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PATHOLOGYA study of e relationship b/w é cause, lesions, & signs in é host.

CONCEPT OF DISEASELISTS CONCEPTS DETAILS

1ST CONCEPT

Disease = Abnormalities

Disease can be referred as any abnormality that can occur.

Contamination: e presence of stimuli on e outer surface of e host.

Infection: e presence of e stimuli in e body of e host w/o exerting any effect.

Disease: a state where e stimuli exert effect on e host.

2ND CONCEPT

Disease = Cause → Lesion → Sign

CAUSE = Infectious + Non-infectious + Inherent Causes.

LESIONS = Structural abnormalities in cells, tissues, organs or systems e.g. enteritis.

SIGNS= Functional abnormalities in cells, tissues, organs or systems e.g. diarrhea.

PATHOGENESIS = Mechanisms how the causative agent cause the lesions and the

signs in the host.

3RD CONCEPTThere 3 primary causes of

disease: Agents (Infectious), Environment (non-infectious), & Host

(Inherent).

E primary causes of disease r connected to each other through adverse connection. Thus, in order to prevent disease, e

adverse interaction b/w those 3 should be blocked & controlled carefully.

Understanding e basis is a very important step for diagnosis, treatment, &

prevention. Px = M how C → L → S.

4TH CONCEPT

Disease = Specific Disease.

E word disease is referred to a specific disease such as tubesclerosis, not e lesion or e

sign. Diagnosis

is based on history, physical signs, lesions, demonstration of e agents, or e antigen, or

e antibody, or e DNA. Dx = Hx

→ S → L→ C.

IDENTIFICATION OF TYPES OF DEGENERATION

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OEDEMAPORTIONS DETAILS

OVERVIEW

Edema denotes accumulation of fluid in interstitial spaces and in body cavity. About 60% lean body mass is water where 2/3 of it is intracellular & most of the rest resides in e

interstitium. Only 5% is intravascular, i.e., which consists of e blood and plasma. These body fluid compartments are controlled very neatly by a balance process b/w hydrostatic,

osmotic, & oncotic pressure sas well as e vital role played by lymphatic drainage system.

TYPES

Pitting edema – reflects a clinical sign. Hydrothorax – fluid inside pleural cavity. Hydropericandium – fluid inside pericardial cavity. Hyperperitoneum (ascites) – fluid inside peritoneal cavity. Anasarca – a severe & generalized edema with profound subcutaneous tissue swelling.

PATHOGENESIS

Fluid movement inside body is governed by vascular hydrostatic pressure and vascular osmotic pressure.

Normally the outflow of the arterial end is almost nearly balanced by the inflow into the venous end, small excess collected by the lymphatic system.

Whenever there is a disturbance of the hydrostatic or osmotic pressure, e equilibrium will be reset.

Edema occurs when e equilibrium is distorted & becomes imbalance.

CAUSES

INCREASED HYDROSTATIC

PRESSURE

2 types of pressure increase:1) Localized increases in intravascular pressure:

- Due to impaired venous return.- Regional obstruction to blood flow with e formation of thrombus within

lumen.- Extrincic: physiological (pregnancy), pathological (tumors).- E.g.: lower extremity deep venous thrombosis can cause edema

restricted to e distal portion of e affected leg.2) Generalized increases in venous pressure:

a) Due to pump failure.- Occurs most commonly in congestive heart failure – affecting Rt.

ventricular cardiac function.- Constriction of cardiac volume: pericarditis, pericardial effusion,

cardiac tamponade b) Due to neurohormonal dysregulation.

- Renal hypoperfusion: Activates renin-angiotensin-aldosterone system, with increased water and salt retention.

Pathogenesis of cardiac edema as a result of congestive heart failure & renal hypoperfusion:

- CO ↓ → renal perfusion ↓ → renal hypoperfusion → renin-angiotensin-aldosteron axis is stimulated → inducing sodium & water retention by e kidneys → heart failure can’t restore CO back to normal (increase) → venous pressure ↑ by e extra fluid load → edema.

REDUCED ONCOTIC PRESSURE

Occurs when albumin is inadequately synthesized or loss from e circulation. Causes of albumin loss:

1) Increased loss: enteropathy, nephrotic syndrome.2) Decreased synthesis: liver failure, malnutrition.

Pathogenesis: - Reduced oncotic pressure → net movement of fluid into e interstitial tissue

with subsequent plasma volume contraction → intravascular volume ↓ → renal hypoperfusion → 2o aldosteronism → 1o defect of low serum proteins persists → edema.

LYMPHATIC OBSTRUCTION

Edema derived from lymphatic obstruction is termed lymphadema. Usually localized. Causes of lymphatic obstruction:

1) Within lumen:a) Tumor (orange peel): edema of e overlying skin which is caused by

infiltration & obstruction of superficial lymphatic in breast carcinoma patients.

b) Parasite (filariasis): causes extensive inguinal lymphatic & lymph node fibrosis.

2) Loss of lymphatic channels (post surgery).

SODIUM & WATER

RETENTION

Can be a primary cause of edema. Can occur with any compromise of renal function as in acute renal failure &

poststreptococcal glomerulonephhritis. Pathogenesis:

- ↑ salt → ↑ water → ↑ hydrostatic pressure (due to expansion of e intravascular volume) → ↓ vascular osmotic pressure → edema.

OUTCOMES NEPHROTIC SYNDROME

Definition:o Heavy proteinuria (>3.5g protein / day)o Hypoalbuminemia o Severe edema o Hyperlipidemia and lipiduria

Causes:o Primary renal (glomerular disease) (children)o Secondary (adults)

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Causes of nephrotic syndromeo Primary glomerular disease

– Glomerulonecphritis (membranous, minimal change)o Systemic disease

– Diabetes mellitus– Sytemic lupus erythematosis – Amyloidosis – Drugs (gold, penicillamine)– Infections (malaria, syphilis, Hep B, AIDS)– Malignancy (carcinoma, melanoma)

o Increased permeability of glomerular basement membrane- Protein passing to the glomerular filtrate → loss of intravascular fluid

accompanies loss of protein → compensatory secretory of aldosterone → massive edema (anasarca).

Hypoclbumineia causes increased lipoprotein synthesis, and lipoprotein also causes increased permeability, resulting in lipiduria.

MALNUTRITION

Kwashiorkor:– Occurs when protein deprivation is relatively greater than the calorie

insufficiency.– In Africa, some SE Asian countries.– Less severe form – in nephrotic syndrome, extensive burns, protein losing

enteropathy.– Severe loss of visceral protein – hypoalbuminema – dependent edema.

Marasmus:– Loss of skeletal muscle protein, with retainment of visceral organ protein.– Serum albumin level normal or slightly reduced.

MORPHOLOGY

Recognized as a clearing & separation of e extracellular matrix elements with subtle cell swelling. Sites that r most commonly encountered:

1) Subcutaneous edema:- Can be diffuse or >prominent in regions with high hydrostatic pressures.- Ultimate distribution depends on e causes.- Dependent edema:

A gravity-dependent edema. Involves: legs when standing & sacrum when recumbent. A prominent feature of cardiac failure – particularly Rt. ventricle.

- Edema due to renal dysfunction or nephritic syndrome is > severe & affects all over e body equally.

2) Pulmonary edema:- Common clinical problem due to Lt. ventricular failure.- Also occurs due to renal failure & acute respiratory distress syndrome, pulmonary infections,

& hypersensitivity reaction.- Lungs appearance:

Weigh 2 to 3 times their normal weight. Sectioning reveals frothy, blood-tinged fluid representing a mixture of air, edema fluid, &

extravasated RBCs.3) Cranial edema:

- May be localized to sites of focal injury: abscesses, infarct, & neoplasm.- May be generalized: encephalitis, hypertensive crises, or obstruction of e brain’s venous blood

flow.- May causes trauma.- Brain is grossly swollen with narrowed sulci & distended gyri showing signs of flattening

against e underlying skull.

EDEMA & INFLAMMATION

Acute inflammation – immediate and early response to injury1) Cellular changes – inflammatory cells recruitment2) Vascular changes:

– Alteration to vessel caliber, and structural changes resulting in changing vascular permeability

– Pathogenesis:– Arteriolar dilatation → Increased permeability, with passage of intravascular protein and fluid

into the extracellular spaces → Increased blood viscosity resulting in stasis → Neutrophils margination and migration.

3) Increased vascular permeability- Pathogenesis:- Initial short phase of arteriolar dilatation results in increased hydrostatic pressure, with

transudation of fluid into the interstitium → Followed by increased vascular permeability → leaking of protein rich fluid → exudation →This reduces intravascular osmotic pressure → resulting in edema.

Mechanisms - I1) Endothelial cell contraction

- leads to intercellular gaps – reversible, elicited by mediators like histamine, bradykinin, leukotrienes

- Immediate and transient- Only affects the small post capillary venules

2) Endothelial cell retraction- Another reversible mechanism- Cytokine mediators (TNF, IL-1) induce structural reorganization of endothelial cytoskeleton

and disruption of cellular junctions Mechanisms - II

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1) Direct endothelial injury- Endothelial cell necrosis and detachment- After severe injury- Leakage begins shortly after injury and persists for a long time

2) Leukocyte dependent endothelial injury- Leukocytes release toxic oxygen species and proteolytic enzymes

3) Leakage from newly formed vessels

TRANSUDATE POINTS EXUDATE

DEFINITION

Hydrostatic MECHANISM Permeability

Normal PERMEABILITY Altered

Low PROTEIN High

Low SPECIFIC GRAVITY High

Absent FIBRINOGEN Present

Mesothelial CELLS Inflammatory

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ATHEROSCLEROSIS

PORTIONS DETAILS

OVERVIEW

Means hardening of e arteries. Characterized by:

1. Types:a) Elastic arteries: aorta, carotid, & iliac arteries. b) Large & medium sized muscular arteries: coronary & popliteal arteries.c) Smaller vessels which r less than 2-3 mm in diameter: uncommon phenomena.

2. Sites:a) Abdominal aorta: > involved than thoracic aorta.b) Origins (ostia) of major branches such as e coronary arteries, e popliteal arteries, e

internal carotid arteries, & e vessels of e circle of Willis: lesions tend to be much more prominent.

In descending order, e arteries affected are:- Lower abdominal aorta → coronary arteries → popliteal arteries → internal carotid

arteries → vessels of e circle of Willis.

RISK FACTORS

NON MODIFIABL

E

Age: risk of complications (IHD) increases 5x between 40 and 60. Sex: men at higher risk than women, risk becoming equalized in post menopausal women.

Family history and genetic predisposition: probably polygenic.

MODIFIABLE

Hyperlipidemia : usually refers to hypercholesterolemia, and increased LDL (HDL – good cholesterol, raised by exercise and moderate ethanol consumption).

Saturated fat, trans fat – increased plasma cholesterol. Hypertension: both systolic and diastolic pressures are important for risk. Smoking: cigarettes’ products r very radical & dangerous to human. Diabetes mellitus: induces hypercholesterolemia. Hyperhomocystinemia: strong relationship with coronary artery diease, peripheral vascular disease, stroke, & venous thrombosis.

OTHERS

Obesity. Physical inactivity. Stress (type A personality). Postmenopausal estrogen deficiency.

High carbohydrate intake. Lipoprotein A. Trans (unsaturated) fat intake. Chlamydia pneumonia

PATHOLOGY

AHA plaque classification:1. Type 1: Early – normal intima or minimal intimal thickening. 2. Type 2: Early – fatty streak: little intracellular lipid deposit of smooth muscle. Lesion

initiation occurs when endothelial cells, activated by risk factors such as hyperlipoproteinemia, express adhesion, and chemoattractant molecules that recruit inflammatory leukocytes such as monocytes and T lymphocytes.

3. Type 3: Intermediate – preatheroma: increased extracellular lipid deposits. Evolution to fibro-fatty stage. Monocytes recruited to the artery wall become macrophages and express scavenger receptors that bind modified lipoproteins. Macrophages become lipid-laden foam cells by engulfing modified lipoproteins. Leukocytes and resident vascular wall cells can secrete inflammatory cytokines and growth factors that amplify leukocyte recruitment and cause smooth muscle cell migration and proliferation.

4. Type4: Advanced – massive confluence lipid deposits covered mainly by intima. As lesion progresses, inflammatory mediators cause expression of tissue factor, a potent procoagulant, and matrix-degrading proteinases that weaken the fibrous cap of the plaque.

5. Type 5: Advanced – fibroatheroma, calcific, or fibrotic type. If fibrous cap ruptures at point of weakening, coagulation factors in blood can gain access to thrombogenic, tissue factor-containing lipid core, causing thrombosis on nonocclusive atherosclerotic plaque. If balance between prothrombotic and fibrinolytic mechanisms prevailing at that particular region and at that particular time is unfavorable, occlusive thrombus causing acute coronary syndromes may result.

6. Type 6: Complicated: disruption, hemorrhage, or thrombotic deposits. When thrombus resorbs, products associated with thrombosis, such as thrombin and mediators released from degranulating platelets, including platelet-derived growth factor and transforming growth factor-beta, can cause healing response, leading to increased collagen accumulation and smooth muscle cell growth. In this manner, the fibro-fatty lesion can evolve into advanced fibrous and often calcified plaque, one that may cause significant stenosis, and produce symptoms of stable angina pectoris.

7. Type 7: In some cases, occlusive thrombi arise not from a fracture of the fibrous cap, but from superficial erosion of the endothelial layer. Resulting mural thrombus, again dependent on local prothrombotic and fibrinolytic balance, can cause AMI. Superficial erosions often complicate advanced and stenotic lesions, as shown here. However, superficial erosions do not necessarily occur following a fibrous cap rupture.

MORPHOLOGY 1. Fatty streak: Composed of lipid-filled foam cells. R not significantly raised & thus causes no disturbance in blood flow. Begins as multiple minute yellow, flat spots that can coalesce into 1 cm/ > of elongated

streaks. Can appear in e aorta of infants younger than 1 year & r present in virtually all children

older than 10 years old. Not all r destined to become advanced atherosclerotic plaque.

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2. Atherosclerotic plaque or atheroma: Identified by intimal lesion called atheromas (atheromatous/ atherosclerotic plaque/

fibrofatty plaques) that potrude into vascular lumina. Key process: intimal thickening & lipid accumulation. Appearance of e atheromas:

1. A raised focal lesion initiating within e intima.2. A soft, yellow, grumous core of lipid: mainly cholesterols & cholesterol ester.3. White to whitish yellow.4. Patchy, eccentric, & involves only a portion of any given arterial wall only

partial of its circumference.5. Impinges on e lumen of e artery.6. Thrombosis superimposed over e surface of ulcerated plaque is red-brown in

color.7. Plaque varies from 0.3 cm to 1.5 cm in diameter but can coalesce to form

larger masses.8. E focality is almost certainly due to e vagaries of vascular hemodynamics.

9. Becomes > numerous & > diffuse by time. Principles of atherosclerotic plaque:

1. Cells, including SMCs, macrophages, & T cells.2. ECM, including collagen, elastic fibers, & proteoglycans.3. Intracellular & extracellular lipid.

Fibrous cap:1. A firm, white cap containing smooth muscle cells & dense collagen

superficially.2. Beneath & to e side of e cap: cellular area containing macrophage,

lymphocytes, & SMCs.3. Deep to e fibrous cap: necrotic area containing lipid, debris from dead cells,

foam cells, fibrin, organized thrombus, plasma protein & crystalline aggregates of cholesterols.

Effects of e atheromas:1. Obstructs blood flow.2. Weakens e underlying media.3. Can rupture & cause acute catastrophic vessel thrombosis.

Clinical significance of atherosclerotic plaque:1. Rupture, ulceration, or erosion of luminal surface of atherosclerotic plaque:

- Exposes e bloodstream to highly thrombogenic substances & induces thrombus formation.

- E thrombi can lead to occlusion & ischemia.- If survival ensues, thrombi may become organized & incorporated into e growing

plaque.2. Hemorrhage into a plaque:

- Rupture of e fibrous cap or e thin-walled vessels in e area of neovascularization leads to intra-plaque hemorrhage.

- A contained hematoma may expand e plaque or induce plaque rupture. 3. Atheroembolism:

- Plaque rupture can discharge debris into e bloodstream.- Results in e production of microemboli composed of plaque contents.

4. Aneurysm formation:- Atherosclerosis-induced pressure or ischemic atrophy of e underlying media with loss

of elastic tissue causes weakness of e vessel wall & development of aneurysm that may rupture.

COMPLICATIONS OF PLAQUE

Focal rupture, ulceration or erosion:– Exposure of highly thrombogenic substance that induces thrombi formation.– Debris discharge into blood – microemboli.

Hemorrhage:– Initiated by rupture of fibrous cap.– Hematoma within plaque may cause lumen reduction or further plaque rupture.

Thrombosis:– Worst complication, use superimposed on complicated plaques.– May partially or completely occlude lumen.– Thrombi may eventually be incorporated into plaque, making the plaque much larger.

Aneurysmal dilatation:– Pressure induced atrophy of media and elastic tissue.– Weakening of the wall with potential rupture.

Calcification:– E plaque becomes calcified & hardened with calcium.

COMPLICATIONS OF ATHEROSCLEROSIS

Myocardial Infarction. Cerebral Infarction. Peripheral vascular disease with gangrene of extremities. Aneurysm:

– Localized abnormal permanent dilatation of an artery or vein.– True versus False Aneurysms.– Clinical features / complication:

1. Pulsatile mass 2. Rupture with catastrophic hemorrhage 3. Pressure effect on adjacent structures4. Vascular occlusion 5. Aortic root dilatation with aortic regurgitation6. Thromboembolism

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Aortic Dissection: The aorta is atherosclerotic and blood could dissected into e wall of aorta. Ischemic Heart Disease (IHD):

– As a result of inadequate blood / oxygen supply. – Majority of cases r due to coronary atherosclerosis.– Clinical features:

1. Angina Pectoris (Stable or Unstable).2. Myocardial Infarction. 3. Chronic Ischemic Heart Disease.4. Sudden Cardiac Death.

GENERAL TREATMENTS

Primary prevention:1. Stop smoking.2. Control of blood pressure.3. Weight reduction.4. Regular exercise.5. Dietary modifications.

Secondary prevention:1. Treatment of hypertension & hyperlipidaemia. 2. For diabetic patient, control of disease. 3. Localized arterial disease: angioplasty or by-pass operation.

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To reduce cardiac events

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PATHOGENESIS OF ATHEROSCLEROSIS

Chronic or repetitive endothelial injury.Causes: hemodynamic disturbance, hypercholesterolemia, toxins from cigarette smoke, homocysteine, or infectious agents >>> may cause

e release of ROS that deactivate NO.Results: endothelial injury & dysfunction which lead to increased permeability, leukocyte adhesion (attracts macrophages & other inflammatory cells into e site of injury), & thrombotic potential.

(2) Insudation of lipoprotein into e vessel wall, mainly LDL with its high cholesterol content.

Lipoproteins accumulate within e intima at sites of increased endothelial permeability.

(3) Modification of lesional lipoproteins by oxidation.Chemical changes of lipid induced by ROS generated in macrophages or endothelial cells in e

arterial wall: LDL is oxidized into oxidized 0r modified LDL which:Is ingested by macrophages through e scavenger c) Stimulates e release of growth

factors & cytokines. receptor distinct from e LDL receptor, thus d) Is cytotoxic to endothelial cells & smooth muscle cells.forming foam cells. e) Can induce endothelial cell dysfunction.

Increases monocytes accumulation in lesions.

(4) Adhesion of blood monocytes & other leukocytes to e endothelium (specific endothelial adhesion molecules induced on e surface of dysfunctional

endothelial cells) followed by their migration into e intima & their transformation into macrophages & foam cells (form as a result of engulfment

of oxidized lipoprotein mainly LDL).

(5) Adhesion of platelets.

(6) Release of factors from activated platelets, macrophages, or vascular cells that cause migration of smooth muscle cells from media into e intima.

Then, smooth muscle cells proliferate in e intima & extracellular matrix elobrates which lead to e accumulation of collagen & proteoglycans. This will

convert a fatty streak into a mature fibrofatty atheroma & contribute to e progressive growth of atherosclerotic lesions.

(7) Enhanced accumulation of lipids both within cells (macrophages & smooth muscle

cells) & extracellularly.

Lesion progression occurs through interactions of modified LDL,

macrophages, T cells, & normal arterial cells.

Response to injury hypothesis: views atherosclerosis as

chronic inflammatory

response of arterial wall towards

endothelial injury.

EMBOLISMPORTIONS DETAILS

OVERVIEW

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

99% due to dislodged embolism: thromboembolism, while another 1% due to fat droplets, bubbles of air or nitrogen, cholesterol, tumor fragments, bits of BM, or foreign bodies such as bullets.

Embolism becomes dangerous when it lodges in smaller vessels which then results in partial or complete occlusion.

E consequence is ischemic necrosis which further leads to organ infarction.

TYPES DETAILS PATHOGENESIS

PULMONARY THROMBO-

EMBOLISM (PTE)

Most common type of embolism. > 95% of cases of venous emboli originate from deep leg thrombosis

above e level of knee. E results:

1. Occlusion of e main pulmonary artery.2. Impact across e bifurcation (saddle

embolism).3. Pass out into smaller branching

arterioles.4. Paradoxical embolism: embolus that can pass through an

interatrial or interventricular defect & enter e systemic circulation.5. Most common result (3/4 of patients) of PTE is no symptom

because due to dual pulmonary blood supply & thrombus usually undergoes lysis & resolution.

Frequently there r multiple emboli from a single larger thrombus: “a patient who has had 1 pulmonary embolus is at high risk of having more”.

Types of thromboemboli:1. Large emboli:

Occlude e main pulmonary artery (major branches). Effects: death, hypoxia, acute Rt. sided heart failure, & >60% of

pulmonary circulation is obstructed. E blockage increases pulmonary artery pressure (ischemia). Prolonged time: increases CO & pulmonary haemorrhage.

2. Moderate emboli: Medium sized or small pulmonary artery. Results:

a. Pulmonary infarction: due to reduced perfusion of a segment of lung tissues.

b. Pulmonary haemorrhage: adequate circulation but there is ischemic damage to e endothelial cells.

3. Small emboli: Unnoticed, lysed & organized. With repeated episodes, it may results in pulmonary hypertension.

PTE:Venus thrombosis → larger vessels → Rt. side of heart → pulmonary vasculature → partial occlusion → complete occlusion → reduced blood & O2 supply → organ ischemic → organ infarction.

Paradoxical embolism: Venus thrombosis → larger vessels → Rt. side of heart → interatrial or intervetricular defect → Rt. to Lt. shunt → systemic circulation → partial occlusion → complete occlusion → reduced blood & O2 supply → organ ischemic → organ infarction.

Most pulmonary emboli (60-80%) r clinically silent because e r small.

E complications: sudden death, Rt. ventricular failure,lung infarction, & etc.

SYSTEMIC THROMBO-EMBOLISM

Refers to emboli in e arterial circulation. 80% arise from intracardiac mural thrombi:

1. 2/3 r associated with Lt. ventricular wall infarcts.2. 1/3 r associated with dilated Lt. atria, 2o to mitral valve disease.

20% results from:1. Aortic aneurysm.2. Thrombi on ulcerated atherosclerotic plaques.3. Valvular vegetations.

E site of arrest depends on:1. E point of origin of e thromboembolus.2. E relative blood flow through e downstream tissues.

E major sites:1. 75%: lower extremities.2. 10%: brain.3. Others: intestines, kidneys, & spleen.

E consequences:1. Depend on:

a) E vulnerability of e tissue to ischemia.b) Caliber of e occluded vessels.c) E collateral blood supply.

2. Result: infarction of e affected tissues.

Intracardiac mural thrombi:Acute Myocardial Infarction → myocytes death → loss of contractility → reduced blood flow rate → stasis → thrombosis → rupture → arterial embolus → occlusion of end artery in kidneys/ spleen/ brain/ lower extremities/ intestines → infarction → necrosis.

FAT EMBOLISM Causes:1. Skeletal injuries (90%): fractures of long bones.2. Soft-tissue trauma.

Results (traumatic fat emboli - 90%):1. Pulmonary insufficiency.2. Neurologic symptoms.3. Anemia.4. Thrombocytopenia.

Symptoms (appear 1 to 3 days after injury):1. Sudden onset of tachypnea, dyspnea, & tachycardia.2. Neurologic symptoms: irritability & restlessness.3. Progression to delirium or coma.

Pathology:

Fat embolism:Skeletal injury → rupture of e marrow vascular sinusoids or rupture of venules in injured tissue → fat enters e circulation → occlusion of vessel → mechanical & biochemical obstruction → ischemia/ infarction.

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These 3 consequences result in PTE.

Fatal in about 10% of e cases.

1. Occlusion of pulmonary & cerebral microvasculature, aggravated by local platelets & RBC aggregation.

2. Release of fatty acids from e fat globules, causing local toxic injury to endothelium.

3. Activation & recruitment of granulocytes release free radical, protease, & eicosanoids.

AIR EMBOLISM

Gas bubbles causing obstruction of e vascular flow:1. Head & neck surgery.2. Chest wall injury in obstetric procedures.

Clinical assessments:1. 40 mL: serious clinical

problems.2. >100 mL: can be fatal.

Decompression sickness:1. Occurs when individuals r exposed to sudden changes in

atmospheric pressure, eg: scuba divers & underwater construction water.

2. Acute progression:a) Within skeletal muscles & supporting tissues in & about joints:

Rapid formation of gas bubbles causing pain called e bends.b) In e lung: Gas bubbles in e vasculature cause edema,

hemorrhages, & focal atelectasis or emphysema which lead to respiratory distress called chokes.

3. Chronic progression: Caisson disease develops where persistence of gas emboli in e bones leads to multiple foci of ischemic necrosis at e head of femurs, tibias, & humeri.

4. Treatments of acute decompression sickness:a) Palcing e affected individual in a compression chamber to increase

barometric pressure & force e gas bubbles back into e solution.b) Subsequent slow decompression permits gradual reabsorption &

exhalation of e gasses so that obstructive bubbles do not reform.

In e lungs:Air → Rt. sided of e heart (ventricle) → whipped into frothy mass → block e flow of blood through e pulmonary artery.

Decompression sickness:Breathing of air at high pressure → ↑ amount of gas becomes dissolved in e blood & tissue → rapid depressurization → gas (N2) expands in e tissue → bubbles out of solution in blood → formation os gas emboli → focal ischemia of brain/ heart/ others.

AMNIOTIC FLUID EMBOLISM

Uncommon complication of labor & e immediate postpartum period. Mortality rate: 20% to 40%. Cause: entry of amniotic fluid & its contents into e maternal circulation

via a tear in e placental membranes & rupture of uterine veins. E onsets:

1. Sudden severe dyspnea.2. Cyanosis.3. Hypotensive shock.4. Seizures5. Coma.

Consequences after e survival of initial crisis:1. Pulmonary edema.2. Disseminated intravascular coagulation (DIC) due to release of

thrombogenic substances from amniotic fluid.3. Diffuse alveolar damage.4. Pulmonary microcirculation contains squamous cells shed from

fetal skin, lanugo hair, fat from vernix caseosa, & mucin derived from fetal respiratory or GIT.

INFARCTIONPORTIONS DETAILS

OVERVIEW

An infarct is an area of ischemic necrosis caused by occlusion of either e arterial supply or e venous drainage in a particular tissue.

Types of infarct:1. Myocardial infarction: cardiovascular disease.2. Cerebral infarction.3. Pulmonary infarction: common complication in several clinical settings.4. Bowel infarction: frequently fatal.5. Gangrene of extremities: serious problem in e diabetic population.

CAUSES 1. Arterial occlusion: Most common cause: ~ 99% results from thrombotic or embolic events. Common cause:

1. Local vasospam.2. Expansion of an atheroma 2o to intraplaque hemorrhage.3. Extrinsic compression of a vessel, e.g. by tumor.

Uncommon cause:1. Vascular compression by edema2. Traumatic vessel rupture.

2. Venous occlusion: Venous thrombosis: merely induces venous obstruction & congestion (infarct more likely to

occur in organs with a single venous outflow channel. Vessel twisting, e.g. testicular torsion or bowel volvulus.

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Air bubbles can coalesce to form frothy masses that can occlude

vessels.

Entrapment in a hernia sac.

DEVELOPMENTAL FACTORS

1. Nature of e vascular supply: Most important determinant. Single blood supply: heart has only a single blood supply, thus more likely to undergo

infarction. Dual blood supply:

a) Lungs: dual pulmonary & bronchial artery blood supply, thus small obstruction in arteriolar blood supply doesn’t cause infarction.

b) Liver: dual hepatic artery & portal vein circulation, thus liver doesn’t likely yo undergo infarction.

c) Hand & forearm: dual radial & ulnar arterial supply, thus > resistance to infarction. End-arterial supply: In renal & spleenic circulations, obstruction usually causes infarction.

2. Rate of development of occlusion: Slowly developing occlusion r < likely to cause infarction because there is time for e

development of alternative perfusion pathway. If 1 of coronary arteries in e heart is occluded slowly, flow within collateral circulation may

increase sufficienly to prevent infarction even though including major coronary artery.3. Vulnerability to hypoxia:

Neurons: undergo irreversible damage when deprived of blood supply for only 3 to 4 minutes. Myocardial cells: die after 20 to 30 minutes of ischemia, but fibroblasts within myocardium

remain viable after many hours of ischemia.4. Oxygen content of blood:

Partial flow obstruction of a small vessel in an anaemic or cyanotic patient might lead to tissue infarction.

Congestive heart failure with compromised flow & ventilation may cause infarction in e setting of an otherwise inconsequential blockage.

PATHOGENESIS

Generally:1. Death of cells in area deprived of its blood supply:

- Blood continues to seep into devitalized area for short time.- Early stage: most infarcts contain ↑ blood (swollen & red because RBCs entering area is

extravasted via damage capillaries. 2. Recognizable microscopic after 6-12 hours & macroscopic after 12-24 hours.3. Progressive autolysis of necrotic tissue & hemolysis of RBC.4. Acute inflammatory response.5. Necrotic debris & hemoglobin r phagocytosed by macrophages.6. 1/52 infarcted area is firmed & dull yellow surrounded by a red zone of inflammation.7. Shrinkage of infarct (white color).8. Progressively ingrowth of granulation tissue at periphery which is then organized into

fibrous scar. Nervous system:

1. Necrotic tissue: rapid liquefaction necrosis.2. Infiltration of macrophages (for monocytes & microglial).3. Demolish debris & phagocytosed disintegrated myelin.4. Cells swell up: lipid material, lipofuscin, haemosiderin, compound granular corpuscle.5. Repair by gliosis.

MORPHOLOGY

RED INFARCT

Also called hemorrhage infarct. With venous occlusion such as in ovarian torsion. In loose tissues such as lung that allow blood to collect in e infarcted zone. In tissues with dual circulations such as lungs & small intestine, permitting

flow of blood from an unobstructed parallel supply into a necrotic area. In tissues that were previously congested because of sluggish venous

outflow. When flow is re-established to a site of previous arterial occlusion & necrosis,

e.g. fragmentation of an occlusive embolus or angioplasty of thrombotic lesion.

E hemorrhage is too extensive to permit e lesion become pale. After few days: e lesion becomes firmer & browner (accumulation of

hemosiderin pigment).

WHITE INFARCT

Also called anemic infarct. With arterial occlusions. In solid organ such as heart, spleen, & kidney.

- E solidity of e tissue limits e amount of hemorrhage that can seep into e area of ischemic necrosis from adjoining capillary beds.

Only few extravasated red cells r lysed, with e released hemoglobin remain in e form of hemosiderin.

After few days: e lesion becomes > paler & sharply defined with time.

SEPTIC INFARCT

Occurs when bacterial vegetations of heart valve embolize or when microbes seed an area of necrotic tissue.

Infarct is converted into an abscess with a greater inflammatory response. E eventual sequence of organization is still e same.

HISTOLOGIC APPEARANCE

Dominant characteristic: ischemic coagulative necrosis. Few hours: inflammatory response begins to develop along e margin of

infarcts. 1-2 days: e margin becomes well-defined. In stable & labile tissues: parenchymal regeneration occurs at e periphery. Mostly r replaced by scar.

GROSS Wedge shape:

‘ALIAH’S Y1B2

APPEARANCE

- Apex: e occluded vessel.- Base: e periphery of e organ. (If serosal surface: there can be overlying

fibrinous exudates). At e outset: all infarcts r poorly defined & slightly hemorrhagic. E margins of both types tend to become better defined with time by a narrow

rim of congestion attributable to inflammation at e edge of e lesion.

‘ALIAH’S Y1B2

[Actions for the sake of Allah only]

Allah Almighty had said:

I am so self-sufficient that I am in no need of having an associate. Thus he who does an action for someone else's sake as well as

Mine will have that action renounced by Me to him whom he

associated with Me.

It was related by Muslim (also by Ibn Majah).

SHOCKPORTIONS DETAILS

OVERVIEW Definition: A clinical syndrome characterized by systemic hypoperfusion which is caused by either

reduced cardiac output or by reduced effective circulating blood volume. E end results r: hypotension, impaired tissue perfusion, & cellular hypoxia.

TYPES

CARDIOGENIC SHOCK

Results from e failure of e cardiac pump. Causes:

1. Intrinsic: myocardial damage & ventricular arrhythmias.2. Extrinsic: extrinsic compression & pressure, & outflow obstruction.

Clinical examples:1. Myocardial infarction.2. Ventricular rupture.3. Arrhythmia.4. Cardiac temponade.5. Pulmonary embolism.

HYPOVOLEMIC SHOCK

Results from e loss of blood or plasma volume. Cause: inadequate blood or plasma volume. Clinical examples:

1. Hemorrhage.2. Fluid loss: vomiting, diarrhea, burns, or trauma.

SEPTIC SHOCK

Caused by microbial infection, mostly (70%) by endotoxin-producing gram-negative bacilli (thus also named with endotoxin shock), but also by Gram +ve & fungal infection.

Also can be caused by a group of bacterial protein known as superantigens which activate polyclonal T lymphocytes & induce systematic cytokine cascade.

Endotoxins r bacterial wall lipopolysaccharides (LPS) consisting of a toxic fatty acid (lipid A) core common to all gram-negative bacteria & a complex polysaccharide coat (including O Ag) unique for species.

Free LPS:1. Can exert cellular & hemodynamic effects of septic shock by itself.2. Causes profound activation of mononuclear cells & production of potent effector cytokines such

as IL-1 & TNF. These cytokines act on endothelial cells & have a variety of effects including reduced synthesis of anticoagulation factors such as tissue factor pathway inhibitor & thrombomodulin.

3. Effects of LPS vary according to its amount:a. Low dose:

- Predominantly activates monocytes, macrophages, & neutrophils.- Directly activates complement system: contributing to local eradication of bacteria.- Mononuclear phagocytes activated by LPS produce TNF & IL-1 that act on endothelial cells to

produce cytokines & induce adhesion molecules.- Results: local acute inflammatory response & improves clearance of e infection.

b. Moderate dose:- Significance of cytokine-induced secondary effectors: NO, PAF, etc.- Significance of systemic effect of TNF & IL-1: fever, increased production of acute phase

reactants & circulating neutrophils. c. High dose:

- Tips e endothelium toward a net procoagulant phenotype.- E syndrome of septic shock supervenes.- A very high level of e same cytokines & 2o mediators, result in:

Systemic vasodilatation (hypotension). Diminished myocardial contractility. Widespread endothelial injury & activation: systemic leukocyte adhesion & diffuse

alveolar capillary damage in e lung. Activation of e coagulant system leading to disseminated intravascular coagulation

(DIC). 4. The events occur at e highest level of LPS can lead to multiorgan system failure that affects

liver, kidneys, heart, & CNS & eventually death if uncontrolled rapidly. Presents with 25% to 50% of mortality rate. Results from e host innate immune response to infectious organisms that may be blood borne or

localized to a particular site.

ANAPHYLATIC SHOCK

Represents systemic vasodilatation & increased vascular permeability caused by IgE hypersensitivity reaction.

In this reaction, acute severe widespread vasodilatation results in tissue hypoperfusion & cellular anoxia.

NEUROGENIC SHOCK

May occur in e setting of an anesthetic accident or spinal cord injury. This leads to e loss of vascular tone & peripheral pooling of blood.

MARPHOLOGYADRENAL GLAND

Seen in all forms of stress. Essentially, cortical cell lipid depletion: reflects conversion of e relatively inactive

vacuolated cells to metabolically active cells that use stored lipids for e synthesis of steroids.

KIDNEYS Reveal acute tubular necrosis. Clinical features: oliguria, anuria, & electrolyte disturbances.

‘ALIAH’S Y1B2

GIT Manifests focal mucosal hemorrhage & necrosis.

LUNGS Seldom affected in pure hypovolemic shock because they r resistant to hypoxic injury. In septic shock, changes of diffuse alveolar damage known as shock lung develop.

CLINICAL COURSE

Clinical manifestation depends on e precipitating insult. Initial complications:

1. In hypovolemic & cardiogenic shock:- Hypotension, weak & rapid pulse, tachypnea, as well as cool, clammy, & cyanotic skin (due to

cutaneous vasoconstriction.2. In septic shock:

- Warmed & flushed skin as a result of peripheral vasodilatation (cutaneous vasodilatation). Secondary complications (2nd phase):

- Renal insufficiency, a progressive fall in urine output,, acidosis, as well as severe fluid & electrolyte imbalance.

E prognosis varies with e origin of shock & its duration:- 80% - 90% of young & healthy patients with hypovolemic shock survive with appropriate

management.- Cardiogenic shock with extensive myocardial infarction or gram-negative sepsis carries mortality

rate of 75% even with care.

‘ALIAH’S Y1B2

STAGES OF SHOCKSTAGES OF SHOCK

INITIAL NON PROGRESSIVE STAGE

Compensatory mechanisms

INITIAL NON PROGRESSIVE STAGE

Compensatory mechanisms

Underlying causes → inadequate perfusion →

cellular hypoxia

Underlying causes → inadequate perfusion →

cellular hypoxia

Cardiac output & blood pressure r maintained

by neurohormonal mechanisms

Cardiac output & blood pressure r maintained

by neurohormonal mechanisms

↓ blood pressure & CO → Persistent O2 deficit → prolonged excessive vasoconstriction →

widespread of tissue hypoxia → conversion

into anaerobic glycolysis → excessive production

of lactic acids → metabolic lactic

acidoasis → lower tissue pH → blunt vasomotor

response.

↓ blood pressure & CO → Persistent O2 deficit → prolonged excessive vasoconstriction →

widespread of tissue hypoxia → conversion

into anaerobic glycolysis → excessive production

of lactic acids → metabolic lactic

acidoasis → lower tissue pH → blunt vasomotor

response.

-ve feedback mechanisms.

CO & blood pressure back to normal.

-ve feedback mechanisms.

CO & blood pressure back to normal.

Baroreceptor reflexes → release of

catecholamines → activation of rennin-

angiotensin axis → ADH hormones release →

generalized sympathetic stimulation →

Baroreceptor reflexes → release of

catecholamines → activation of rennin-

angiotensin axis → ADH hormones release →

generalized sympathetic stimulation →

Underlying causes r not corrected → shock

passes imperceptibly to e progressive phase.

Underlying causes r not corrected → shock

passes imperceptibly to e progressive phase.

Arterioles dilate → blood begins to pool in e microcirculation → high risk

of endothelial cells in developing anoxic injury wih subsequent DIC → in wide spread tissue hypoxia, vital

organs r affected & begin to fail.

Arterioles dilate → blood begins to pool in e microcirculation → high risk

of endothelial cells in developing anoxic injury wih subsequent DIC → in wide spread tissue hypoxia, vital

organs r affected & begin to fail.

Intervention registration.

-ve feedback mechanisms

correct back into normal state.

Intervention registration.

-ve feedback mechanisms

correct back into normal state.

SECOND PROGRESSIVE STAGE

Tissue hypoperfussion & onset of worsening

circulatory & metabolic imbalance.

SECOND PROGRESSIVE STAGE

Tissue hypoperfussion & onset of worsening

circulatory & metabolic imbalance.

No intervention → Underlying causes r not

corrected → shock passes imperceptibly to e irreversible stage.

No intervention → Underlying causes r not

corrected → shock passes imperceptibly to e irreversible stage.

FINAL IRREVERSIBLE STAGE

Severe incurred cellular & tissue injury.

Survival is not possible even hemodynamic defects r corrected.

FINAL IRREVERSIBLE STAGE

Severe incurred cellular & tissue injury.

Survival is not possible even hemodynamic defects r corrected.

Cell death (necrosis) in:Kidney: acute tubular necrosis.Lungs: ARDS.Liver: necrosis of central region

of hepatic lobules.Heart: AMI.GIT: ischemic necrosis.

Cell death (necrosis) in:Kidney: acute tubular necrosis.Lungs: ARDS.Liver: necrosis of central region

of hepatic lobules.Heart: AMI.GIT: ischemic necrosis.

Widespread vasodilatation & stasis → progressive fall

in blood pressure → increased imperfusion to myocardium & brain → widespread cell injury

such as lysosomal enzyme leakage →

myocardial contractile function worsens (due to

NO synthesis).

Widespread vasodilatation & stasis → progressive fall

in blood pressure → increased imperfusion to myocardium & brain → widespread cell injury

such as lysosomal enzyme leakage →

myocardial contractile function worsens (due to

NO synthesis).

Cerebral & myocardial hypoxia as well as →

complete renal shutdown (due to acute tubular

necrosis) → coma

Cerebral & myocardial hypoxia as well as →

complete renal shutdown (due to acute tubular

necrosis) → coma

DEATHDEATH

‘ALIAH’S Y1B2

CA

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Excessive fluid loss

Excessive fluid loss

Inadequate plasma volume

Inadequate plasma volume

Reduced vascular

resistance

Reduced vascular

resistance

Reduced cardiac output

Reduced cardiac output

Impaired cellular

metabolism

Impaired cellular

metabolism

ShockShock

Failure of myocardial

pump

Failure of myocardial

pump

Reduced sympathetic stimulation &

increased parasympathetic stimulation

Reduced sympathetic stimulation &

increased parasympathetic stimulation

Reduced vascular tone

Reduced vascular tone

Reduced systemic vascular

resistance

Reduced systemic vascular

resistance

Inadequate cardiac output

Inadequate cardiac output

Impaired cellular

metabolism & shock

Impaired cellular

metabolism & shock

Second & successive

exposures to Ag or allergen.

Second & successive

exposures to Ag or allergen.

Massive IgE production: mast cells

degranulation.

Massive IgE production: mast cells

degranulation.

Complement activation, histamine,

kinins, & PG.

Complement activation, histamine,

kinins, & PG.

↑ Capillary permeability,

peripheral vasodilatation, smooth muscle contraction.

↑ Capillary permeability,

peripheral vasodilatation, smooth muscle contraction.

Edema, systemic

venous return, bronchoconstri

ction, laryngospasm,

GIT cramps

Edema, systemic

venous return, bronchoconstri

ction, laryngospasm,

GIT cramps

Relative hypovolemia

Relative hypovolemia

Reduced CO & tissue

perfusion.

Reduced CO & tissue

perfusion.

Impaired cellular

metabolism

Impaired cellular

metabolism

Shock & eventually

death.

Shock & eventually

death.

Infection: LPS.Infection: LPS.Release of chemical

mediators: TNF, NO, IL-1.

Release of chemical

mediators: TNF, NO, IL-1.

Vessels vasodilatation

& reduced systemic vascular.

resistance..

Vessels vasodilatation

& reduced systemic vascular.

resistance..Increased

peripheral blood pooling, reduce

in effective circulating blood

volume.

Increased peripheral blood pooling, reduce

in effective circulating blood

volume.

Reduced BP & CO, inadequate

perfusion of cells

Reduced BP & CO, inadequate

perfusion of cells

ShockShock

CELLULAR INJURYPORTIONS DETAILS

CONCEPTS1) Smith’s - Cellular injury: Biochemical lesions occur at molecular level.2) Robin’s - Cellular injury as reversible or irreversible condition which occurs after e limit of adaptive response to a stimulus r exceeded.

CAUSES

1) Environment (Non-infectious): Oxygen Deprivation: Hypoxia or oxygen deficiency interferes with aerobic respiration & leads to

ATP depletion as well as cellular injury & death. Common cause of hypoxia is ischemia which is a loss of blood supply in a tissue due to impeded arterial blood flow or reduced venous drainage.

Physical Agents: Trauma, extreme of temperatures, radiation, electric shock, & sudden changes in atmospheric pressure.

2) Chemical Agents: Any substance such as oxygen, salt, n glucose can cause cellular injury if sufficiently concentrated. Poisons can cause severe damage at cellular level by altering membrane permeability, osmotic

homeostasis, e integrity of e enzymes or cofactors, & etc. Eg of potentially toxic agents: air pollutants, insecticides, CO, asbestos, & social stimuli such as

ethanol.

3) Infectious Agents: Submicroscopic viruses, rickettsiae, bacteria, fungi, protozoan, & tapeworms.

4)Host (Inherent): Immunologic Reactions: Eg – autoimmune reactions against one’s own tissues & allergic reactions

against environmental substances in genetically susceptible individuals. Genetic Defects: May cause cell injury due to e deficiency in functional protein or accumulation of

damaged DNA or misfolded proteins. Variations in genetic makeup can also influence e susceptibility of cells to injury by any insults.

Nutritional Imbalance: Eg in lack of protein-calorie diet or excess in animal fat content. Aging: Cellular senescene leads to alterations in replicative & repair abilities of individual cells &

tissues. This results in a diminished ability to respond to damage & eventually e death of cells or organism.

PRINCIPLES

1) Dr. Ungku’s principles: Cellular response is e response of e cell to e biochemical lesions in order to get back to normal

(homeostasis). Tissue response to injury = Lessions (10 abnormalities - will be described later).

2) Robin‘s general principles: E cellular response to injurious stimuli depends on e type of injury, its duration, & its severity. E larger e dose n e longer e duration of a stimulus, e severe e injury or e > it to become

irreversible. E consequences of an injurious stimulus depend on e type, status, adaptability, & genetic makeup

of e injured cells. E same injury has vastly different outcomes depending on different cells with different types,

status, & genetic makeup. 4 intracellular systems r particularly vulnerable:

1. Cell membrane integrity. 2. ATP generation3. Protein synthesis.4. E integrity of e genetic apparatus.

E structural & biochemical components of a cell r so integrally connected that regardless of e initial locus of injury, multiple 2o effects rapidly occurs.

Diminished activity of Na+-K+ pumps leads to cell swelling & rupture. Cellular function is lost far before cell death occurs & e morphological changes of cell injury/death

lag far behind both. This is because e specific activity of a cell typically relies on all systems being intact.

REVERSIBLE CELLULAR INJURY

BIOCHEMICAL MECHANISMS

ATP depletion

Major causes of ATP depletion: reduced O2 & nutrients supply, mitochondrial damage, & e action of some toxins.

Depletion of ATP to less than 5% to 10% of normal levels has widespread effects on many critical cellular systems.

Ischemia → ↓ oxidative phosphorylation → ↓ ATP → ↑ plasma membrane energy-dependent Na+ → ↑ Ca2+, water, & Na+ influx & ↑ K+ efflux → Cellular swelling, ER dilation, & loss of microvilli blebs → ↑ compensatory anaerobic glycolysis (to maintain energy sources) → ↓intracellular glycogen stores → ↑ lactic acid accumulation → ↓ intracellular pH → ↓ activity of many cellular enzymes → clumping of nuclear chromatin → prolonged ATP depletion → detachment of ribosomes from RER & dissociation of polysomes into monosomes → ↓ protein synthesis → irreversible damage to mitochondria & lysosomal membrane → necrosis.

Mitochondrial damage & dysfunction

Causes of damage: ↑ cytosolic Ca2+, ↑ ROS, O2 deprivation, & injurious stimuli such as hypoxia & toxins.

2 major consequences of mitochondrial injury:1) Mitochondrial damage → formation & opening of mitochondrial permeability

transition pores → loss of mitochondrial membrane potential & pH change → failure oxidative phosphorylation → progressive depletion of ATP → necrosis.

2) Mitochondrial damage → ↑ permeability of mitochondrial membrane → leakage of protein capable of activating apoptotic pathway (cytochrome c) →

‘ALIAH’S Y1B2

apoptosis.

Calcium influx

Ischemia & toxins → ↑ release of Ca2+ from intracellular stores → ↑ cytosolic Ca2+ → activation of a no. of enzymes (phospholipase: membrane damage, protease: breaks down membrane & cytoskeletal protein, endonuclease: DNA & chromatin damage, ATPase: ATP depletion) → membrane damage → apoptosis.

ROS accumulatio

n

ROS r chemical species with a single unpaired electron in an outer orbital. They r extremely unstable & readily react with other chemicals. Generation of ROS:

1) Redox reactions that occur during normal mitochondrial metabolism generate small amounts of toxic intermediate species such as superoxide radicals, hydrogen peroxide, & etc.

2) Free-radical formation catalyzed by transition metals such as iron in Fenton reaction.

3) Absorption of radiant energy hydrolyzes water into hydroxyl & hydrogen free radicals.

4) E enzymatic metabolism of exogenous chemicals such as CCl4.5) Production of free radicals by leukocytes in inflammatory reactions.6) NO acts as free radical or can be converted into highly reactive nitrite species.

Removal of ROS:1) Action of superoxide dismutases in catalyzing e spontaneous decay of

superoxide.2) Action of glutathione peroxidase in catalyzing free-radicals breakdown.3) Action of catalase in catalyzing e breakdown of hydrogen peroxides into O2 &

water.4) Blockage & scavenge of free-radicals by antioxidants such as vitamin E,A, & C.

Pathologic effects of ROS:1) Lipid peroxidation of membranes: ROS attacks double bonds in membrane

polyunsaturated lipids to yield peroxides & leads to autocatalytic chain reactions.2) Cross-linking of proteins: ROS promotes sulfhydryl-mediated proteins cross-

linking & results in enhanced degradation or loss of enzymatic activity.3) DNA fragmentation: ROS reaction with thymine in nuclear & mitochondrial

DNA leads to DNA damage (single-strand breaks).

Defect in membrane

permeability

Most important sites: mitochondrial membrane, lysosomal membrane, & plasma membrane.

Causes of membrane damage:1) Injurious stimuli → ↓ O2 → ↓ ATP → ↓ phospholipid synthesis → ↑ phospholipid

loss→ membrane damage.2) ROS & ↑ cytosolic Ca2+ → lipid peroxidation & activation of phospholipase → ↑

phospholipid breakdown → ↑ phospholipid loss & ↑ lipid breakdown products → membrane damage.

3) ↑ cytosolic Ca2+ → protease activation → cytoskeletal damage → membrane damage.

Effects of membrane damage:1) Mitochondrial membrane damage: leads to decreased production of ATP,

culminating in necrosis, & release of proteins that trigger apoptosis.2) Plasma membrane damage: leads to loss of osmotic balance & influx of ions &

fluids & loss of cellular contents & metabolites that important for ATP reconstitution → ATP depletion.

3) Lysosomal membrane damage: leads to leakage of its enzymes into cytoplasm & activation of hydrolases acid which result in digestion of cell components & necrosis.

DNA & protein damage

If e repair system of DNA is severely damaged by injurious stimuli, e cells is accumulated with damaged DNA & misfolded proteins & leads to apoptosis.

COMMON FORMS

Ischemic & hypoxic injury

Results in reduced O2 supply to e cells (ischemia injures tissues faster than does hypoxia).

Leads to ATP depletion & failure of many energy-dependent cellular systems. If O2 is restored, all of these disturbances r reversible. If ischemia persists, irreversible injury & necrosis ensue. After necrosis, e cells will be replaced by large mass composed of phospholipids in e

form of myelin figures & become calcified.

Ischemia-reperfusion

injury

Sometimes, blood restoration to ischemic tissues results in exacerbated & accelerated injury.

As a result, tissues sustain e loss of cells in addition to those that r irreversibly damaged.

Exacerbation of e injury is due to:1) E increased generation & accumulation of ROS by parenchymal & endothelial

cells as well as infiltrating leukocytes.2) Increased inflammatory reaction with increased reperfusion attracts >

leukocytes & plasma protein influx that can cause further injury. 3) Reperfusion activates complement system & exacerbates e injury.

Chemical toxic injury

Chemicals cause cells injury by 2 mechanisms:1) Act directly by combining with a critical molecular component or cellular

organelle & leads to cell damage.2) Conversion of chemicals into reactive form & then act on target cells & cause

cell injury & death.

‘ALIAH’S Y1B2

SUBCELLULAR

RESPONSES- occur in acute lethal injury &

chronic cell injury.

Autophagy

Refers to lysosomal digestion of e cell’s own components. A survival mechanism during nutrient deprivation & may also signal death by

apoptosis. Process: organelles + portion of cytosol sequestered from e cytoplasm in an

autophagic vacuole formed at e ribosome-free end RER → vacuole fused with lysosome forming autophagolysosome → digestion of cellular components by lysosomal enzyme → exocytosis.

Initiated by proteins that sense nutrient deprivation. Lysosomal enzymes break down protein & carb. Lysosomes with undigested debris may persist as residual bodies or may be

extruded. Lipofuscin pigment granules represent indigestible material resulting from free

radical-mediated lipid perodixation.

Induction of smooth ER

SER involves in e metabolism of various chemicals such as barbiturates. Cells exposed to these chemicals show SER hypertrophy which leads to increased

capacity of removing e toxin, a mechanism called compensatory mechanism.

Mitochondrial

alterations &

dysfunction

In nonlethal pathological condition, there may be alterations in size, shape, & function of mitochondria as response to chronic injury.

E.g.:1) In hypertrophy: increase no. of mitochondria.2) In alcoholic liver disease: large & abnormal shape of mitochondria

(megamitochondria).3) In metabolic diseases of skeletal muscle: mitochondrial myopathies (large

mitochondria with abnormal cristae).

Cytoskeletal abnormaliti

es

Occur in pathologic states & can be manifested as an abnormal appearance & function of cells.

E.g.:1) In alcoholic liver disease: aberrant movement of organelles, defective cell

locomotion, or intracellular accumulation of fibrillar material.2) Chronic respiratory infection: impaired clearance of inhaled bacteria due to

defective mobility of cilia.

MORPHOLOGY OF

REVERSIBLE CELLULAR

INJURY

E cellular derangement of reversible injury can be repaired & if e injurious stimulus abates, e cell will turn to normalcy.

Morphologic correlates of reversible injury r:1) Cellular swelling:

Difficult to appreciate with e light microscope but may be > appreciated at e level of e whole organ.

Causes pallor, increased turgor, & increase in weight of e organ. 2) Fatty change:

Manifested by e appearance of lipid vacuoles in e cytoplasm. Encountered in cells participating in fat metabolism such as hepatocytes & myocytes. Show increased eosinophilic staining: becomes > pronounces with progression to necrosis.

3) Hydrophobic change: Small & clear vacuoles within e cytoplasm: represent distended & pinched-off segments of e ER. Also known as vacuolar degeneration.

E ultrastructural changes r:1) Plasma membrane alterations: blebbing, blunting, or distortion of microvilli, & loosening of

intercellular attachments.2) Mitochondrial changes: swelling & e appearance of phospholipid-rich amorphous densities.3) Dilation of e ER with detachment of ribosomes & dissociation of polysomes.4) Nuclear alterations: clumping of chromatin.

PRINCIPLE OF CLASSIFYING LESIONS INTO GROUPS & TYPES Lesion groups Concept Principles of classification

into groupsPrinciples of classification

into types

1 Degeneration

Non-pigmented cytoplasmic

changes

Abnormalities located in the cytoplasm with accumulation

of non-pigmented endogenous substances

Based on the type of SUBSTANCE

accumulated & on the TYPE of cell

2 Necrosis

Cytoplasmic, nuclear and membrane changes

Abnormalities located in the nucleus, cytoplasm & cell

membrane

Based on GROSS APPEARANCE of the tissue & the STRUCTURE of the cell

3 Inflammation

A complex sets of tissue

response to injury involving

neural, vascular, humoral &

cellular reaction within the site

Complex abnormalities involving degeneration,

necrosis, growth disturbances, circulatory

disturbances and increase of inflammatory cells in tissues

Based on EXUDATES & type of

LESIONS

‘ALIAH’S Y1B2

of injury

4Growth

Disturbances

Abnormal cell growth but still under control of

the body

Abnormalities of cell growth affecting the whole cell in

terms of size, number, type and arrangement of cells in

tissues

Based on the SIZE , NUMBER ,TYPE &

ARRANGEMENT of cells,

Circulatorydisturbance

s

Abnormalities in the

cardiovascular system (CVS)

Abnormalities located in the CVS i.e. in the blood, heart & vessels (which can effect on other tissue (e.g. liver, lung)

Based on the ORGAN, TISSUE & VESSEL

6 TraumaPhysical & chemical

Injury to organs

Abnormalities located in organs that have undergone anatomical displacements

due to physical injury

Based on the ORGAN & LOCATION

7 Pigmentation

A condition where

there is accumulation

of excess pigments in

the cells

Abnormalities located in the cytoplasm with accumulation of pigmented substances of endogenous or exogenous

origin

Based on the type of EXOGENOUS &

ENDOGENOUS PIGMENTS, HEPATOGENOUS or HAEMATOGENOUS

8 Neoplasia

Growth disturbance

without control of thebody

Abnormalities of cell growth affecting the whole cell in

terms of size, number, type and arrangement of cells in tissues, but with anaplastic

features

Based on HISTOGENESIS (where the tumor come from) & its BEHAVIOUR (benign or

malignant)

9 Congenitalanomalies

Abnormalities during

the development of

theembryo or

foetus

Abnormalities of cell growth affecting the whole cell, in terms of size, number, type and arrangement of cells in

tissues, but occurring during the development of the

embryo or foetus

Based on the FAILURE OF THE

DEVELOPMENTAL PROCESS (e.g. failure of organ to

close, separate, persisting structures, abnormal location

& enzyme defects

10

Miscellaneous

Miscellaneous conditions not

in the other groups

Abnormalities that are excluded from the other

groupsBased mainly on location

AMYLOIDOSISPORTIONS DETAILS

OVERVIEW

PATHOGENESIS

CONTRIBUTING FACTORS

TYPES OF AMYLOIDOSIS

AL

AA

Aβ

TTR

Β2-µglobulin

CLASSIFICATIONS

PRIMARY

SECONDARY

HEREDITARY

LOCALIZED

ENDOCRINE

AGING

MORPHOLOGY

‘ALIAH’S Y1B2

‘ALIAH’S Y1B2

CELLULAR ADAPTATIONS & DIFFERENTIATIONS PHYSIOLOGICAL ADAPTATIONS PATHOLOGICAL

- Adaptations: reversible changes in e no., size, phenotypes, metabolic activity, or function of cells in response to change in their environment.

- Occurs in sublethal (reversible) cellular injury.

Represent responses of cells to normal stimulation by hormones or endogenous

chemical mediators.OVERVIEW

Responses to stress that allow cells to modulate their structure & function & then escape injury.

-

METAPLASIA- Is thought to

arise by genetic reprogramming of stem cells rather than transdifferentiation of already differentiated cells.

Uterine cervix:- Squamous epithelium replaces the

endocervical glandular epithelium due to change in hormonal status or inflammation.

Bronchial epithelium in smokers:- E normal ciliated columnar epithelial

cells r replaced by stratified squamous epithelial cells, but its protective mechanisms r lost.

Esopahgus in GERD:- From stratified squamous epithelium to

columnar epithelium. Mesenchymal cells:

- Less clearly as an adaptive response.- Eg: bone is occasionally formed in soft

tissue particularly in foci of injury.

- Reversible change.- One adult cell type is replaced by another adult cell type.

- Cells sensitive to a particular stress r replaced by other cell types better able to withstand e adverse environment.- Change of cellular differentiation & mostly occur in epithelial cells, rarely in mesenchymal (stromal) cells

- Protective mechanism purpose.

2 types of physiological hyperplasia:1. Hormonal hyperplasia

- Breast glandular epithelium at puberty

- Uterus in pregnancy2. Compensatory hyperplasia

- After partial hepatectomy – mitotic activity increases as soon as after 12 hours, & increased cell number to restore organ to its normal size / weight.

- E stimuli r polypeptide growth factors produced by remnant hepatocytes & nonparenchymal cells in e liver.

- After restoration, cell proliferation is turned off by various growth inhibitors.

HYPERPLASIA

Due to excessive hormonal or growth factor stimulation.- Eg: disturbance of normal hormonal

balance between estrogen and progesterone → unopposed estrogen effects → endometrial hyperplasia → abnormal menstrual bleeding.

Stimulation of growth factor is also involved in hyperplasia.

- Eg: skin wart – HPV induced increase in growth factor → hyperplastic epithelium.

- Eg: prostatic hyperplasia – reduced androgen in elderly male.

- An increase no. of cells in an organ.- Often associated with hypertrophy.

- Takes place in cell population that is capable of replication: labile & stable cells.

Early Development Decrease functional demand

- Reduced uterine size after pregnancy Loss of endocrine stimulation

- Atrophy of genital organs in menopause

Senile atrophy (heart, brain)

ATROPHY- May also

accompanied by autophagy which results in increasing e no. of autophagic vacuoles.

- Autophagy: process in which starved cell eats its own components in an attempt to find nutrients & survive.

Disuse muscle atrophy Denervation nerve atrophy Ischemia Pressure atrophy Nutrition deficiency Cellular mechanism of atrophy:

- Lyzosomes containing autophagic enzymes.- Ubiquitin-proteasome pathway: nutrient

deficiency → activate e pathway → nuclear and cytosolic proteins r conjugated with ubiquitin and degraded within cytoplasmic proteasome → atrophy.

- Shrinkage in the size of the cell by loss of cell substance.- The tissue or organ may become smaller.

- There may be diminished function but e cells r not dead.- Causes: a decreased workload, loss of innervations, diminished blood supply, inadequate nutrition, loss of endocrine

stimulation, & aging.- Results from decreased protein synthesis because of reduced metabolic activity & increased protein degradation in

cells.

Hormonal hypertrophy1) Breast during lactation2) Uterus enlargement during pregnancy

- Due to massive secretion of estrogen

HYPERTROPHY Increased functional demand – muscle hypertrophy.

Muscle in adults can only undergo hypertrophy in response to increased demand

‘ALIAH’S Y1B2

which stimulates smooth muscle hypertrophy.

because muscle cells cannot divide. Synthesis of more protein and myofilaments

per cell to share the increased workload. There is a limit as to the increased workload

tolerence -may eventually result in ‘degenerative’ changes

Eg: left ventricular hypertrophy:- Hypertension → mechanical trigger

(stretch) → trophic triggers (activation of α-adrenegic receptors) → genes induction → cellular protein synthesis → hypertrophy → prolonged injury → hypertrophy reaches e limit → degenerative changes occur → DNA fragmentation & loss of myofibrillar contractility → cardiac failure.

- An increase in e size of cells resulting in increase in e size of e organ.- There r no new cells, just bigger cells, enlarged by an increased amount of structural proteins & organelles.

- Occurs when cells r incapable of dividing.- Caused either by increased functional demand or by specific hormonal stimulation.

- Often associated with hyperplasia.

DYSPLASIA

- Disorderly but non neoplastic proliferation.- Usually refers to epithelial cells.

- Loss of uniformity of the cells and loss of architectural orientation.- Dysplastic cells show significant pleomorphism, nuclear hyperchromasia and increased NC ratio.

- Mitotic figures are more frequently seen than usual.- May be abnormal in form.

- May not be limited to basal layers.- Progressive maturation of epithelial cells is lost.

- Dysplasia is usually found next to cancer.- Not all dysplastic foci will progress to cancer.

- Mild to moderate dysplastic changes may be reversible.

PATHOLOGIC CALCIFICATION OVERVIEW:

1) Implies e abnormal deposition of calcium salts with smaller amounts of iron, magnesium, & other minerals.2) Hypercalcaemia can exacerbate its progession.

DETAILS TYPES OF CALCIFICATION MORPHOLOGY

Occurs in e absence of calcium metabolite derangements, i.e., with normal serum level of calcium).

Encountered in e area of necrosis of any type

Inevitable in e atheromas of advanced atherosclerosis, associated with intimal injury in e aorta & large arteries & characterized by accumulation of lipids.

Indicates insignificant past cell injury. May cause organ dysfunction. E.g.: dystrophic calcification of aortic

valves can lead to aortic stenosis. Pathogenesis:

DYSTROPHIC CALCIFICATION Regardless of site, calcium salts r:1) Grossly seen as fine, white

granules or clumps. 2) Often felt as gritty deposits.

Sometimes, a tuberculous lymph node is converted to radio-opaque stone.

Histologically, calcification appears as intracellular and/or extracellular basophilic deposits.

In time, heterotropic bone may be formed in e focus of calcification.

‘ALIAH’S Y1B2

Narrated abu Juhaifa : … Salman told Abu Ad-Darda’, “Your Lord has a right on you, your soul has right on

you, and your family has a right on you; so you should give the rights of all those who has a right on

you.” Abu Ad-Darda’ came to the Prophet and narrated the whole story. The Prophet said, “Salman has spoken

the truth.” -Saheh Bukhari-

1) Initiation (in mitochondria of damaged cells): calcium is concentrated in membrane-bound vesicles by its affinity for membrane phospholipids → phosphates accumulate by e action of membrane-bound phosphatases →

2) Propagation of crystal formation: depends on: E [ ] of Ca2+ & PO4

- in e extracellular spaces.

E presence of mineral inhibitors. E degree of collagenization

Enhances e rate of crystal growth.

Reflects some derangement in calcium metabolism (hypercalcaemia).

4 major causes of hypercalcaemia:1) Increased secretion of parathyroid

hormone.2) Destruction of bone due to e

effects of accelerated turnover, immobilization, or tumors.

3) Vitamin D-related disorders.4) Renal failure: phosphate retention

leads to 20 hyperparathyroidism.

METASTATIC CALCIFICATION

Occurs widely throughout e body. Principally affects e interstitial

tissues of e vasculatures, kidneys, lungs, & gastric mucosa.

E calcium deposits r seen as fine white granules or clumps & felt as gritty deposits.

Does not generally cause clinical dysfunction.

Extensive calcifications in lungs may produce remarkable radiographs & respiratory deficits.

Massive deposits in e kidney can cause renal damage.

INTRACELLULAR ACCUMULATION

OVERVIEW

Location: in e cytoplasm, within e organelles, or in e nucleus. 3 main pathways:

Pathways Production Removal Example 1 Normal or increased Inadequate or low Fatty change in liver2 Normal or increased Defective in folding & transportation α1-anti-trypsin deficiency3 Normal or increased Inherited defect of degradation Storage diseases

-

DETAILS SUBSTANCE ACCUMULATED MORPHOLOGiCAL APPEARANCE

Known as fatty change (steatosis): abnormal accumulation of triglycerides within parenchymal cells.

Often seen in liver: major organ of fat metabolism, also seen in heart, muscle, & kidney.

Causes: alcohol, toxins, protein malnutrition, DM, obesity, & anoxia.

Pathogenesis:Free fatty acids r transported to hepatocytes → esterification into triglycerides → conversion into cholesterols or phospholipids → oxidized into ketone bodies → defect at any step into lipoprotein exit → inhibition of fatty acid oxidation → accumulation of triglycerides → fatty change.

Severe fatty change may impair cellular function as in CCl4 poisoning.

TRIGLYCERIDES

Appears as clear vacuoles within parenchymal cells.

Fat is identified by staining with frozen Sudan IV or oil red O which seen as orange red substance.

In liver:- Organ enlarges & becomes progressively

yellow in color.- Weight: 3-6 kg.- Appears as bright yellow, soft, & greasy.- Nucleus is displaced to e periphery.- In cell rupture: fat globules unite to produce

fatty cysts. In heart:

- Lipid is found as small droplets in one of 2 patterns: 1) hypoxia- focal intracellular fat deposits, creating grossly apparent bands of yellowed myocardium alternating with bands of darker, red-brown, uninvolved heart. 2) Toxic injury-more uniformly affected myocytes.

Pathogenesis:Macrophages engulf lipid debris or abnormal lipoprotein → foamy appearance of macrophages (in cytoplasm) → foamy cells.

CHOLESTEROL & CHOLESTERYL ESTERS

Atherosclerosis: smooth muscle cells & macrophages r composed of cholesterol & cholesteryl esters which give atherosclerotic plaque its yellow in color.

Hyperlipidaemia: in subepithelial connective tissue of skin or in tendons, clusters of e foamy macrophages forms masses called xanthomas.

Less common than lipid. Occurs because of excessive production,

over reabsorption, or less secretion of proteins.

E.g.: nephritic syndrome.

PROTEINS

Histological appearances:1) Pynocytic vesicles containing excess

protein: pink, hyaline cytoplasmic droplets.2) Accumulation of Igs in RER of plasma

cells: rounded, eosinophilic Rusell bodies.

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Exogenous pigments

1) Carbon (coal dust): when inhaled, paghocytosed by alveolar macrophages & transported into lymph nodes.

PIGMENTSColored substances

that r either exogenous or

endogenous in origin.

1) Blacken draining lymph nodes & pulmonary parenchyma.

Endogenous pigments

1) Lipofuscin: Accumulates in a variety of tissue: heart,

liver, & brain. Represents complexes of lipid & protein

that derived from free radical-catalyzed perodixation of polyunsaturated lipids of subcellular membranes.

1) Insoluble brownish-yellow granular intracellular material. In large amount, presents as brown pigment (brown atrophy). In electron microscopy, e pigment appears as perinuclear electron-dense granules.

2) Melanin: Produced by melanocytes located in e

epidermis. Acts as a screen against UV radiation.

2) An endogenous, brown-black pigment. Can be accumulated in keratinocytes of e skin.

3) Hemosiderin: A haemoglobin-derived granular pigment. Accumulates in e tissue where there is a

local or systemic excess of iron. Its accumulation is usually pathologic, but

normal small amounts r present in e mononuclear phagocytes of e BM, spleen, & liver where there is extensive RBC breakdown.

3) Appears as golden yellow to brown pigments. Represents large aggregates of ferritin micelles (associated with apoferritin)which r readily visualized by light & electron microscopy.

‘ALIAH’S Y1B2

The best and most beautiful things in the world cannot be seen or even touched.

They must be felt with the heart…

Your vision will become clear only when you can look into your own heart.

Who looks outside dreams, Who looks inside awakens...

"Allah the Exalted does not look at your bodies, He looks at your hearts"

THROMBOSISPORTIONS DETAILS

DEFINITION & OVERVIEW

Thrombosis: formation of solid mass in e circulation from e constituents of e stream blood. Thrombus: e mass itself which consists of aggregated platelets &fibrin in which e RBCs & WBCs r

trapped. It occurs in e wrong time at e wrong place & always pathologic.

VIRCHOW’S TRIAD

Suggested by Rudolf Virchow

in 1860.

ENDOTHELIAL INJURY Predominant factor of thrombosis. Important for thrombus formation in e heart & arterial circulation where high blood flow rate is

noted. 2 reactions:

1) Endothelial injury: Actual physical loss of endothelial cells → exposure of subendothelial ECM & collagen →

adhesion of platelets → release of tissue factor → local depletion of PGI2 & plasminogen activators → platelets aggregation→ activation of coagulation cascades → thrombosis.

Causes of endothelial injury:- Atherosclerosis - Chemicals - Acute Myocardial Infarction - Infection- Disease valve – Chronic Endocarditis - Immune system

2) Endothelial dysfunction: Any perturbation in e dynamic balance of e prothrombotic & antithrombotic activities of

endothelium can influence local clotting events. Endothelial dysfunction may elaborate greater amounts of procoagulant factors or may

synthesize fewer anticoagulant effectors. Activation of endothelial cells also results in a procoagulant phenotype. Causes of endothelial injury:

- Hypertension - Homocystinuria - Action of bacterial endotoxins - Hypercholesteromia- Turbulent flow over scarred valves - Products of cigarette during smoking

ALTERATIONS IN NORMAL BLOOD FLOW

TURBULENCE

Is of particular importance in relation to areas where arteries branch & to narrowed segments of arteries.

Turbulent flow contributes to arterial & cardiac thrombosis by causing endothelial injury or dysfunction & by forming countercurrents & local pockets of stasis.

Eg: Ulcerated atherosclerosis plaques. Atherosclerosis → endothelial injury → ulcerated arterial or cardiac walls →

plaque formation & implantation → turbulent flow → thrombosis.

STASIS

Local slowing tend to occur in particularly in e veins of e leg under a no. of different circumstances:1) Prolonged dependence of e limbs.2) Reduced muscle pumping activity.3) Proximal occlusion of e venous drainage.

Stasis can’t cause thrombosis by itself: must occur with e help of s/thing else such as turbulence & dysfunctional endothelial cells.

Stasis causes thrombosis because of:1) Prolonged intact b/w platelets to e subendothelial surface.2) Reduced concentration of coagulation inhibitors.3) Increased concentration of activated coagulation factors.

Causes of stasis:1) Acute Myocardial Infarction: myocytes death → loss of contractility →

reduced blood flow rate → stasis → thrombosis.2) Aneurysm: vasodilatation of arterial walls → local stasis → thrombosis.3) Atrial fibrillation: Lf. Atrial dilatation → profound stasis → thrombosis.

BOTH FLOWS

Disrupt laminar flow & bring platelets into contact with e endothelium. Prevent dilution of activated clotting factors by fresh-flowing blood. Retard e inflow of clotting factor inhibitors & permit e buildup of thrombi. Promote endothelial cell activation, resulting in local thrombosis, leukocyte

adhesion, etc.

HYPERCOAGULABILITY A hypercoagulable state is one in which e normal haemostatic equilibrium is titled in such a way

that thrombosis is favored. It is also defined as any alteration of e coagulant pathway that predisposes to thrombosis. Less important & less contributor to thrombosis. Can be divided into:

a) Primary (inherited) hypercoagulable state:1) An increase in procoagulant factors such as fibrinogen & Factor VII.2) A decrease in natural anticoagulant factors such as Protein C & S, anti thrombin III as in

Factor V Leiden gene mutation.3) Increased viscosity of blood due to increase in fibrinogen, Igs, & polycythaemia.

b) Secondary (acquired) hypercoagulable state:1) Usage of oral contraceptive pills - both may be related to increase hepatic

synthesis of2) Hyperestrogenic state of pregnancy coagulantion factors & reduced

synthesis of anti thrombin III.

‘ALIAH’S Y1B2

3) E release into blood of procoagulant compounds from malignant tumour (adenocarcinomas).

4) An increase in platelets counts (thrombocytosis).5) An increase in platelets adhesiveness.

MORPHOLOGY

a)Site: anywhere in cardiovascular system – cardiac chamber, on valves, in arteries, veins, or capillaries.

b)Size & shape: variable – depend on e site of origin & e cause.c)Point of origin: arterial or cardiac thrombi (sites of endothelial injury or turbulence) & venous

thrombi (sites of stasis).d) Line of Zahn:

Grossly & apparent lamination. Represents pale platelets & fibrin layers alternating with darker RBCs-rich layers. Significant only in thrombosis formation in e flowing blood (distinguishable from blood clots in e

postmortem state). Prominent in e heart & aorta but less apparent in veins & small arteries because thrombi formed

in these vessels resemble statically coagulated blood.

e) Mural Thrombi:

Occurs in e heart or in e aortic lumen.

Cardiac MT is promoted by abnormal myocardial contraction or endomyocardial injury.

Aortic thrombosis is promoted by atherosclerosis & aneurysm.

f) Arterial Thrombi: Frequently

occlusive. Produced by

platelets & coagulation activation.

Typically a friable meshwork of platelets, fibrins, RBCs, & WBCs.

Usually superimposed on atherosclerosis plaque.

g) Venous Thrombi:

Phlebothrombosis or red stasis.

Invariably occlusive. Creates a long cast

of e lumen (snake like).

Result of activation of coagulation cascade & platelets.

Contains > enmeshed RBC.

Most commonly affect e veins of lower extremities (90%).

h) Vegetation: Thrombi of e heart

valves. Caused by bacterial

or fungal blood –borne infection

Non-bacterial thrombatotic endocarditis: sterile vegetations developed on noninfected valves in hypercoagulable state.

i)Postmortem clots: Gelatinous Presence of dark red dependent portion where RBCs have settled by gravity. Presence of yellow chicken fat supernatant & not attached to endothelial walls.

SEQUELE OF THROMBI

PROPAGATION Accumulation of > platelets & fibrin which leads to obstruction.

EMBOLIZATION Thrombi dislodge or fragment & r transported elsewhere in e vasculature.

DISSOLUTION Removed of thrombi due to fibrinolytic activity (plasmin). Leads to rapid shrinkage & total lysis of recent thrombi.

ORGANIZATION Thrombi induce inflammation & fibrosis. Older thrombi become organized by e ingrowth of endothelial cells &

fibroblast into e fibrin-rich clots.

RECANALIZATION

Re-establishing some degree of flow. Potentially converts a thrombus into a vascularized mass of connective

tissue that is eventually incorporated into vessel walls & remains as a subendothelial swelling.

Cleft appears within e thrombotic material. Becomes lined by mesenchymal cells which differentiate intoendothelial

cells.

CLINICAL SIGNIFICANCE

1) Obstruction of arteries & veins.2) Embolism: pulmonary embolism.3) Venous thrombosis:

Superficial veins - varicosities, local congestion, swelling, pain, & tenderness, rarely embolized. Deep veins – popliteal, femoral, & iliac veins.

4) Cardiac & Arterial thrombosis: MI, atrial fibrillation, & atheriosclerosis, obstruction, & embolization in brain, kidneys, & spleen.

‘ALIAH’S Y1B2

Arterial thrombosisMajor initiator: atherosclerosis because it is associated with loss of endothelial integrity & abnormal vascular flow. Cardiac MT can occur in e setting of MI related to dyskinetic myocardial contraction & damage to e adjacent endocardium.Pathogenesis: atherosclerosis of e arterial wall → plaque ulcerated → endothelial injury exposing blood to subendothelial surface & release of tissue factor → platelet adhesion & aggregation → fibrin meshwork formation in which RBCs & WBCs r trapped → this protrudes further into e lumen causing > turbulence & forming e basis for platelets deposition → propagation of thrombus.

FUNCTIONS OF ENDOTHELIAL CELLS

Anti thrombotic properties:Anti platelets effects: intact endothelium, prostacyclin, & NO.Anti coagulant properties: antithrombin III, protein C & protein S.Fibrinolytic properties: tissue plasminogen activator.

Prothrombic properties: Von Willebrand Factor (VWF) & tissue factor.Platelets: platelets adhesion (secretin: ADP, Ca) & platelet aggregation (ADP, Tromboxane A2).Coagulation cascade: intrinsic & extrinsic pathway.

Venous thrombosis

90% of cases affect e veins of e lower extremities.Most begin at e valves.Primary cause: stasis caused by cardiac failure.3 mechanism involved:Venous stasis

Predisposes patients to venous thrombosis mainly by impairing e clearance of activated coagulation factors from e local site.

Injury to e venous wallContributes to e genesis of

venous thrombosis through either direct trauma or activation of endothelial cells by cytokines.

Hypercoagulable stateNumerous genetic

abnormalities r associated with an increased risk for venous thrombosis: mutation in factor V & Protein C gene, & Protein S & antithrombin deficiency.

Clinical predispositions:Cardiac failure &

immobilazationNeoplasia & postoperative

statePregnancy & obesity