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Unit 01

The Normal Cell

The Cell Membrane

a. Membrane Lipidssome cell phospholipid constituents may be integral to cell signalling; phosphatidylserine, a phospholipid actively concentrated on the inner leaf of the cell membrane, is suggested to “flip” to the outer leaf during certain forms of cell death (apoptosis, described shortly), and might

signal this change to adjacent cells.

b. Membrane Proteins A variety of proteins provide anchors for internal cytoskeletal elements, as ell as for e!ternal e!tracellular matri! components; "imilarmembrane#bound proteins are necessary for cell signal reception (termed $receptors%), hich trigger a variety of intracellular changes(depending on the balance of receptors activated). "ome of the proteins bound specifically onto the inner leaf of the membrane arecomponents of en&yme systems that propagate these receptor signals into the cell.

Chemical Composition of the Cell

a. Ions. 'hese include potassium, sodium, magnesium, chloride, bicarbonate, sulphate and others.

b. Proteins.'hese are basically of to functional types. ibrillar proteins provide structural strength. lobular proteins (found in thelysosomes, dissolved in the cell fluid, or attached to membranes) have important en&ymatic functions.

c. Carbohydrates. *nly small amounts are normally stored, in the form of glycogen.

+ote certain intracellular structures and systems are particularly vulnerable to disease processes. 'hese are : aerobic respiration (and thus energyproduction), the integrity of the cell membrane, metabolic processes, and the genetic apparatus.

Cells and Tissues

"ingle cell types, grouped together, form several basic tissue types of the body. 'hese are the

-. epithelium, hich covers surfaces, forms absorptive linings of hollo organs, lines cavities and forms secretory glands;

. connective tissue, hich supports the structures of organs, and is also termed stroma;

/. nervous and muscular tissues

0. 1emolymphatic tissues, hich include those that comprise the immune systems, inflammatory cells, and the blood

2ithin an organ, the functional cells of the organ are termed the parenchymal cells.

Cellular Injury

As cells undergo various stresses or injuries, they can undergo a variety of adaptive responses (atrophy, hypertrophy, hyperplasia, and metaplasia.When the adaptive ability of the cell is exceeded, hoever, then cell inury develops

3ell 4njury and 3ell 5eath are discussed on pp. 6#-6 of your te!t.

“7echanisms of 3ell 4njury”# general principles

-. 3ellular response to injurious stimulidepends on the type of injury, duration and severity. 3onse8uences of injurious stimulus depend on type, status adaptability and genetic makeup of

injured cell “genetic polymorphism”/. 3ell injury results from functional and biochemical abnormalities in one or more of several

essential cellular component0. 7ultiple biochemical alterations may be triggered by any one injurious insult

'he principal targets and biochemical mechanisms of cell injury are (-) mitochondria and theirability to generate A'9 and :*" under pathologic conditions; () disturbance in calciumhomeostasis; (/) damage to cellular (plasma and lysosomal) membranes; and (0) damage to5+A and misfolding of proteins.

!onlethal cell inury "degeneration#

:eversible state. 3ells, tissues and organs may degenerate for a time and then reach a static condition continue to function at a subma!imal level“compensated” state, in hich the inefficient function is sufficient to maintain the life of the body. 'he body is able to invoke various compensatorymechanisms to maintain homeostasis.

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$ethal cell inury "necrosis#

4rreversible state. +ecrosis can only occur in a living organism it refers to local cell death, as opposed to death of the hole body (somatic death).

Mechanisms of Cell Degeneration and Necrosis

(Text pp 11-16) The most important targets of injurious stimuli are the mitochondria (sites of ATP generation), cell membranes (integral to cell andorganelle homeostasis), protein synthesis, the cytoseleton, and the cell genetic apparatus!

Depletion of ATPA"P is phosphorylated to produce ATP, #ia the oxidation of reduced substances in the respiratory chain! The important point is that asthis is an oxidati#e phosphorylation, oxygen is re$uired!)

When %ill impaired energy production occur&

-. 'ypoxia "insufficient oxygen in the cells#

• disease or obstruction of the respiratory system ill mean that blood entering the lungs is not ade8uately o!ygenated.

(pulmonary emphysema, viral pneumonias or severe asthmatic ) 'hose of you ho are familiar ith horses may be aare of thedisease “heaves” (also knon as chronic obstructive pulmonary disease, or 3*95).

• decreased ability of blood to carry oxygen. 5iseases such as anemias, here there are feer red blood cells to carry o!ygen or

insufficient hemoglobin to bind the o!ygen, ould mean that o!ygen is not carried effectively by the blood to the tissues. (carbonmono!ide poisoning.)

• failure of the blood, once oxygenated, to flo% ade(uately to the tissue. ”delivery system) occurs systemically in patients ith

congestive heart failure, and can also occur locally, ith local vessel obstruction (think of a tourni8uet being left in place too long).

. 'ypoglycemia "lo% glucose levels in the blood## glucose is the main substrate for energy production in most cells

/. *n+yme inhibition# anything hich interferes ith vital en&ymes in the respiratory chain ill lead to insufficient A'9 production.

0. ncoupling of oxidative phosphorylation# anything hich “messes up” mitochondrial membrane ill lead to decreased A'9 production

What effect %ill impaired energy production have in cells&

-. Intracellular accumulation of %ater and electrolytes

occurs because lack of A'9 leads to dysfunction of the cell membrane energy dependent sodium pump. 'he intracellularconcentration of other electrolytes (<=, 3a =, 7g =) can also be affected, hich can lead to inhibition of en&ymes and changes inelectrical activity in the cell.

. -%elling of organelles

'he influ! of sodium and ater leads to selling of cytoplasmic organelles. mitochondria causes physical uncoupling of o!idativephosphorylation # that is, selling alters the orderly arrangement of the respiratory en&ymes on the cristae. ("elling of themitochondria in fact probably accounts in large part for the granular > vacuolated appearance of cloudy selling.) 4f a lack of o!ygenhas lead to impaired energy production by the cell, the cells may sitch from aerobic to anaerobic glycolysis

/. -%itch to anaerobic metabolism

'his leads to lactic acid production, hich causes the intracellular p1 to decrease. 'he decreased p1 then causes furtherdisruption of organelle membranes; damage to lysosomal membranes leads to the release of lysosomal en&ymes into thecytoplasm, e!acerbating cellular injury.

'he effects of defective energy production ill first affect those cells ith the highest basal metabolic rate those cells hich havethe highest o!ygen demand. (?rain cells)

Impaired Cell Membrane Function

'his is the second major group of mechanisms leading to cell degeneration and necrosis. 'he cell membrane normally has an important function as a

semipermeable membrane, separating the cytoplasm from the environment around the cell. :ecall that it consists of phospholipids and proteins.

2hat can cause cell membrane damage@

• ree /adicals free radicals are highly reactive particles having an unpaired electron in their outer shell. ree radicals in cells, hich may

damage lipid pero!idation, proteins modification , and 5+A mutation, resulting in cell injury. +ote that the body has systems, hich aid in

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the inactivation of free radicals.-. 3onversion to 1* by "*5 (super o!idase dimutases) ! 5ecomposition to 1* by glutathione

pero!idase, catalase.

• 0ctivation of the Complement -ystem final compounds of the activated complement pathay can damage cell membranes.

• 1irect $ysis of the Membrane, induced by

-. en&ymes ith lipase#like activity.

. viruses lysis by initiating an immune response against infected cells.

/. physical and chemical agents e!treme heat or cold, and chemical solvents can induce membrane lysis.

What %ill be the effects of cell membrane damage&

a. loss of structural integrity change in the shape of the affected cell, as occurs ith red blood cells.

b. loss of function loss of the normal selective permeability function of the cell membrane may lead to abnormal entry of ater into thecell.

c. 1eposition of lipofuscin pigment this is a granular, golden bron pigment hich is deposited in the cytoplasm, particularly in

myocardial cells, liver cells and neurons. 4t consists of phospholipids and proteins (ie., remnants of the cell membranes). 4t has no effect on

cell function, and is considered a normal aging change ($ear and tear% pigment), though it is also seen in cases of starvation and chronic

disease. 4t is the result of organelle membrane damage caused by a lack of cellular antio!idants, hich normally prevent lipid pero!idation

injury.

Intracellular Accumulations

('e!t pp /#0)

A variety of agents can have deleterious effects on cellular metabolism. endogenous substances. *ften cell injury can lead to intracellular

accumulations of various substances

-. atty 5egeneration (atty change)

2hen triglyceride accumulates in the cytoplasm of parenchymal cells in organs such as the liver, it is termed fatty degeneration or fatty

change. 4t is a nonspecific response to many types of injury.

atty liver 2 ree fatty acids are normally carried in the portal blood from the intestine to the liver, here they are processed to become

triglycerides, phospholipids, and cholesteryl esters. 'hese lipids comple! ith certain proteins (apoproteins, also made by the liver), and are

secreted into the plasma as lipoproteins. 'hus, normal liver cells contain very little triglyceride. Alcohol abuse is a significant cause of fatty liverin humans.

Anything hich disturbs or upsets the balance of this processing and e!porting mechanism

can potentially lead to triglyceride accumulation in liver cells.

-. increased mobili&ation of adipose tissue (as in starvation or diabetes mellitus),so increased amounts of fatty acids reach the liver

. overactivity of certain en&yme systems (eg., induced by alcoholconsumption) increase the conversion of fatty acids into triglycerides

/. the o!idation of triglycerides to other forms is decreased (as occurs inanemia and hypo!ia)

0. apoprotein synthesis is decreased (as occurs in protein malnutrition, or ith

specific hepatoto!ins)

4f sufficient levels of fat accumulate in the liver, this may become apparent grossly.

o 'he liver ould be unusually pale (occasionally almost hite) and enlarged

(because of all the e!tra added fat)

o friable (this ord means abnormally fragile, softer and easier to break) and ould feel greasy in te!ture. 4n rare circumstances,

fatty liver is so fragile that the liver may rupture and bleed into the abdominal space (peritoneum), resulting in shock

. 4ron 5eposition (:ead p. 0, te!t)

+o mechanism for getting rid of e!cess iron, iron deficiency (particularly in omen, due to menstrual blood loss) is more common than

problems of e!cess iron. 1oever, e!cess iron does occasionally accumulate in tissues.

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$ocal accumulation of iron occurs hen hemoglobin is broken don at sites of hemorrhage this is the cause of the lovely colour changes

hich bruises undergo as they resolve. 'he iron is deposited either in local macrophages (they ill be introduced in the section on

inflammation) or in connective tissue as hemosiderin; hemosiderin is a hemoglobin#derived granular pigment.

3ruises (also termed a contusion) is an area of hemorrhage ithin the tissue. 4t is caused by some sort of blunt trauma, hich injures small

blood vessels in the tissues. ?lood escapes the vessels (“e!travasation”) and moves into the tissue spaces, or interstitium.

'emosiderin can also be deposited more generally ( in macrophages throughout the body, but particularly in the bone marro, spleen and

liver) in situations of iron e!cess (eg., ith multiple blood transfusions, minor e!cess dietary iron). 'he hemosiderin is visible microscopicallyas golden bron granules ithin the cytoplasm. 4t usually has no particular clinical significance, as it does not harm the cell.

'here is a rare inherited defect in iron metabolism termed hemochromatosis. 4ntracellular storage mechanisms are overhelmed, free ferric

iron accumulates, and is chemically reduced to produce to!ic free radicals. 'hese harm cells in tissues such as the heart, liver and pancreas.

A similar situation can occur folloing major iron overload.

/. ?ilirubin Accumulation (aundice or 4cterus) ('e!t pp. 6BC#6BD)

*ld red blood cells are broken don and recycled; the hemoglobin molecule is broken porphyrin ringcataboli&ed to become bilirubin.

?ilirubin is then bound to albumin, and carried in the plasma in an unconjugated (lipid soluble) form to the liver. 4n the liver it is conjugated

(Eattached%) to glucuronide (becoming ater soluble), and can be e!creted by liver cells into the bile, hich travels via the bile duct into the

intestine.

4aundice is an increase in serum bilirubin. a sign of disease.

aundice can result from three different general mechanisms

o 'emolytic aundice if red blood cells are broken don in

overly large numbers, production of bilirubin is increased,and the liver cannot conjugate bilirubin fast enough.Fnconjugated bilirubin accumulates in the serum. ('hisbilirubin is bound to albumin and is lipid soluble, so it isnot e!creted in the urine.)

o 'epatocellular aundice if the liver has been injured in

some ay

o 5bstructive aundice if the biliary tract is obstructed,

then bilirubin cannot be e!creted ade8uately. 'hisobstruction can be either ithin the liver (intrahepatic), oroutside the liver (e!trahepatic). 3onjugated bilirubin illreflu! into the plasma, causing jaundice.

What is the functional significance of this bilirubin accumulation&

4n all types of jaundice, the increased serum bilirubin causes deposition of bilirubin in the connective tissue of the skin, sclera (the hite

portion of the eye) and internal organs, leading to a yelloish discolouration, but no functional abnormality.

bilirubin can also be deposited in parenchymal cells (the functional cells of an organ), in hich case it can cause cellular injury. or e!ample,

bilirubin deposition in liver cells (folloing obstructive jaundice) can lead to to!ic cellular injury, hich may progress to cell death. ?ilirubin

accumulation in brain cells (as may occur ith neonatal hemolysis due to :h blood group incompatibility) can lead to neuronal dysfunction and

cell death (termed kernicterus).

0. *ther 4ntracellular Accumulations

include proteins, glycogen, cholesterol, and pigments such as carbon and melanin. 'hese are discussed in more detail in your te!t on pages

/#0.

Genetic Abnormalities

'he chromosomes of cells contain 5+A, hich controls the synthesis of structural and grothregulating proteins and en&ymes. 5+A abnormalities can

be either inherited (having a genetic basis or ac8uired (resulting from somatic mutations, caused by damage to genetic material by agents such as

radiation, mutagenic drugs and viruses).

-omatic#refers to the body (ie., pertaining to the body).

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At a cellular level, 5+A abnormalities are manifested by

• interference ith mitosis if this occurs in actively dividing cells

• failure of synthesis of structural proteins if vital structural proteins are affected, necrosis of cells can result (eg., radiation injury)

• failure of groth#regulating proteins can lead to cancer.

• failure of en&yme synthesis in the embryo can lead to congenital diseases or in later life ac8uired en&yme defects .

3an cell degenerations be recogni&ed grossly@

3ell degenerations may cause visual changes at a gross (nonmicroscopic) level. or e!ample, the affected tissue or organ may appear pale, sollen orenlarged, and more turgid. :ecall that a liver ith fatty degeneration ill appear enlarged, yello, and greasy on cut surface.

'he microscopic morphologic changes hich indicate reversible injury (degeneration) have been already discussed, and are

-. 3ellular sell ing

. atty change

ecogni!ing Cell Degeneration and Cell Death

1o do you kno that a cell has died@

7orphologic evidence ## visuali&able changes hich indicate that cell death has occurred. 9robably 6 G hours need to pass before the changes of

necrosis are visible by light microscopy. 'he appearance of necrosis is the result of concurrent en&ymatic digestion of the cell and denaturation of

proteins.

'he morphologic evidence of necrosis is basically of three types gross evidence, and cytoplasmic and nuclear evidence (hich are both at a

microscopic level).

-. ross evidence of necrosis

'he microscopic changes may be reflected at a Egross% level. 'hese gross appearances have been termed coagulation necrosis, li8uefaction necrosis,

caseation necrosis and fat necrosis (:efer to the discussion on pp. -B#-- of your te!t).

Type of !ecrosis Cause 0ppearance *xamples of 5ccurence

3oagulationcell deathdue toischemia(lack ofbloodsupply)

• proteins are denatured ($coagulated%)

• microscopic

o basic cell outline preserved, nuclei lost

• gross

o pale, dry demarcated areas

• injection sites

• infarcts

(necrosis dueto lack of bloodsupply)

Hi8uefaction ?acterial or ungal

infections• 7icroscopic

o accumulation of inflammatory cells and en&ymes of leukocytes

to digest “li8uefy” tissue

• ross Hi8uid viscous mass

o 3reamy Iello material called 9us

• ?acterial

4nfections

• 1ypo!ic death

3+"

3aseous 'uberculous

4nfection• ross

o 3heese Hike “Iello#2hite appearance”

• 7icroscopic

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o necrotic focus appears as a collection of fragmented or lysed

cells ith an amorphous granular pink appearance in the usual

1JK#stained tissue

o tissue architecture is completely obliterated and cellular

outlines cannot be discerned. 'he area of caseous necrosis is

often enclosed ithin a distinctive inflammatory border

“ranuloma”

at *n+ymatic fat

necrosis

!onen+ymatic fat

necrosis

• ross

o released fatty acids combine ith calcium to produce grossly

visible chalky hite areas (fat saponification)

• 7icroscopic

o the foci of necrosis contain shadoy outlines of necrotic fat

cells ith basophilic calcium deposits, surrounded by an

inflammatory reaction.

at necrosis

• *n+ymatic fat necrosis is most often associated ith pancreatic injuries or acute pancreatitis, hich cause the release of pancreatic

en&ymes (particularly lipase) into the adjacent tissue (there are typically considerable amounts of adipose tissue in the abdominal mesentary

and omentum, the membranes hich hold the intestines and stomach in place). 'he chalky hite appearance of en&ymatic fat necrosis is due

to the action of pancreatic lipase, hich breaks don the triglycerides in fat cells into glycerol and fatty acids. 'hese then comple! ith plasma

calcium ions to form 3a = soaps, hich give the chalky hite appearance.

• !onen+ymatic fat necrosis occurs in other fat deposits (such as the breast or subcutaneous tissue), usually

folloing trauma. (4t can also be termed traumatic fat necrosis.) 'he necrotic fat induces an inflammatory response, hich is typically

granulomatous.

What is the cytoplasmic evidence of necrosis&

-. The cytoplasm becomes more homogenous and deeply staining'his occurs because of the denaturation of cytoplasmic proteins and the loss of ribosomes hich occur ith necrosis. 'his causes thecytoplasm to stain more EpinklyE ith the standard hemato!ylin and eosin (1JK) stains used on tissues.

. The cytoplasm may have a vacuolated "bubbly# appearancethat impaired energy production in the cell (caused by things such as hypo!ia, hypoglycemia, respiratory en&yme inhibition...) leads tofailure of the energydependent cell membrane sodium pump, hich leads to sodium and ater moving into the cell, hich causes the celland more specifically its mitochondria to sell, hich causes the cell cytoplasm to look vacuolated.

/. The cell may 6digest7 itself "autolysis#:elease of lysosomal en&ymes may cause the cell to digest itself, hich is visible as lysis, or Ebreaking up% of the cell (the cells appearEfu&&y%). 'he term for this autodigestion is autolysis.

0. Calcification of dead cells may occur.

2hat is the nuclear evidence of necrosis@

'he cytoplasmic changes described above are !uclear changes are a more definitive indicator of necrosis.

4n a dead cell, the nuclear chromatin clumps, and the nucleus becomes smaller and more densely staining (darker blue ith 1JK). 'hese shrunken,

darker nuclei are said to be py8notic break up into fragments, in the process of 8arrhyorhexis or undergo complete lysis (8arrhyolysis) due to the

action of lysosomal en&ymes. 'he “take home message” here is that a pathologist can recogni&e necrotic (dead) cells as such, by using a microscope,

and that certain nuclear changes are a more reliable indicator of cell death than are cytoplasmic changes. 'hat%s all you really need to rememberL

5ystrophic 3alcification

5ystrophic calcification refers to the abnormal deposition of calcium salts in dead or dying tissues; this occurs in the face of normal serum calcium levels

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5ystrophic calcification can be seen in association ith necrosis of any type. K!amples include the calcification seen in the fatty pla8ues (atheromas) of

atheosclerosis, dystrophic calcification of heart valves, and calcification seen in the foci of necrosis associated ith chronic granulomatous lesions (these

ill be discussed later, in Fnit BC).

2hat types of problems are associated ith tissue necrosis@

-tro8es 2 eakness of one side of the body, loss of bladder control, drooping eyelid,...

'eart attac8s 2 myocardial infarction. such as severe chest pain, difficulty breathing, pallor, irregular heart beats, and fainting; sudden death

-tomach ulcers 2 abdominal pain, bleeding into the boel, and indigestion or vomiting.

-. 0ltered function

• sufficient numbers of cells become necrotic.

• number of necrotic cells hich are Esufficient% to cause disease depends on the type of tissue affected.

• "ome tissues have a large functional reserve, and large numbers of cells need to be lost before organ function is impaired (eg., the

liver). 4n comparison, necrosis of a small area of the motor corte! of the brain (a Estroke%), hich occurs because blood supply to this

area of the brain is blocked, can have devastating conse8uences.

. $oss of Tissue

•

"evere enough cell and tissue death can result in loss of the affected tissue or organ, such as is seen ith loss of arterial bloodsupply. 4n some conte!ts, this is referred to as “gangrene”.

• ?ecause the driving disease process is typically vascular, loss of tissue tends to follo patterns of blood flo

• 'he appearance ill be darkly discoloured and clearly demarcated from normal adjacent tissues. 4f complicated by secondary

bacterial infection, they may be et, sollen, foul#smelling, and eventually li8uefy.

• "ome bacterial infections (such as 3. perfringens infection) ill produce gas ithin affected necrotic tissue (a disease sometimes

called as angrene). 4f uninfected, the tissue ill often become dry, brittle, and shrivelled. Kventually, all such tissue ill slough.

/. -econdary Infection

• necrotic tissue often contains little#to#no inflammation; blood flo is necessary to allo inflammatory cells entry into tissue. necrotic

tissue they are beyond the reach of inflammatory cells and the immune system.

0. -ystemic effects

ever and increased hite blood cell counts are often seen ith cell necrosis if it has occurred to any significant degree. 'he fever is due to

the release of pyrogens (fever inducing agents) from necrotic cells.

C. $ocal effects

2ill depend on the tissue affected and the e!tent of necrosis.

6. /elease of en+ymes from necrotic cells

'he cytoplasmic en&ymes of necrotic cells may be released into the blood. 5iagnostically# serum using various tests. or e!ample, elevation

of specific en&ymes may indicate necrosis of liver cells that of other en&ymes may indicate injury to heart muscle, etc.

2e can summari&e the problems associated ith necrosis as clinical evidence that necrosis has occurred

o altered function of affected tissue

o loss of tissue

o secondary bacterial infection may be present

o systemic effects may occur (fever, increased hite blood cell counts)

o local effects may be seen (bleeding, pain)

o specific serum en&yme levels may be elevated

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Post"Mortem Changes

/igor mortis, the stiffening of a dead body, occurs due to reduction in A'9 in the muscles. Post mortem lividity is the gravitational settling of the blood

in dependent (loer) parts; subse8uent breakdon of hemoglobin produces the typical green discoloration of the skin. Post mortem blood clotting ill

result in the formation of large clots in places such as the chambers of the heart. Putrefaction results from the fermentation caused by saprophytic

bacteria; gas accumulation may produce rupture of the stomach or a typical “foamy liver”, hich is full of gas bubbles.

Apoptosis

'e!t pp. -G#)

-. programmed cell death during embryogenesis

. hormonally#driven regression of tissues (involuting uterine endometrium, posteaning lactating breast)

/. cell death in tissues ith normal rapid turnover (skin cells, intestinal cells)

0. elimination of potentially harmful self#reactive lymphocytes during maturation

Apoptosis is also of great importance as it can be induced by a variety of endogenous and e!ogenous signals under certain circumstances. All cells haveinternal mechanisms for inducing apoptosis that may be activated under pathologic circumstances, such as

• damage to 5+A (radiation, cytoto!ic anticancer drugs)

• accumulation of misfolded proteins (such as seen in some mutations, prion infections)

• viral infections

• pathologic atrophy of organs

3ertain cells in the immune system (termed cytoto!ic '#cells) are capable of inducing cell death through apoptosis in their neighbours if they detectabnormalities in those cells (such as cell changes associated ith neoplasia and viral infection.

'he details of apoptosis are comple! and largely beyond the scope of this undergraduate course, but some important details are belo

-. 2here necrosis is passive and disorderly (a cell returning to entropy), apoptosis is active, organi&ed and orderly; apoptosis re8uiresenergy derived from the cell and occurs according to a plan, ith en&ymatic degradation of proteins and 5+A (see te!t ig. -#, p B).

. 2here necrosis of cells produces cell debris and releases inflammatory mediators locally and systemically, apoptosis produces neatly#packaged cell fragments that are cleared 8uietly by adjacent cells (recycling cell components and inducing negligible inflammation).

/. "ignalling for apoptosis is mediated by a mi!ture of e!ternal signals (from adjacent cells or circulating factors) and internal signals (largelyarising from the mitochondria).

0. Apoptosis is largely mediated by a family of en&ymes called caspases, hich are maintained in the cell in inactive forms and form acascade that culminates ith activation of so#called “e!ecutioner caspases”, functional en&ymes that degrade 5+A and cell proteins.

5iseases driven by apoptosis can e!hibit altered function similar to necrosis, but tend not to induce loss of tissue in the same manner, nor predispositionto bacterial infection, local and systemic effects, and release of cellular en&ymes.

'he path to apoptosis is also not completely distinct from that leading to necrosis there is some overlap in the signals and mechanisms beteen these

$ysosomal en+yme release occurs because lack of o!ygen causes the cells to utili&e anaerobic metabolism rather than the normal aerobicmetabolism. 'his leads to lactic acid production, hich has the effect of loering cell p1. 'he acidic cell environments damages lysosomal membranes,releasing lysosomal en&ymes into the cell cytoplasm.

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nit 9

Normal Fluid #$change

5smosis refers to the tendency of a solvent (e.g. ater) to pass from a solution of lesser concentration to one of greater solute concentration

;5ncotic pressure< refers to the pressure generated by this act of osmosis. draing fluid into vessels

;'ydrostatic pressure< refers to the pressure of ater (pushing fluid out of vessels)

• tissue hydrostatic and oncotic pressures are near &ero, and as such contribute little to fluid e!change.

• Arteriolar end of the capillary bed vascular hydrostatic pressure (pushing fluid out of vessels) is higher than the vascular oncotic

pressure (draing fluid into vessels). 'he net effect drives fluid into the tissues

• Menular end vascular hydrostatic pressure N than the vascular oncotic pressure (O). 'his drives fluid back into blood vessels,

+ormally, the fluid gains and losses beteen the arteriolar and venular ends of the capillary bed are balanced, such that the net

gains and losses of fluid from the vasculature are e8ual.

4t is orth pointing out here that normally, tissue hydrostatic and colloid oncotic pressures are near &ero, and do not really affect this fluid e!change.

1o does the fluid move out of the capillary@

VIA pores, the junctions beteen endothelial cells. This fluid which has passed out of the normal capillary is termed ultrafiltrate. 'he larger proteinmolecules and the cellular elements of the blood are retained in the capillary.

5oes all of the ultrafiltrate return to the capillary@

+o, although most of it does, via the “pull” of the oncotic pressure of the plasma proteins in the capillary. Any remaining fluid, and the small protein

molecules hich may also have moved out, drains from the tissue via the lymphatic system eventually drain into the bloodstream.

+o that e%ve revieed normal fluid e!change, let%s move on to a discussion of “abnormal” fluid e!change and the problems that it can cause.

#dema

('e!t reference pp. DC#DG)

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Kdema refers to the accumulation of e!cess fluid in the tissue spaces (also termed the interstitium). seen in the skin and the associated subcutaneous

tissues. insect bite localized edema. Kdema of the skin is often termed pitting edema; Localized edema is the result of a locali&ed disturbance of the

fluid e!change mechanism in the tissue.

Kdema can also be more generalized , ith e!cess fluid being seen in many tissues. An e!ample of this is the edema of congestive heart

failure. When tissue fluid accumulates in body cavities such as the pleural space, pericardial sac, or the peritoneal cavity, the term effusion is used (eg.

pleural effusion, pericardial effusion). (And, just to further confuse the issue, you may also see the terms hydrothorax and hydropericardium used to

describe pleural and pericardial effusions, respectively; as hydro! refers to water, these terms actually ma"e sense#$ An effusion into the peritoneal

cavity is %iven the specific name, ascites. 'he term anasarca is used to indicate massive edema of the hole body, including the body cavities.

3ody Cavities

?ody cavities are “potential spaces” ithin the body. 'he pleural space is the “space” beteen the surface of the lung (the visceral pleura) and the pleura

lining the chest all (the parietal pleura). 'he pericardial sac is the membranous sac hich surrounds the heart, separating it from the adjacent lungs.

'he peritoneal cavity is the abdominal cavity, limited by the diaphragm, the abdominal alls, and the pelvic floor, and containing the abdominal organs.

'hink of the thin layer of tissue hich lines the peritoneal all as being reflected onto the abdominal organs, here it is termed the serosa.

'hese cavities normally contain only a small amount of fluid, preventing friction beteen adjacent serosal or pleural surfaces. Fnder a variety of disease

conditions, fluid may collect in these cavities.

%ocali!ed #dema

3ase "tudy

What might cause this locali+ed edema& Het%s return to the situation in a normal capillary bed. At the arteriolar end of the capillary bed, fluid tends to

move out of the capillaries because hydrostatic pressure (19) e!ceeds the oncotic pressure (*9). At the venular end of the capillary bed, fluid tends to

move back into the capillaries, because the *9 in the vessels e!ceeds the 19.

+o, hat ill happen if the venous drainage of the capillary bed is obstructed@ 4 have included a diagram of this situation belo.Indicate %hether you

thin8 the osmotic and hydrostatic forces at the venular end of the capillary bed %ill increase, decrease, or remain the same.

hydrostatic force at the venular end of the capillary bed %ould be increased the

venous drainage of the tissue is obstructed can not return to the capillaries as

easily at the venular end of the capillary bed, as 19 still e!ceeds *9 fluid remainsin the tissue spaces as edema.

'here are other differential diagnoses for hat this mass could be; these include an

tumour, enlarged lymph node (the popliteal lymph node is located in this area behind the

knee), or a granuloma (a focus of granulomatous inflammation).

lymphatic draina%e of the limb mi%ht also be obstructed by the mass lymphatic obstruction can also cause edema over time. lymphatic obstruction,

initially small amounts of fluid ill remain in the interstitium. 7ore importantly, the accumulation of small protein molecules over time ill lead to

increased tissue colloid oncotic pressure (recall that tissue colloid oncotic pressure is normally essentially &ero)

Two important causes of localized edema are:

-. venous obstruction

. lymphatic obstruction

There are two additional causes of local edema – acute inflammation, as in the spider bite mentioned earlier, and acute allergic reactions (suchas “hives”). 4n both acute inflammation and allergic reactions an increase in capillary permeability allos fluid and plasma proteins to move out of the

capillaries and into the tissues.

Generali!ed #dema

A person in congestive heart failure may sho puffy selling of the loer legs and ankles.

Why does this occur? right entricular failure, venous blood &bac"s up' in the systemic circulatory system think of it as a “body#ide” venous

obstruction causin% a %eneralized increase in venous hydrostatic pressure. luid thus gradually builds up in the interstitium. (dema is most noticeable in

dependent parts of the body, such as the loer legs and ankles, because of the effects of gravity. 4f a patient in heart failure is hori&ontal, fluid ill tend to

collect in the region of the loer back (the sacral region).

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What if failure of the left heart is of greater significance? 4f the left heart is failing its role as a forard pump, then blood ill tend to “build up” in the

pulmonary circulation ( pulmonary venous con%estion). 'he increased pulmonary venous hydrostatic pressure means that fluid ill tend to remain in the

lungs, as edema. 2hen the 19 is increased, fluid leaves the capillaries, and as there is not much interstitial space for it to collect in, fluid moves into the

alveolar spaces this is pulmonary edema. Pulmonary edema will interfere with gas e!change in the lungs"

What clinical effects %ill these changes in the lungs have& )ulmonary venous con%estion results in dyspnea, a sensation of difficult respiration, or

“shortness of breath”.

"odium and 2ater :etention

1eart failure decreased “forard” output from the left ventricle decreased glomerular filtration pressure in the kidney stimulates renin production

in the kidney to increased aldosterone production (by the angiotensin mechanism)0ldosterone leads to increased sodium resorption *with water

retention$ by the distal tubules of the kidneys All of these can contribute to bodyide edema

Aldosterone results in retention of salt and ater ithin the blood, hich in turn

-. increases vascular hydrostatic pressure (by increasingblood volume)

. decreases vascular oncotic pressure (by diluting theblood albumin that largely determines the vascularoncotic pressure)

&ypoproteinemia' effect of a decreased colloid osmotic force

#ypoproteinemia $ low leels of serum protein% will decrease the plasma osmotic pressure" As the blood circulates throughout the body, the effect

of this change ill obviously be generali&ed, but certain tissues develop edema more readily. ('his varies ith species in the dog, hypoproteinemia

tends to cause ascites first.) luid moves out of the capillaries normally, under the influence of hydrostatic pressure, but then tends to remains in the

tissues, as the plasma osmotic pressure is not sufficient to pull it back into the vasculature.

As fluid fails to return to the vasculature because of lo plasma osmotic pressure, there is a decrease in overall plasma volume. 'his causes decreased

glomerular filtration in the kidney and increased secretion of renin ... ultimately leadin% to sodium and water retention by the "idneys.

In this respect, both heart failure and hypoproteinemia share a common result 2 they both decrease glomerular filtration, leading to sodium

and %ater retention by the body, %orsening the edema.

The causes of hypoproteinemia

Ho serum protein (specifically lo serum albumin, termed hypoalbuminemia) can have a variety of causes, including insufficient dietary intake of

protein (starvation or protein malnutrition), decreased synthesis of albumin in the liver (as might occur ith severe chronic liver disease), and increased

loss of albumin, either into the intestine (”protein#losing enteropathy”) or into the urine, as occurs ith certain renal diseases (renal amyloidosis and

glomerulonephritis) the “protein#losing nephropathies”.

&lbumin and 'lobulins

&lbumin is a major protein of human blood plasma. 4t is synthesi&ed in the liver and is the major determinant of plasma osmotic pressure. 4t is soluble in

ater and coagulates ith heat.

'lobulins include the immunoglobulins (antibodies), complement, blood clotting factors, en&ymes, and a variety of transport proteins.

2hat are the clinical effects of edema@

• (ffusions into body caities can affect the function of the organs in these cavities. 'his is particularly true ith effusions in the pleural and

pericardial spaces, respectively restricting the e!pansion of the lungs and heart. (dema of the lungs can be life # threatening.

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• 1ead trauma, vascular accidents, infections or tumours may lead to edema in the brain $cerebral edema%, hich is of particular concern. as

pressure increases, parts of the brain may be forced to herniate donard, ith fatal conse8uences. *smotic agents (mannitol) and high

doses of anti#inflammatory agents (corticosteroids) are used in an attempt to reduce cerebral edema.

Plasma s )erum

Plasma refers to the fluid part of the blood in hich the blood cells are suspended. 4t is composed of ater, electrolytes and proteins (albumin and a

variety of globulins), as ell as glucose, en&ymes, and products of protein and nucleic acid metabolism.

)erum is the fluid hich remains after blood has been alloed to clot in a tube. 4t is similar in composition to plasma, e!cept that fibrinogen and otherclotting factors have been depleted by clot formation.

3auses of systemic (generali&ed) edema.

-. increased hydrostatic pressure

. reduced plasma osmotic pressure (hypoproteinmia)

/. sodium (and ater) retention

Hocali&ed increase in hydrostatic pressure (due to venous obstruction), lymphatic obstruction, and inflammation are causes of locali&ed edema.

&emorrhage

1emorrhage is the presence of blood in the interstitial tissues, into a “third space” ithin the body (into the peritoneal or pleural spaces), or e!ternally.

injury to the blood vessels, but blood cells can also escape through intact vessels, by s8uee&ing through spaces beteen the endothelial cells. *nce red

blood cells are “free” in the interstitium, they are rapidly broken don to form hemosiderin

2hat are three causes of injury to blood vessels (leading to rupture of the vessel all) 'rauma, atherosclerosis, or inflammatory or neoplastic erosion of

a vessel all

1o hemorrhage is seen clinically

• Petechiae are small “pinpoint” focal hemorrhages

• Purpura are multiple, /#C mm si&ed, oval to irregularly shaped hemorrhages,

• ecchymoses (bruises) are larger areas of hemorrhage. A large “blood blister” (an area here blood has pooled ithin the tissue) is termed

a hematoma.

1emorrhage into one of the

•

9eritoneal “hemoperitoneum”,

• pleural “hemothora!

• pericardial spaces “hemopericardium loer blood pressure ithin the right

atrium and ventricle collapse of the right atrium and ventricle.

• eye “hyphema”.

1emorrhage can also present as e!cessive bleeding from a cut or folloing surgery, or

as &spontaneous hemorrha%e' (ithout trauma) from the nose (epista!is), gums, lungs

(seen as coughing up of blood, &hemoptysis' )

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'he clinical significance of hemorrhage depends on four things volume of blood lost, the rate of bleeding, site of hemorrhage

+ormal 1emostasis

1emostasis simply refers to the arrest of bleeding . . . ho bleeding is stopped. 'his reaction is caused by contraction of smooth muscle in the vessel

all. 4t is effective for hemostasis in small vessels, but is not sufficient hen larger vessels are injured.

'he general se8uence of events in normal hemostasis involves (ill in the descriptions, using point form)

A. 'ransient arteriolar vasoconstriction (/ points)

?. ormation of a hemostatic plug (primary hemostasis) (/ points)

3. "econdary hemostasis (formation of a fibrin clot) (0 points)

5. ormation of a permanent plug, ith concurrent counter#regulatory mechanisms ( points)

'he Kndothelium

+ote that blood vessels are lined by a layer of endothelial cells, hich are supported by a basement membrane. Fnder the basement membrance is the

e!tracellular matri!, containing collagen, then a layer of smooth muscle. +ormally, the endothelium has critical roles in preventin% clotting. 'hese

antithrombotic properties include

*ndothelial 0ntithrombotic Properties

i. 0ntiplatelet *ffects

o the endothelium must be intact to prevent platelets.

o nonactivated platelets ill not adhere to the endothelium.

o if platelets are activated, they are prevented from adhering to uninjured endothelium by prostacyclin and nitric o!ide. 'hese

mediators are potent vasodilators and inhibitors of platelet aggregation.

ii. 0nticoagulant properties

o mediated by membrane#associated, heparin#like molecules and thrombomodulin

iii. ibrinolytic properties

*ndothelial Prothrombotic Properties

Kndothelial cells also have important prothrombotic properties

• synthesis of von 2illebrand factor

• endothelial cells are induced by cytokines or bacterial endoto!in to secrete tissue factor

• binding to activated coagulation factors to augment their activities

• secretion of inhibitors of plasminogen activators

Platelets

Are found in the blood; they are smaller than red blood cells, and appear as membrane# bound smooth discs, lacking a nucleus. 'hey have a central role

in normal hemostasis, in formation of the platelet (hemostatic) plug; this is termed primary hemostasis. 2hen the vessel all is injured, damaging the

endothlium, platelets are e!posed to constituents of the e!tracellular matri!, including collagen and a variety of adhesive glycoproteins.

'his leads to three general reactions (ill in the ?lanksL)

-. P9latelet Adhesion

o mediated largely by v2 and platelet glycoprotein p-b .

. P9latelet Activation

o released 3a== is important in the several coagulation factors

o A59 is a potent mediator of :esting 9latelet , and also

augments 'hrombo!ane A .

o platelet activation results in surface e!pression of a phospholipid comple! that provide binding sites for both calcium and

coagulation factors, and a conformation change in platelet p44b>444a that permits it to bind fibrinogen.

/. P9latelet Aggregation

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o A59 and thrombo!ane A (also a vasoconstrictor) are important stimuli for aggregation

o the enlarging platelet aggregate is termed the primary hemostatic plug

o concurrent activation of coagulation leads to the generation of thrombin, hich binds to platelet surface receptors and

futhers aggregation; platelet contraction contributes to formation of the secondary hemostatic plug

ibrinogen (a plasma protein) also has an important role in platelet aggregation, by acting to connect numbers of platelets together to form large

aggregates.

Create a table as belo%. 'o prostaglandins, 94 (synthesi&ed by endothelial cells) and thrombo!ane A ('QA ) (derived from platelets) act together to

modulate platelet function

*ffect on blood vessels *ffect on platelet

aggregation

94 vasodilator inhibits

'QA vasconstrictor Acti#ates

'he 3oagulation 3ascade

:ead the discussion of the &+oa%ulation +ascade' , on pages G/G6 of your te!tbook, and complete the folloing

Create a table as belo%. 3oagulation mechanisms have to main functions

unction Purpose

to form thrombin proteoly&es fibrinogen into fibrin monomers

ibrin polymers are stabili&ed by the cross#linking activity of factor Q444a, hich also is activated by thrombi

to produce insoluble fibrin insoluble gel; this gel encases platelets and other circulating cells in the definitive secondary hemostatic plug (3lot)

+ote that the cascade is basically a series of en&ymatic conversions, hich convert inactive proen&ymes into the active en&yme, hich then act to

initiate the ne!t step in the cascade. ?lood coagulation has classically been divided into e!trinsic and intrinsic pathays; as noted in your te!t, this

division is $man made%, and in reality, the to pathays are not clearly separated.

0ns%er the follo%ing (uestions:

-. To what does the &intrinsic' pathway of coagulation refer?

. ow is the &extrinsic' pathway of coagulation initiated? actiated by tissue factor, a membrane*bound glycoprotein e!pressed atsites of in+ury"

Additional factors re8uired to optimi&e coagulation include

-. 3alcium ions

. a phospholipid surface

/. Mitamin < needed for synthesis of prothrombin and clotting factors M44, 4Q, and Q

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both the e!trinsic and intrinsic pathays lead to the same result, conversion of the

proen&yme prothrombin to the active en&yme thrombin, hich then acts to

convert fibrino%en to fibrin. 4birin polymeri&es as lon% insoluble strands, formin%

a meshwor" hich is the basis of the clot.

ibrinolysis

2hile fibrin is being formed, the proen&yme plasminogen is incorporated into the developing clot.

2ithin the clot, it is activated to form the proteolytic enzyme, plasmin (also knon as fibrinolysin).

'his activation occurs either via a factor Q44#dependent pathay, or via the action of plasminogen

actiators"

'issue#type plasminogen activator (t9A), synthesi&ed by endothelial cells, is a useful therapeutic

agent in the management of thrombosis

Plasmin acts to brea down fibrin, and also interferes ith its polymeri&ation.

+o

Clinical Problems associated (ith Abnormal &emostasis

A. 3oagulation disorders

All coagulation disorders have similar clinical manifestations the tendency to bleed e!cessively folloing minor trauma, and spontaneousbleeding in severe cases.

=. 1eficiency of coagulation factors

'emophilia 0

“3lassic” hemophilia is an inherited sex-lin"ed *-lin"ed recessive$ disease, affecting males ith greater fre8uency. 'here is a

deficiency in normally functioning factor -..., a critical component of the intrinsic pathay, due to insufficient synthesis of a

factor M444 subunit

>on Willebrand<s 1isease

'his is also an inherited disease *autosomal dominant$, in hich there are reduced leels of circulating on Willebrand factor,

and the entire factor -... comple! is deficient" :ecall that an important function of von 2illebrand factor (v2) is to facilitate

platelet adhesion to damaged blood vessel alls. 'hus, patients ith deficient circulating v2 ill sho bleeding problems, related

to both platelet function and coagulation"

. Increased anticoagulant activity

Anticoagulants are used therapeutically to treat a variety of disorders, some of hich ill be described later in this unit. 'hese

“induce” factor deficiencies, and can lead to bleeding problems unless carefully monitored.

?. 5isorders of platelets

platelets have important roles in forming the initial hemostatic “plug” to seal a vascular injury and in secreting substances hich cause both

continued platelet aggregation and coagulation at the site. Platelet disorders are characterized clinically by /small bleeds0 in the skin

=. Thrombocytopenia ?decreased platelet numbers@ "text, pp. AB)ABA#

A variety of disorders can lead to thrombocytopenia, by causing deficient production or maturation of platelets in the bone marro,

. 0bnormalities of platelet function

'he signs of platelet disorders are present, but platelet counts are normal.

Thrombosis and &ypercoagulability

1lotting within a essel is termed thrombosis"

'he distinction beteen thrombosis and clottin% is rather vague, but consider “clotting” to imply something hich is protective, and prevents e!cessive

hemorrhage. 'hrombosis, on the other hand, doesn%t have a beneficial effect, and can in fact be considered as clotting “gone rong”.

'here is a discussion on thrombosis in your te!tbook on pages G6#RB. :ead this (-C#B minutes), then complete the folloing discussion of thrombosis.

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Ta8e a moment to ans%er the follo%ing (uestions:

-. describe the morphology of a thrombus. have grossly (and microscopically) apparent laminations called lines of Sahn; these represent paleplatelet and fibrin layers alternating ith darker red cellrich layers.

. ho do arterial thrombi differ in appearance from venous thrombi@

• Arterial or cardiac thrombi typically arise at sites of endothelial injury or turbulences, retrograde direction

• venous thrombi characteristically occur at sites of stasis, direction of blood flo (more :ed)

/. 1o can a thrombus be differentiated from a clot hich occurs after death@

3lots are gelatinous and due to red cell settling have a dark red dependent portion and a yello “chicken fat” upper portion;

red thrombi typically are firm, focally attached to vessel alls, and contain gray strands of deposited fibrin.

'he three basic causes of thrombosis comprise $Mircho%s triad%, and include (/ points)

=. Changes in the vessel %all "*ndothelial inury or dysfunction#

&cute in+uries to the endothelium can be caused by trauma or surgery, inflammation, and a lack of blood supply (as might occur hen the

blood supply to an area is temporarily interrupted, eg. during surgery). 'he post#surgical period thus carries an increased risk for thrombosis,

especially if the patient is inactive. *ne of the therapeutic uses of anticoagulants (hich 4 a lluded to earlier) is the prevention of post#surgical

thrombosis.

1hronic in+ury to the endothelium is more common, hich leads us to a discussion of atherosclerosis

Atherosclerosis

:ead the description of atherosclerosis hich begins on p //C of your te!tbook, and continues to p /0/. Iou can then complete the folloing


-. Atherosclerosis is characteri&ed by presence of intimal lesions called atheromas (or atheromatous or atherosclerotic pla8ues). Atheromatous pla8ues are raised lesions composed of soft grumous lipid cores (mainly cholesterol and cholesterol esters, ithnecrotic debris) covered by fibrous cap

. 5oes atherosclerosis principally involve large arteries or veins@ +*

Artherosclerosis is of clinical significance because it can cause

/. "ymptomatic atherosclerotic disease involving arteries supplying the heart, brain, kidneys and loer e!tremities

0. 3ompromise of blood flo in smaller arteries, leading to

C. 'hrombus formation that further obstructs blood flo

6. Aneurysm formation, due to eakening of vessel alls

D. Kmbolism (hich ill be discussed shortly...)

What causes atherosclerosis&

actual cause of these associations is unclear.

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%! 0lterations in normal blood flo%

2ithin larger vessels, blood normally flos in a layered (laminar) pattern; the central column of blood moves very siftly, hile that adjacent to

the endothelium moves more sloly. 'hree changes can occur to alter this normal blood flo

-. 'urbulence rather than traveling in discrete columns, blood flo is fast yet erratic

. "tasis and sludging blood flos much more sloly than normal either because of

a. failure of forard pressure,

b. donstream obstruction of flo,

c. abnormal flo 8ualities to the blood itself (such as hyperviscosity).

. Changes in the blood 2 'ypercoagulability

Anythin% which alters the normal balance of the clottin% and fibrinolytic mechanisms can lead to thrombosis.

Polycythemia is an increase in red blood cell numbers, hich ill lead to increased viscosity of the blood *hyperviscosity$


-. 9rimary polycythemia refers to

. "econdary polycythemia refers to

Ta8e a moment to complete the follo%ing statement: K!amples of physiologic polycythemia include

4nappropriate, non#physiologic increased erythropoietin levels are seen ith certain renal (kidney) tumours, hich secrete erythropoietin, and

hen erythropoietin is used (illegally) by endurance athletes. 'his has been a particular problem in elite cyclists, such as in the 'our#de

rance, and in elite cross#country skiiers. +ote that polycythemia also contributes to small vessel stasis, further favouring thrombosis (as

discussed in T above, alterations in normal blood flo).

1ypercoagulability

#ypercoagulability refers to any alteration in the balance of clotting and fibrinolytic mechanisms

which faour thrombosis"

'here are a variety of inherited (genetic) causes of hypercoagulability, ith factor M or prothrombin

mutations being most common.

'here are also a number of conditions associated ith hypercoagulability and increased risk of

thrombosis. 'hese are considered $secondary%.

;*conomy Class -yndrome<

'he development of deep venous thromboses in the legs of passengers in cramped seating on long

distance air flights has been termed the $Kconomy 3lass "yndrome%.

What happens to a thrombus once it has formed?

Propagation

D *mboli+ation) Part or all of the thrombus is dislodged and transported else%here in the vasculature.

D 1issolution) activation of fibrinolytic factors may lead to its rapid shrin8age and complete dissolution.

D 5rgani+ation and recanali+ation.) convert a thrombus into a vasculari+ed mass of connective tissue that is eventually incorporated into the

%all of the remodeled vessel

Changes in )lood *upply " Ischemia and Infarction

4schemia and 4nfarction

& reduction or failure of blood supply to tissues is termed ischemia"

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'his localized area of necrosis, resulting from inade2uate blood supply (and thus inade8uate o!ygenL), is termed an infarct"

Will ischemia always lead to infarction?

+ot necessarily. 4f the cause of the ischemia (the obstruction of the blood supply) is resolved, then sufficient blood supply may be restored so that tissue

necrosis is avoided (remember that cell degeneration and necrosis can be considered a continuum). *ther factors influencing this outcome ill be

discussed belo.

What effects will ischemia hae?

:ecall that hypo!ia (insufficient o!ygen) can lead to cell de%eneration and necrosis ischemia is an important cause of hypo!ia.

4 used the term “locali&ed failure of blood supply” hen defining an infarct , because arterial obstruction by embolism is not the only cause of

infarction. Anythin% which obstructs either the arterial blood supply or the enous drainage of the tissue can lead to infarction, provided there is

insufficient collateral circulation.

4schemia and infarction due to arterial obstructionWhen an area of the myocardium "heart muscle# is deprived of blood due to the occlusion of a coronary artery (usually byatherosclerosis),

a myocardial infarction (commonly called a heart attack) occurs. +ote that a DCU or greater narroing of the lumen of a major coronary artery is

considered a $critical% level; at this point, the artery is unable to meet even moderate increases in myocardial o!ygen demand, so myocardial ischemia

ill occur. +ote that most acute myocardial infarctions are caused by coronary artery thrombosis.

Prognosis

'he prognosis is the “forecast” as to the most likely outcome of a disease. 4t is an attempt to predict the prospect of recovery from the disease, given the

nature and symptoms of the case, and knoledge of the outcome of similar cases.

actors influencing the outcome of arterial obstruction

/any factors influence the outcome of arterial obstruction. 'he effect of arterial obstruction is ultimately related to the degree of obstruction of blood flo

in relation to the metabolic needs of the tissue. 'he resulting tissue changes are influenced by factors hich can be summari&ed as follos

-. availability of collateral circulation

o 3ollateral circulation refers to the presence or development of alternate pathays through hich blood might flo in order to

reach the donstream target tissue> organ (such as the presence of a dual blood supply), should the primary means ofdelivery become obstructed.

o some knoledge of anatomy and blood supply is helpful here in predicting the outcome of arterial obstruction

. the integrity of the collateral arteries (are they also affected by a disease process such as atherosclerosis@)

/. the tissue susceptibility to ischemia

o tissues such as the brain and heart are very susceptible

o other tissues may ithstand several hours of ischemia before necrosis occurs

0. the tissue metabolic rate

o the state of “demand” of the tissue at the time of the obstruction

C. the rate of development of the obstruction

o a sudden obstruction produces more severe ischemic changes as there is less time for enlargement of potential collateral

vessels

Het%s take a break from “facts” and look at a clinical e!ample.

'he term /idiopathic0 refers to a disease of unknon cause.

What does an arterial infarct loo lie?

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In dense tissues such as the heart and "idney which lac" si%nificant collateral circulation, arterial infarcts tend to be pale . 'he area lacks blood, and

venous drainage is still intact. In those tissues havin% a double blood supply *lun%, liver$ or %ood collateral arterial supply , some blood continues to flo

into the area (though not enough to prevent infarction), so hemorrhage occurs from necrotic small vessels. "uch infarcts will have

a hemorrhagic appearance.

2ith time, this appearance ill be modified the body ill react (inflammation) to the necrotic tissue and a red line may develop around the margin of

the infarct. Hater, the necrotic tissue may be removed and replaced by scar tissue, so the infarct appears sunken.

.schemia and infarction due to enous obstruction

*bstruction of veins occurs 8uite fre8uently. 'he thinner#alled veins are more susceptible to e!tramural pressure (pressure from “outside”) thanarteries. or e!ample, a groing tumour mass can put pressure on a vein and obstruct its flo (leading to thrombosisL). 2e%ve discussed some of the

other causes favouring venous thrombosis above.

Torsion, the tisting of the pedicle of an organ (the “stalk” by hich it receives its blood supply) can have severe conse8uences.

Testicular torsion occurs hen the testicle becomes tisted on its on a!is, completely obstructing all venous drainage through the spermatic cord,

and leading to edema and hemorrhagic infarction.

/eperfusion Inury

4n the previous case study on colonic torsion in a mare, one might ask the 8uestion “hy not simply surgically untist the affected segment of boel,relieving the venous obstruction and resolving the problem@” 'he anser is a phenomenon termed :eperfusion 4njury, herein resolving tissue ischemia

actually promotes and e!acerbates the severity of the initial injury.

Ta8e a moment to ans%er the follo%ing (uestion: ?y hat to processes are reperfusion injury mediated@

4 hope you described increased severity of o!idative stress and inflammation respectively

4t is also important to remember that if venous outflo is impaired, then any inflammatory mediators and to!ic by products (such as reactive o!ygen

species) of cell death are relatively contained (ie. they have limited means by hich they can leave the affected tissue e!cept by passive diffusion). 4f

you restore blood supply to such tissue, you can release all of those to!ic and inflammatory mediators into the bloodstream, hich are likely to

precipitate shock.

*mbolism

An embolus is a free#floating intravascular solid, li8uid or gaseous mass that is carried by the blood to a site different from its point of origin. 'he

majority of emboli originate as part of a dislodged thrombus, so the term thromboembolism is commonly used.

Kmboli ill generally obstruct arteries and arterioles rather than veins; think of arteries as “coning don”, becoming more narro as they reach capillary

beds, and veins as “flaring out”, becoming more broad as they leave capillaries. Kmboli ill obstruct arteries as they become narro enough that the

embolus is too large to pass.

-. *ther types of embolism hich can occur include fat embolism, air embolism, and amniotic fluid embolism. ive an e!ample of situationshere each might occur

a. at embolism

b. Air embolism

decompression sickness (%the bends%)

c. Amniotic fluid embolism

What effects will embolism hae?

An embolus lodging in an artery ill block the lumen of the artery, preventing blood from reaching the tissue.

5rgans %hich have a 3dual4 blood supply include the:

-. Hungs both pulmonary and bronchial arterial blood supply

. Hiver both hepatic artery and portal veins supply blood

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4f the embolus is sufficiently large and embolism occurs in a tissue lacking an alternate blood supply, then insufficient blood ill reach the tissues. 'his

sudden lack of blood supply ill lead to infarction

Disseminated Intra+ascular Coagulation

543 is a thrombohemorrhagic disorder resulting from actiation of coagulation, which leads to widespread thrombosis in the microcirculationof the body, ith serious and often fatal complications.

Ta8e a moment to complete the follo%ing statement: 543 can occur as a complication of a variety of disorders>disease processes, such as*bsterric comlications, 4nfections, neoplasms, massive tissue injury.

(tiology and Pathogenesis

543 can be triggered in to major ays

-. release of tissue factor, or other thromboplastic substances into the circulation

. idespread endothelial cell injury

543 is most often associated ith sepsis, malignancy (cancer), obstetric complications, and severe trauma (especially cerebral trauma); both of themechanisms listed above may have a role in the development of 543 associated ith these disorders.

5.1 is often termed a /consumption coagulopathy0, as clotting $thrombosis% leads to the consumption of clotting factors and platelets,ultimately leading to generalized hemorrhage" or many patients ith 543, this hemorrhage is the predominant clinical effect.

'he bleeding tendency is e!acerbated by the activation of the fibrinolytic system. :ecall that fibrin breakdon products (resulting from the action ofplasmin on fibrin) also have anticoagulant properties.

Ta8e a moment to complete the follo%ing statement: 'he cycle of thrombus formation and fibrinolysis in the microcirculation occuring in 543 leads tothese conse8uences (to points)

The obstruction of the microcirculation by microthrombi can cause widespread impaired tissue perfusion, leading to tissue hypo!ia, shock (as ill bediscussed ne!t) and microinfarction in many organs.

Ta8e a moment to complete the follo%ing: The dia%nosis of 0I+ is made by laboratory testing, looking for changes such as (five points, includingthose belo)

• seeing damaged red blood cells (:?3) on a 3?3 # :?3s are injured hen passing through the fibrin strands of microthrombi

• 'hrombocytopenia # thrombocytes are $consumed% in thrombus formation

*hoc,

"hock can be defined as a physiologic state characteri&ed by a generali&ed reduction in tissue perfusion related to a decrease in either effective cardiacoutput, or in effective circulating blood volume.

What can cause shoc?

'he causes of shock can be considered under three general categories

-. 'ypovolemia "decreased blood volume#

o type of shock associated ith hemorrhage (blood loss) or fluid loss (vomiting, diarrhea, dehydration), hich leads to

decreased plasma volume

. Peripheral vasodilation

o type of shock associated ith anaphyla!is, neurogenic, and septic shock

o idespread vasodilation increases the capacity of the vascular bed; the resulting decreased hydrostatic pressure leads to tissue

hypoperfusion

/. Cardiogenic shoc8

7/26/2019 unit 1 + 2.docx


o failure of the heart to function effectively as a pump type of shock associated ith primary diseases of the heart

(myocardial infarction, myocarditis) and ith conditions obstructing blood flo in the heart or filling of the ventricle

:egardless of the cause, the “final common path” of these mechanisms is the reduction of tissue perfusion.

)tages of )hoc

Karly in shock (the 3nonprogressie4 phase), various neurohumoral refle! mechanisms come into play, to help maintain cardiac output and bloodpressure.

'he decrease in blood pressure causes the heart to beat more rapidly to increase cardiac output (tachycardia). )eripheral vasoconstriction helpsmaintain blood pressure in vital or%ans, the brain and heart (by diverting blood from other vascular beds) this is hat causes the pallor and coolness ofthe skin. 3onstriction in renal arteries decreases the glomerular filtration pressure, leading to fluid retention by the "idneys and a decreased urine output'his helps retain fluid in the body.

'hese effects may not be sufficient, and shock then enters the 3progressie4 phase, during hich there is development of idespread tissue hypo!ia.

-. 2idespread tissue hypo!ia leads to lactic acidosis causing (/ points)

'he idespread hypo!ia begins to affect the function of vital tissues and organs. 5ecreased blood flo to the brain leads to signs of confusion; urinaryoutput declines further.

'he prolonged vasoconstriction acts to further impair tissue perfusion, leading to a cycle in hich acidosis and lysosomal en&yme release further cellularinjury.

"ome of the effects of this are

• myocardial contractile function orsens

• decreased renal blood flo leads to ischemic injury to the kidneys; epithelium of the renal tubules is particularly sensitive. :enal tubular

necrosis can lead to acute renal failure (renal $shutdon%)

• “shock lung” damage to the lung by hypo!ia causes edema and hemorrhage, termed A:5" (acute respiratory distress syndrome)

• ischemic necrosis of the intestine, hich can lead to intestinal bacteria entering the circulation; endoto!ic shock maybe superimposed.

• 543

'erminally, there is a failure of the refle! peripheral vasoconstriction, and the movement of blood into these vascular beds causes a steady fall in bloodpressure perfusion of the brain and heart becomes inade8uate. 3erebral hypo!ia causes brain dysfunction, and myocardial hypo!ia further decreases

the cardiac output. 5eath then occurs.

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unit 1 + 2.docx