything that can be recognized by antibody whereas an immunogen is an
antigen which can generate an immune response.
An antibody is a protein produced by the body's immune system when it detects harmful substances, called
antigens.

Examples of antigens include microorganisms (bacteria, fungi, parasites, and viruses) and chemicals.

Antibodies may be produced when the immune system mistakenly considers healthy tissue a harmful substance.
This is called an autoimmune disorder.

COMPLEMENT PATHWAY:

1)Classical complement pathway: Begins with the formation of antibodies (IgG or IgM) which bind with the antigen
(e.g. bacteria).

 Results in binding of the C1q over the Fc portion of the antibodies.

 C4 and C2 are proteolysed and activated to form C4b2b complex (C3 convertase)
 C3 convertase results in formation of C3b.
 C4b2b3b complex (C5 convertase) activates C5b.
 Formation of Membrane attack complex (MAC) (C5-C9)

2)Alternate complement pathway: Is triggered by microbial surface molecules (e.g lipopolysaccharides or

endotoxins)

 Results in spontaneous proteolysis of C3 and factor B and formation of C3b and Bb.
 The C3bBb complex thence formed is known as C3 convertaseC3 convertase breaks down C3 into C3b.
 The C3bBb3b complex now formed is known as C5 convertase.C5 convertase cleaves C5 into C5b.
 C5b remains attached to the complex and forms a substrate for the subsequent binding of the C6-C9
components.
 Results in the formation of membrane attack complex.

3)Lectin complement pathway: Begins with plasma mannose binding lectin binds that carbohydrates on microbes.

 Similar to classical pathway, except for there is direct activation of C4b and C2b into C3 convertase.
 And the steps proceeds as in classical complement pathway.

Function of complement cleavage products:

1) C3a, C5a – Anaphylatoxins (Stimulates mast cell release of histamine.

2) C3b - Opsonization .

3) C5a – Activation of neutrophil adhesion molecules, Neutrophil chemotaxis .

4) C5-C9 – Membrane attack complex (MAC) – Cell lysis