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Homeostasis


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EDEMA

Increased fluid in the interstitial tissue spaces

Massive edema is calledAnasarca.

Fluid may also accumulate in body cavities

These collections of fluid are referred to based on

location as:

Hydrothorax, hydropericardium, hydroperitoneum (Ascites


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maintained by opposing effects of vascular hydrostatic

pressure and plasma colloid osmatic pressure


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Homeostasis ismaintained by the

opposing effects of

vascular hydrostatic

pressure and plasma

colloid osmoticpressure

Fluid Homeostasis


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Edema

Development

Picture

Fig 2.2

Either increased

vascular hydrostatic

pressure or decreased

plasma colloidosmotic pressure can

lead to EDEMA

Inflammatory

mediators can alter

vascular permeability

causing local

EDEMA


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Edema Fluid = TRANSUDATE

A transudate is protein-poor (specific gravity

1.020)


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Pathophysiologic Categories of Edema

I. Increased Hydrostatic Pressure

II. Reduced Plasma Oncotic PressureIII. Inflammation

IV. Other



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I. Increased Hydrostatic Pressure:

Generalized increases in venous pressure, with

resultant SYSTEMIC EDEMA, occur MOSTCOMMONLY in CONGESTIVE HEARTFAILURE

Thus, Congestive Heart Failure is the most

common cause of EDEMA due to IncreasedHydrostatic Pressure

Types of disease causing Edema:

A. Congestive Heart Failure

B. Portal HypertensionC. Venous Thrombosis


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Congestive Heart Failure

The Pump is FAILING!!! (All the bloodgoing in IS NOT going out!)

Blood backs up, first into the lungs, then into the venous circulation - increasing

Central Venous Pressure (CVP)

Increased CVP leads to increased capillarypressure (Hydrostatic Pressure) leading to Edema


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Overall, there are TWO main effects..

1. Increased Central Venous Pressure

(we just talked about this one)

2. Decreased Renal Perfusion


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Decreased Renal Perfusion Decreased Cardiac Output

Leads to decreased ARTERIAL blood volume Activates the Renal Defense Mechanisms:

Renin-Angiotensin-Aldosterone Axis

Renal VasoconstrictionIncreased Renal Anti-diuretic Hormone (ADH)


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Decreased Renal Perfusion Decreased Renal Perfusion activates the Renal

Defense Mechanisms:Renin-Angiotensin-Aldosterone Axis

Renal Vasoconstriction

Increased Renal Anti-diuretic Hormone (ADH)


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Congestive Heart FailureRenin-Angiotensin-Aldosterone Axis

Renin AldosteroneRenal Na

reabsorption

Renal retention of

Na + H2OPlasma volume

Transudation

EDEMA

Decreased Renal Perfusion


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Congestive Heart FailureRenal Vasoconstriction

Renal

Vasoconstriction

Glomerular Filtration

Rate (GFR)

Tubular

reabsorption of

Na + H2O

Plasma volume

Transudation

EDEMA


Renal retention of

Na + H2O


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Congestive Heart FailureRenal Vasoconstriction

Anti-Diuretic

Hormone (ADH)

Renal retention of

H2O

Plasma volume

Transudation

EDEMA


Renal retention of

Na + H2O


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CentralVenous

Pressure

RenalPerfusion

Renin Renal

Vasoconstriction

ADH


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Portal Hypertension

Portal Hypertension is Increased resistance to portal bloodflow

The most common cause of Portal Hypertension is

CIRRHOSIS. Pathogenesis of Ascites is complex

Increased Portal Pressure (hydrostatic pressure) leads to increasedliver sinusoidal hypertension. Fluid moves into the Space of Dissethen into lymphatics


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Pathogenesis of Ascites is

complex Cirrhosis leads to hypoalbuminemia sneaking

into the next category And ultimately, there is decreased renal

perfusion leading to secondary

hyperaldosteronism (increased renin etc.)


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Portal Hypertension

Sinusoidal

HypertensionRenal

Perfusion

Hepatic LymphOverwhelms

Thoracic Duct

Aldostero

ASCITES

Cirrhosi

Serum

Albumin


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Venous Thrombosis

Impaired venous outflow increases hydrostatic

pressure


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Pathophysiologic Categories of Edema



IV. Other


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Reduced Plasma Osmotic Pressure

Albumin is the serum protein MOST responsible forthe maintenance of colloid osmotic pressure.

A decrease in osmotic pressure can result fromincreased protein loss or decreased protein synthesis.

Increased albumin Loss: Nephrotic SyndromeIncreased protein permeability of the glomerular basement

membrane

Reduced albumin synthesis

CirrhosisProtein malnutrition


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Pathophysiologic Categories

of EdemaI. Increased Hydrostatic Pressure


IV. Other


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Inflammation

Both Acute and Chronic Inflammation are

associated with EDEMA


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Pathophysiologic Categories

of EdemaI. Increased Hydrostatic Pressure


IV. Other

Lymphatic Obstruction


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Lymphatic Obstruction

Impaired lymphatic drainage with resultantlymphedema, usually localized

Usually due to INFLAMMATION orNEOPLASTIC OBSTRUCTION

Inflammatory (Filariasis - A parasitic infection

affecting inguinal lymphatics resulting inelephantiasis


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Picture of Elephantiasis


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Resection and/or radiation to auxiliary lymphatic

can lead to arm edema

Carcinoma of breast with obstruction of superficia

lymphatic can lead to an unusual appearance of th

breast - peau dorange (orange peel)

Neoplastic


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GENERALIZED EDEMA

(Walkers Law) HEART

LIVER KIDNEY


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Edema

Morphology Edema of the Subcutaneous

Tissue is most easily detected

Grossly (not microscopically)

Push your finger into it and a

depression remains


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Dependent Edema is a prominent feature of


Facial edema is often the initial manifestation of

Nephrotic Syndrome

Edema

Morphology


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Pulmonary Edema is mostfrequently seen in CongestiveHeart FailureMay also be present in Renal

failure, Adult RespiratoryDistress Syndrome (ARDS),Pulmonary Infections andHypersensitivity Reactions.

The Lungs are typically 2-3times normal weight

Cross sectioning causes anoutpouring of frothy,

sometimes blood-tinged fluid

Normal Pulmonary Edema


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Normal Pulmonary Edema


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Edema of the Brain :

Trauma, Abscess, Neoplasm, Infection (Encephalitis), etc.

The big problem is: There is no place for the fluid to go!!! The skull is

the limit. Herniation into the foramen ovale will kill

Subcutaneous Edema :

Annoying but Points to Underlying Disease However, it can impair wound healing or clearance of Infection.

Pulmonary Edema :

May cause death by interfering with Oxygen and Carbon Dioxideexchange

Creates a favorable environment for infection

Culture Media


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Hyperemia and Congestion

Hyperemia : is an active process resulting from

augmented tissue inflow due to arteriolar dilation

(e.g. acute inflammation).

Congestion is a passive process resulting from

impaired outflows from a tissue

(e.g. cardiac failure or venous obstruction)


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Hyperemia in PneumoniaHyperemiaInfection

(Pneumonia)


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Hemorrhage

extravasation of blood due to rupture of blood vessels

Rupture of a large vessel: Trauma, Atherosclerosis, Inflammatory orNeoplastic Erosion

Rupture of small vessels: hemorrhagic diathesis. May be external, into a body cavity or into a tissue

hematoma: accumulation of blood enclosed or confined withintissue

petechiae: minute hemorrhages into skin or lining surface


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Hemorrhage Purpura (slightly larger hemorrhages than petechia) Ecchymoses (over 1-2 cm subcutaneous hematoma aka bruise).

Accumulation of blood in a body cavity: Hemothorax

Hemopericardium

Hemoperitoneum

Hemarthrosis

The RBCs in a hemorrhage are broken down: hemoglobin (red) bilirubin (blue-green) hemosiderin (golden-brown)

Thats why bruises change color as they resolve

Cli i l Eff t f


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Clinical Effects of

Hemorrhage


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Clinical Effects of

Hemorrhage >20% blood loss, hemorrhagic shock

Bleeding into the brainstem is fatal while sameblood loss from a finger cut is trivial

Chronic recurrent bleeding can lead iron

deficiency anemia!


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Anemia from Blood Loss

This may be the only hint of Occult Cancer

Carcinoma of the Colon

Gastric Carcinoma (less common)


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Hemostasis & Thrombosis

Hemostasis is the normal, rapid formation of

a localized plug at the site of vascular

injury Thrombosis is thepathologic formation of a

blood clot within the non-interrupted

vascular system in a living person


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Hemostasis

Normal - blood is flowing and not clotting

Injury - blood is clotting and not flowing This works due to a daily interaction between the

vascular wall, platelets and the coagulation

cascade


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Thrombosis

Abnormal activation of the normal hemostatic

process

Thrombosis is Pathologic


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Hemostasis

after initial injury, there is a brief period of

arteriolar vasoconstriction (neurogenic

reflex augmented by local factors such as

endothelin)

Vasoconstriction A transient effect


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Vasoconstriction A transient effect


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Hemostasis

Endothelial injury exposes the blood to the

extracellular matrix (ECM)

The ECM is highly thrombogenic

Platelets adhere, flatten and then activate

To form hemostatic plug (primary hemostasis)


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vWF = von Willebrand Factor


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summary

Adhere

FlattenActivate

Recruit

HemostaticPlug


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Secondary Hemostasis

Tissue factor together with platelet factors

activate the coagulation cascade with fibrin

deposition. Thrombin activation induces further

platelet recruitment and granule release

(secondary hemostasis)


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Secondary Hemostasis

Polymerized fibrin and platelet aggregates to

form permanent plug


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Secondary Hemostasis Pic


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Anti-thrombotic Regulation

Components of Normal


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Components of Normal

Hemostasis

Endothelium

Platelets

Coagulation Cascade


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Endothelium

Anti-thrombotic and Procoagulant Properties

Anti-thrombotic - Anti-platelet, anti-coagulant and

fibrinolytic effects

Procoagulant - Tissue Factor, vWF attachment

Figure 4-5 pro- anti coag


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Figure 4 5 pro anti coag

effects of endothelium


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Endothelial Anti-platelet Effects

Physical Barrier

prevent platelet contact with ECM;

Endothelial production of prostacyclin and nitric

oxide inhibits platelet adhesion to normal

endothelium


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Endothelial Anticoagulant Effects

Mediated by membrane-associated, heparin-like

molecules and thrombomodulin and anti-

thrombin III


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Endothelial Fibrinolytic Effects

Synthesize tissue type plasminogen activation

(t-PA) promoting fibrinolytic activity

Pro-thrombotic Properties


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Pro-thrombotic Properties

- Normal endothelium produces : von Willebrandfactor (vWF) facilitates adhesion of platelets to ECM

- Tissue Factor secretion by endothelium is induced by

cytokines or bacterial endotoxin

Tissue Factor activates the extrinsic clotting pathway.

- Endothelial cells secrete plasminogen activator

inhibitors (PAIs) which depress fibrinolysis thus

promoting thrombosis

Pl t l t


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Platelets

When circulating are (membrane-bound smooth discs)

They contain two specific types of granules:

alpha granules and delta granules.

1- Alpha: contain fibrinogen, fibronectin, factors V andVIII, platelet factor 4, platelet-derived growth factor(PDGF), and transforming growth factor (TGF- ) .

2- Delata: contain adenine nucleotides (ADP and ATP),

ionized calcium, histamine, serotonin and epinephrine

Pl t l t A ti ti


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Platelet Activation

On contact with ECM, platelets undergo:

(1) Adhesion and shape change

(2) Secretion (release reaction)

(3) Aggregation

Pl t l t Adh i


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Platelet Adhesion

Adhesion to ECM is mediated largely via

interactions with vWF which acts as a bridge

between platelet surface receptors and exposedcollagen.

Platelet Secretion


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Platelet Secretion

Both granules Explode soon after adhesion Calcium and ADP: potent mediators of

coagulation and platelet aggregation

Platelet Aggregation


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ADP and thromboxane A2 (TXA2) stimulate further

platelet adhesion

This sets up an autocatalytic reaction leading to anenlarging platelet mass(the primary hemostatic plug)

This is a reversible collection of platelets



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With activation of the coagulation cascade, thrombin is

generated, causing further aggregation then platelet

contraction constituting the secondary hemostatic plug This is an irreversible fusion of platelets

Prostaglandin Balancing Act


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Prostaglandin Balancing Act

PG12 (endothelium)

vasodilator

inhibits platelet aggregation TXA2 (platelets)

vasoconstriction

Stimulates platelet aggregation

Clinical Use of ASPIRIN in


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Cardiac Patients

Inhibits TXA2 Synthesis by platelets

Benefits Patients at risk for Coronary Artery

Thrombosis

New


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New

CoagulationCascadeFactor XII Tissue

Factor

X

Prothrombin

Fibrinogen

Fibrin

Thrombin

Activates Activates

Activates Activates

Xa

Coagulation Cascade


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Conversion of Pro-Factors to Activated Factors , ending in the

formation ofThrombin, Thrombin converts Fibrinogen toFibrin, Fibrin is critical for hemostasis.

Each reaction is the result of the assembly of:

Enzyme (activated) coagulation factor

Substrate (pro-enzyme form of a coagulation factor)

Co-Factor (reaction accelerator).

Occurs on a phospholipid substrate

Such as on the surface of activated platelets

Held together by calcium ions

This helps to Localize the thrombus To sites of platelet aggregation


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Fig 4-7 Thrombosison a phospholipid

surface


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Thrombosis

Pathogenesis Of Thrombosis


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Pathogenesis Of Thrombosis

Virchows triad

endothelial injury

stasis or turbulence of blood flow

blood hypercoagulability


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Endothelial Injury


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Endothelial Injury

exposure of subendothelial collagen and other

platelet activators

adherence of platelets release of tissue factor

local depletion of postacyclin (prostaglandin)

and plasminogen activator (PA)

ALTERATIONS IN


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NORMAL BLOOD FLOW

turbulence of blood flow (arterial and cardiac

thrombosis); stasis of blood flow (venous

thrombosis)

disrupt laminar flow and brings platelet in

contact with endothelium

prevent dilution of activated clotting factors

ALTERATIONS IN NORMAL BLOOD FLOW


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ALTERATIONS IN NORMAL BLOOD FLOW

Retard the inflow of clotting factor inhibitors

and permit thrombi build-up

Promote endothelial cell activation Aneurysms, mitral valve stenosis, hyperviscosity

syndromes (e.g. polycythemia)

HYPERCOAGULABILITY


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HYPERCOAGULABILITY

any alterations of the coagulation pathways that

predispose to thrombosis primary (genetic) or secondary (acquired)

disorders

HYPERCOAGULABILITY


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(contd)

mutation of factor V gene with functional

deficiency of protein C, and other anticoagulants

(protein S, antithrombin III). Patient will havevenous thrombosis and recurrent

thromboembolism

smoking, obesity, lupus anticoagulant with lupuserythematosis (arterial and venous thrombosis)


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Arterial thrombi


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Arterial thrombi

Usually begin at site of endothelial injury and

grow along flow of blood

Typically are firmly adherent to the injured

arterial wall (atherosclerotic plaque)

Clinical Settings for Cardiac/arteria

Th b F ti


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Thombus Formation

Myocardial Infarction (MI)

Rheumatic Heart Disease

Atherosclerosis


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Morphology of Thrombi


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p gy

Arterial Thrombi Are Usually Occlusive

Venous Thrombi Are Almost Always Occlusive

85-90% of Venous Thrombi Form in Lower

Extremities

Walkers Law :-)

VENOUS THROMBOSIS (PHLEBOTHROMBOSIS


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Superficial venous thrombi, usually occur in

saphenous system, may cause local congestion,

swelling, and pain; rarely embolize

Deep thrombi, usually in large leg veins at or

above knee joint (e.g. popliteal, femoral, and

iliac veins); cause edema of foot and ankle; may

embolize

Ch i i ll


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Characteristically occur at

site of stasis and extend inthe direction of blood

flow (towards heart);

contains more enmeshederythrocytes (red)

Superficial Veins of the Lower Extremities

Cause Pain, Swelling - Rarely with emobolization


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Cause Pain, Swelling Rarely with emobolization

Associated With Varicosities

Varicose Veins - Abnormally Dilated, Tortuous Veins

Increased Risk of Infections

Increased Risk of Varicose Ulcers.

Thrombi in Deep Veins (Femoral, Iliac)More Likelyto show emobolization

About 50% Are Asymptomatic (Formation of

Collaterals)

May Produce Edema, Pain and Tenderness

Clinical Settings for Venous Thrombus Formation


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Cardiac Failure (CHF)

Trauma

Surgery

Burns. 3rd Term Pregnancy and Postpartum

Cancer

Migratory Thrombophlebitis (Trousseaus Syndrome)

Bed Rest Immobilization

Valvular Thrombi


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Infective Endocarditis

Non-bacterial Thrombotic Endocarditis

Verrucous Endocarditis (Libman-sacks)

Lupus Related

FATE OF THROMBOSIS


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Propagation and obstruction

Embolization

Dissolution

Organization and recanalization


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Dissolution of Thrombi


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Recent Thrombi Can Undergo Total Lysis

After the First 2-3 h, Thrombi wont undergo

Lysis

Thus the Use of TPa Is Only Effective in the First 1-

3 Hours

Organization/Recanalization


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Granulation Tissue Followed by Capillary

Channel Formation or may heal so totally As to

Leave Only a Small Fibrous Lump AsEvidence of a Previous Thrombus


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EMBOLISM


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An embolus is a detached intravascular solid, liquid

or gaseous mass that is carried by the blood to a sit

distant from its point of origin 99% are dislodged thrombus

potential consequence: ischemic necrosis (infarctio

PULMONARY THROMBOEMBOLISM


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Generally originates from deep leg veins

Usually pass through the right heart into

pulmonary vasculature and may occlude main

pulmonary artery, across the bifurcation (saddle

embolus) or pass into the smaller, branching

arterioles; multiple emboli may occur


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Paradoxical Embolism


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Paradoxical Embolism

An embolus pass through an interarterial or

intraventricular defect to gain access to the

systemic circulation( from vein to artery)

Most pulmonary emboli (60-80%) are clinically

silent because of small size

PULMONARY THROMBOEMBOLISM


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When 60% or more of the pulmonary circulation isobstructed, sudden death may occur as caused by right

heart failure .

Embolic obstruction of medium-sized arteries may

result in hemorrhage without infarction because ofintact bronchial circulation (unless bronchial

circulation is compromised - left heart failure).

multiple pulmonary emboli over time may causepulmonary hypertension and right heart failure

SYSTEMIC THROMBOEMBOLISM


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emboli traveling within the arterial circulation

80% arise from intracardiac mural thrombi, others

from ulcerated atherosclerotic plaques, aortic

aneurysm, or from fragmentation of valvularvegetation

major sites are lower extremities (75%), brain

(10%), intestines and kidneys

FAT EMBOLISM SYNDROME


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characterized by pulmonary insufficiency,

neurologic symptoms, anemia, and

thrombocytopenia. 10% of cases are fatal

typically are caused by microscopic fat globules

derived from long bone fractures (fatty marrow),

or rarely from soft tissue trauma and burns

AIR EMBOLISM


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gas bubbles within the circulation can obstruct

vascular flow to cause distal ischemic injury

air may enter circulation in chest wall injury or

in individuals exposed to sudden atmospheric

pressure changes (decompression sickness)

AIR EMBOLISM (contd)


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Caisson Disease: chronic form of decompression

sickness in which persistent of gas emboli in the

bones (heads of femora, tibia, and humera) leadsto multiple foci of ischemic necrosis

Amniotic Fluid Embolism


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Torn placental membrane - amniotic fluid

release

Rupture of uterine veins

Infusion of amniotic fluid into maternal venous

circulation



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Lungs show squamous cells, lanugo hair, fat

from vernix caseosa

Pulmonary edema, diffuse alveolar damage

DIC



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Present with dyspnea, cyanosis, shock, seizures

and coma

Mortality of 80% Walkers Law :-)

Embolism

Potential Consequences


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Potential Consequences

Ischemic Necrosis (Infarction)

Though Pulmonary Emboli Are Common and

Important, Secondary Pulmonary Infarction Is Not

CommonLung Is Protected by a Dual Blood Supply

The Brain Is Not So Protected and Gets Infarcts

(Stroke) LIQUEFACTIVE NECROSIS

INFARCTION


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An infarct is an area of ischemic necrosis caused

by occlusion of either the arterial supply or

venous drainage in a particular tissue

nearly 90% of all infarcts result from thrombotic

or embolic events in arterial vasculatures

Venous infarcts are more

likely in organs with a

single venous outflow


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single venous outflow

channel (testis, ovary)

All infarcts tend to be

wedge-shaped, with theoccluded vessel at the

apex

RED INFARCTSO


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Occur:

with venous occlusions (e.g. ovarian torsion)

in loose (spongy) tissues (e.g. lung) that allow blood

to collect in the infarcted zone

in tissues with dual circulations (e.g. lung and small

intestines)

in tissues that were previously congested

when the occluded site is re-perfused


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FACTORS THAT INFLUENCE

DEVELOPMENT OF AN


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INFARCT

nature of the vascular supply (dual arterial

supply?)

rate of development of occlusion

vulnerability of the tissue to hypoxia

oxygen content of blood

SHOCK


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Constitutes systemic hypoperfusion due to reductioneither in cardiac output or in the effective circulatingblood volume. The end results are hypotension,followed by impaired tissue perfusion and cellular

hypoxia Three main categories: cardiogenic, hypovolemic, and

septic

Others: neurogenic shock and anaphylactic shock

CARDIOGENIC SHOCK


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Results from myocardial failure (infarction),

ventricular arrhythmia, extrinsic compression

[cardiac tamponade, or outflow obstructionpulmonary embolism)]

HYPOVOLEMIC SHOCK


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Results from loss of blood or plasma volume

(hemorrhage, fluid loss from severe burns or

trauma)


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SEPTIC SHOCK


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Caused by systemic microbial infection, most

often by gram-negative infection (endotoxic

shock) but can also occur with gram-positive and

fungal infections

PATHOGENESIS OF

SEPTIC SHOCK


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Endotoxic shock: endotoxins are bacterial wall

lipopolysaccharides (LPS) which consists of atoxic fatty acid (lipid A) core and a complex

polyssacharide cost (including O antigen)

PATHOGENESIS OF

SEPTIC SHOCK (contd)


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LPS TNF (macrophages) 1L-1

1L6/1L8

systemic vasodilation (hypotension), diminishedcardiac contractility, endothelial injury and

activation (alveolar capillary damage), activation

of coagulation system


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ANAPHYLATIC SHOCK


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IgE mediated hypersensitivity response

associated with systemic vasodilatation andincreased vascular permeability

NEUROGENIC SHOCK


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Occur in esthetic accident or spinal cord injury

with loss of vascular tone and peripheral pool ofblood

STAGES OF SHOCK

1- Initial non-progressive stage: compensatory


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1 Initial non progressive stage: compensatory

reflex, perfusion of vital organs maintained

2- Progressive stage: characterized by tissue

hypoperfusion and onset of circulatory and

metabolic imbalance

3- Irreversible stage: tissue and organ damage

22791884 is for dr raed al ani

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