Pathology Exam 1: The Obfuscation

Front 1

steady state importance

Back 1

-Cellular derangements may be expressed as clinical signs and symptoms of "disease"
-"Health" depends on the ability of cells to maintain structural and functional stability (a steady state) in the face of a constantly changing micro environment; homeostasis

Front 2

basic cellular structure

Back 2

Except for mature red blood cells, each cell of the body contains a nucleus surrounded by cytoplasm which is enveloped by a plasma (cell) membrane.

Front 3

Nucleus characteristics

Back 3

-contains all of the genetic information, within DNA, required to produce and maintain viability of the organism
-in dividing cells DNA in chromosomes, in non-dividing it is chromatin
-also contains RNA
-genetic info identical in nucleus unless mutation occurs

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specificity and differentiation in a particular cell due to

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-within any specific cell, only selected genetic information is translated into protein products

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cytoplasm characteristics

Back 5

-contains a cytoskeleton consisting of microfilaments, intermediate filaments (cell type specific), and microtubules which maintain cell structure and allow for cell mobility
-also an amorphous ground substance, or cytosol, consisting of water and soluble nutrients, CHO, lipids, and proteins
-within cytoplasm are various cellular organelles which have specific fxns in the maintenance of cell viability

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mitochondria characteristics

Back 6

-supply the energy needed to fuel all of the other activities of the cell, produced in form of ATP
-also have their own DNA which is derived solely from the mother and which, in rare instances, may lead to Anon-Mendelian inherited genetic diseases.

Front 7

ribosomes characteristics

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-consist of aggregates of RNA and either are present within the ground substance of the cytoplasm (polysomes) or attached to the membranes of the endoplasmic reticulum (see below)
-essential in the production of proteins.

Front 8

smooth endoplasmic reticulum fxns

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functions to metabolize drugs, hormones, etc. and to synthesize steroid hormones

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rough endoplasmic reticulum fxns

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-associated with ribosomes
-is responsible for manufacturing protein for export from the cell

Front 10

golgi apparatus fxn

Back 10

responsible for producing the building blocks of cellular membranes and packaging protein or protein complexes either for use within the cell or for export from the cell

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lysosomes characteristics

Back 11

-derived from the Golgi apparatus and consist of digestive enzymes which are most active in an acid environment
-enzymes are isolated from the surrounding cytoplasm by a lysosomal membrane, but the lysosomes can fuse with other cytoplasmic structures to digest, degrade, recycle, or expel from the cell unwanted or no longer needed materials

Front 12

plasma membrane structure

Back 12

-comprised of proteins, lipids, and carbohydrates arranged as a complex polar bilipid membrane

-membrane receptors for a wide variety of chemicals, transmembrane ionic channels, signal transducers, adhesion molecules, etc

Front 13

plasma membrane fxns

Back 13

-separates the cell cytoplasm from adjacent cells and the extracellular matrix
-cell's communication port with external environment
-an active, metabolic, living structure which is essential for cell viability and which requires a significant amount of energy to maintain in functional order

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3 embryonic layers

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ectoderm, endoderm and mesoderm.

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epithelial cells characteristics

Back 15

-come from ectoderm and endoderm

-cover the external and internal surfaces of the body, including the inner lining of the vessels, ducts, and small spaces

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mesenchymal cells characteristics

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-come from mesoderm
-form the blood and connective tissue which contribute to the structural framework of organs (fibrous tissue) or lend structural support to the body as a whole (bones, cartilage, muscle).

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parenchymal tissue definition

Back 17

refers to the essential functional elements of an organ and generally is comprised of epithelial cells

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stromal tissue definition

Back 18

makes up the architecture or structural framework of the organ and is generally comprised of mesenchymal cells

Front 19

altered steady state characteristics

Back 19

-alteration of the cellular micro-environment, due to normalprocesses or abnormal processes, may produce an "altered" steady state which may be reflected by biochemical and/or morphologic changes of the cell
-specialized cells more vulnerable to changes
-cell will either adapt to survive in the new environment or it will become injured

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cell adaptation characteristics

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-Adaptive changes frequently involve processes governed by those genes that mediate cell growth and differentiation
-coping mechanisms may allow tissues to maintain viability for extended periods of time and are reversible if the environment should revert back to the normal steady state
-sometimes "adaptive" responses may ultimately prove to be destructive.

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atrophy characteristics

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-decrease in the size (or in some instances the number) of individual cells that had previously been of normal size
-can result from either normal (physiologic) or abnormal (pathologic) changes in the cellular environment

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hypertrophy characteristics

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-increase in the size of individual cells in response to an increased functional demand
-involves an increase in structural components of those cells that are not commonly considered capable of mitotic division
-refers mostly to cardiac and skeletal mm cells when they are required to work against increased resistance

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hyperplasia characteristics

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-increase in the # of cells in response to increased hormonal or growth factor stimulation
-hyperplasia and hypertrophy may occur concurrently in some instances (the gravid uterus), and since hyperplasia necessitates increased mitotic division, it is not surprising that hyperplasia and neoplasia may sometimes be closely associated

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metaplasia characteristics

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-substitution of one mature cell type for another mature cell type
-metaplasia is often a process in which a new harsher environment induces a change to a more protective tissue type

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dysplasia characteristics

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-an atypical or abnormal (but still potentially reversible) growth of cells that is usually induced by chronic irritation or stimulation
-dysplasia is generally regarded as a potential precursor to malignant neoplasia which is a permanent abnormal growth of cells that is uncoordinated with the growth of normal cells

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cellular swelling characteristics

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-first morphologic change to occur after injuries that interfere with plasma membrane permeability and thus the regulation of ICF volume and ionic [ ]
-cell appears enlarged with a pale cytoplasm but a normally positioned nucleus

Front 27

Hydropic change (vacuolar degeneration) definition

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an exaggerated state of cellular swelling where segments of swollen distended endoplasmic reticulum appear in the cytoplasm as clear vacuoles that may displace the nucleus to the periphery of the cell

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fatty change (steatosis) characteristics

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-an absolute increase in lipids w/ in parenchymal cells
-often seen in the liver but may involve heart and kidney
-w/ any interruption of normal cellular lipid uptake, synthesis, metabolism or excretion, clear lipid vacuoles appear in the cytoplasm
-As the vacuoles enlarge, they displace the nucleus

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Fatty in-growth definition

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-separate from steatosis
-usually asymptomatic, process in which adipose cells accumulate within stromal connective tissue that lies between parenchymal cells
-most frequently seen in the pancreas and heart

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Glycogen infiltration characteristics

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-involves an increase in intracellular glycogen due to abnormal glucose or glycogen metabolism as in the inherited glycogen storage diseases or in hyperglycemic states such as diabetes, etc

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hyaline degeneration characteristics

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-Accumulations of protein appear as homogeneous, glassy, pink-staining hyaline
-term "hyaline" only refers to the histologic appearance of the protein and not to its specific chemical composition
-hyaline may be deposited intracellularly or extracellularly

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pigments in cells characteristics

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-pigments may accumulate within cells because of increased synthesis, impaired excretion, phagocytosis, etc.
-presence of intracellular pigment may or may not in itself be injurious, but excessive accumulation of exogenous pigments (carbon, iron, lead, silver, etc) may reflect environmental contamination
-excessive accumulation of endogenous pigments may reflect an underlying disease or metabolic disorder

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LIPOFUSCIN (LIPOCHROME) characteristics

Back 33

-finely granular yellow-brown, "wear and tear" pigment indicates chronic free radical injury (lipid peroxidation) of cell membranes
-frequently becomes more apparent with the aging of a cell and tends to be present as residual bodies in perinuclear lysosomes
-does not appear to interfere with cell fxn, when extensive may impart a brown discoloration to the tissue ("brown atrophy" of the heart and liver).

Front 34

MELANIN characteristics

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-brown-black pigment produced by melanocytes and in specific areas of the brain (neuromelanin)
-Certain disorders may be related to either generalized or localized underproduction or overproduction of melanin

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Iron characteristics

Back 35

-may be stored in various forms such as ferritin or hemosiderin
-Hemosiderin is a granular gold-brown pigment derived from the breakdown of hemoglobin. -Hemosiderin-laden cells (usually macrophages) are frequently found around areas of hemorrhage or chronic vascular congestion

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hemosiderosis definition

Back 36

-hemosiderin may also be found in the reticuloendothelial system and a variety of parenchymal cells such as heart, liver, pancreas, skin, etc. when present in excessive amounts (hemosiderosis)
-usually as the result of hemolysis of red blood cells

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hemochromatosis definition

Back 37

-common inherited (autosomal recessive) genetic defect in normal iron metabolism produces a severe metabolic disorder
-results in massive deposition of iron in tissues throughout the body leading to extensive damage

Front 38

Prussian blue definition

Back 38

presence of iron in pigment can be identified by special histologic stains

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bilirubin characteristics

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-green-brown pigment that is also a breakdown product of hemoglobin (porphyrin rings) but, unlike hemosiderin, does not contain iron
-major pigment of bile, and can accumulate in fluid and tissue whenever there is a disturbance in bilirubin uptake, conjugation, or excretion by hepatocytes or when there is obstruction to normal biliary flow

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cell death definition

Back 40

-Although the line between reversibly and irreversibly injured cells may be indistinct, when an altered steady state induces sufficient biochemical disturbances to cause permanent, irreparable damage to the cell, cell death ensues

Front 41

2 major forms of cell death

Back 41

-apoptosis and necrosis

-have different etiologies, different outcomes, and different clinical significance

Front 42

2 histologic indicators of cell death

Back 42

cytoplasmic changes

nuclear changes

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Cytoplasmic changes characteristics

Back 43

Eosinophilia (redness) and homogenization of the cytoplasm is due to loss of cytoplasmic RNA and to the disaggregation of polysomes and denaturation of cytoplasmic proteins

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nuclear changes characteristics

Back 44

-nucleus responds by chromatin condensation (pyknosis), fragmentation (karyorrhexis), or dissolution (karyolysis)
-these nuclear changes are the definitive morphologic evidence of irreversible injury and cell death.

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apoptosis characteristics

Back 45

-a distinctive form of cell death which involves individual cells or small clusters of cells
-necessary physiologic event in embryologic development and tissue remodeling, but may represent a pathologic destruction
-energy-dependant, active process under strict regulatory control
-Apoptosis, unlike necrosis, does not elicit an inflammatory response

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necrosis characteristics

Back 46

-form of cell death initiated by overwhelming exogenous injury to the cell
-morphologic expression of necrosis is caused by the physical deterioration of an irreversibly injured cell in living tissue
-the result of cellular changes brought about over time by either endogenous degradative enzymes liberated from disintegrating cellular lysosomes (autolysis), exogenous degradative enzymes released from invading leukocytes (heterolysis), or protein denaturation
-ultimately associated with inflammation and subsequent tissue repair

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6 patterns of necrosis

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1. Coagulative necrosis
2. Gangrenous necrosis
3. Liquefactive necrosis
4. Caseous necrosis
5. Fat necrosis
6. Fibrinoid necrosis

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coagulative necrosis characteristics

Back 48

-most common pattern of necrosis and is due to inadequate oxygenation of cells
-generally the result of a reduction in blood flow (ischemia) to the cells, but other factors that lead to hypoxemia may also produce this pattern of necrosis.

Front 49

Dry gangrene characteristics

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-usually refers to ischemic coagulative necrosis of the skin and subcutaneous tissues of the extremities
-affected tissue desiccates and assumes a dark green-black coloration

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Wet gangrene characteristics

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-usually results from tissue hypoxia secondary to ischemia or venous congestion of tissue which secondarily becomes infected resulting in putrefaction of the necrotic tissue
-tissue is moist, dark, and malodorous

Front 51

gas gangrene definition

Back 51

variant caused by Clostridium bacteria which ferment carbohydrates to produce carbon dioxide. The tissue appears much like wet gangrene but is also crepitant to palpation

Front 52

Liquefactive necrosis characteristics

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-results when proteolytic digestion of dead cells is not delayed by enzyme denaturation
-characteristic of tissues injured by bacterial infections which attract large numbers of neutrophils (creating an abscess) and ischemic destruction of brain tissue

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Caseous necrosis characteristics

Back 53

-preservation of the underlying tissue outlines is lost and replaced by a granular, amorphous, acellular substance
-encountered principally in infectious diseases involving mycobacteria and fungi
-frequently is seen in association with a specialized form of chronic inflammation known as granulomatous inflammation.

Front 54

Enzymatic fat necrosis characteristics

Back 54

-produced by lipolytic activity of pancreatic enzymes on fat cells
-usually seen during the course of pancreatitis when pancreatic lipases are released into abdominal fatty tissues and convert triglycerides to free fatty acids which complex with calcium to form calcium soaps. -produces white chalky deposits in fatty tissue

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Traumatic fat necrosis characteristics

Back 55

-produced by traumatic rupture of fat cells with subsequent phagocytosis of the lipid material by macrophages
-most frequently in female breast tissue, traumatic fat necrosis produces a granulomatous foreign body inflammation and histologically does not have the enzymatically "digested" appearance seen with enzymatic fat necrosis

Front 56

Fibrinoid necrosis characteristics

Back 56

-characterized by a smudgy, amorphous, eosinophilic material usually deposited in or around the walls of small blood vessels
-histologic appearance resembles fibrin deposits -often associated with immunologically related disease

Front 57

DYSTROPHIC CALCIFICATION characteristics

Back 57

-refers to deposition of calcium salts, often in necrotic tissue, in the face of normal serum calcium levels
-in dying cells calcium accumulates in the irreparably damaged mitochondria but extracellular calcium deposits also develop utilizing membrane bound vesicles as a nidus for propagation
-calcium may appear as small concentrically laminated spheres (psammoma bodies) or as variably sized amorphous basophilic deposits.

Front 58

METASTATIC CALCIFICATION

Back 58

-refers to the deposition of calcium in normal tissues of patients with high serum calcium levels
-histologic appearance is similar to dystrophic calcification but the distribution is generally more widespread

Front 59

hypoxemia definition

Back 59

poor O2 saturation of the blood

Front 60

ischemia definition

Back 60

insufficient vascular supply

Front 61

hypoxia definition

Back 61

oxygen deficiency

Front 62

HYPOXIA/ANOXIA characteristics

Back 62

-interferes with the cellular production of energy and the ability to maintain a normal intracellular chemical composition
-Influx of Ca, Na, and H2o causes cellular swelling and protein production is disrupted
-if prolonged, cell becomes irreversibly injured because of damage to the cell membrane

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FREE RADICAL FORMATION characteristics

Back 63

- Free radicals are extremely unstable and reactive molecules, able to provoke inappropriate disulfide bonding of proteins, peroxidation of lipids, and damage to DNA
--The impact of free radicals in cell injury is dependent on the balance between the rate of formation and the rate of inactivation

Front 64

mechanical trauma characteristics

Back 64

-results when sufficient outside force is applied to body tissues to disrupt their structure or function
-produces wounds such as abrasions (loss of superficial cells as the result of friction or crushing), contusions (disruption of blood vessels produced by blunt force), lacerations (the tearing of tissue resulting from excessive stretching), incisions (cuts produced by a sharp instrument), avulsions (tearing away of body parts), and puncture wounds (piercing or penetration of tissue caused by a sharp object or instrument)

Front 65

temperature extremes cell injury/death

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-results if tissue is maintained at a temperature greater than 15o C below or more than 5o C above normal body temperature
-Freezing of tissue interferes with ionic concentrations due to crystallization of intracellular water, denatures proteins, and physically disrupts cell membranes leading to cell death (frostbite). -Excessive heat applied causes’ nuclear swelling w/ disruption of nuclear membranes and coagulation of intracellular proteins

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IONIZING RADIATION characteristics

Back 66

-High lvls of ionizing radiation causes cellular injury by the transfer of radiant E which may, through radiolysis of intracellular water, induce the formation of free radicals (esp. hydroxyl ions) and cause acute death of the cell
-low levels of radiation may cause disruption of molecular bonding within the DNA that can result in single or double-stranded breaks
-may lead to mutations, inhibit cell division, or alter the ability to divide or to maintain normal homeostasis by interfering with the regulation and/or structure of the protein products of the genes

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ELECTRICITY cell injury

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can cause cell injury or death either due to interruption of neural transmissions of the cardiac conduction/respiratory control systems or by the generation of heat

Front 68

ATMOSPHERIC PRESSURE cell injury

Back 68

-degree of injury depends on the magnitude, direction, rate, and duration of pressure change
-In general, increased pressure is tolerated better than decreased pressure.

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CHEMICAL / DRUG INJURY characteristics

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-Chemicals and drugs can be inhaled, ingested, or absorbed through the skin and can stimulate, suppress, or disrupt critical biochemical pathways, alter membrane permeability, or destroy essential molecular components and cell organelles

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biologic injury characteristics

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wide spectrum of infectious organisms (viruses, bacteria, fungi, parasites, etc) can induce cell injury through direct cytopathic or cytotoxic effects or indirectly through inflammatory/immunologic host defense mechanisms

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nutritional injury characteristics

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Nutritional imbalances (either deficiencies or excesses) may interfere with the ability to maintain cell structure and function

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INFLAMMATORY/IMMUNOLOGIC INJURY

Back 72

Although these host defense mechanisms are crucial to the well-being of the body as a whole, either excessive or inadequate expression of these mechanisms may result in cell injury and death.

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GENETIC INJURY characteristics

Back 73

Genetic damage may interfere with the ability to maintain normal cell homeostasis by altering the regulation and/or structure of the protein products of the genes or by disrupting the normal replication and differentiation of the cells.

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EDEMA definition

Back 74

This refers to the accumulation of excess fluid in cells or tissues

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intracellular edema definition

Back 75

is generally a reflection of cellular injury and altered cell membrane permeability

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interstitial edema definition

Back 76

(the extracellular, extravascular fluid compartment) reflects either a disturbance in the normal hemodynamic forces that control fluid transfer between the vascular and extravascular space, or it indicates injury to the vessels that results in increased vascular permeability

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anasarca definition

Back 77

Interstitial edema may be confined to a localized area or it may be a diffuse process involving all tissues of the body

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Fluid balance percentages

Back 78

total body water- 60%
a. intracellular- 40%
b. extracellullar- 20%
i. intravascular- 5%
ii. interstitial- 15%

Front 79

INCREASED OSMOTIC PRESSURE OF THE INTERSTITIAL FLUID effects

Back 79

An increase in total body sodium due to excessive salt intake, increased absorption or decreased excretion of sodium by the kidneys, or reduced renal blood perfusion can lead to a generalized edema.

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DECREASED ONCOTIC PRESSURE OF THE PLASMA PROTEIN effects

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A decrease in serum albumin may also produce a generalized edema. This may be due to a failure of albumin synthesis (liver disease, malnutrition) or excessive albumin loss (glomerulopathy, enteropathy), etc.

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INCREASED HYDROSTATIC PRESSURE OF THE INTRAVASCULAR FLUID effects

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-leads to a localized edema and usually involves increased hydrostatic pressure on the venous (rather than arterial) side of the vascular bed resulting from interference with or obstruction to venous blood flow.

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OBSTRUCTION OF LYMPHATIC DRAINAGE (lymphedema) effects

Back 82

-This also produces a localized edema and is usually the result of lymphatic obstruction by cancer, scarring (post-inflammatory, post-radiation, etc), parasitic disease (filaria), or lymphadenectomy.

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INCREASED CAPILLARY PERMEABILITY effects

Back 83

-The inner surface of all vessels are lined by endothelial cells which, among other functions, control the permeability (“leakiness”) of the vessel
-Injury to the endothelial cells as the result of inflammation, immunologic reactions, or other tissue injury will produce a localized edema.

Front 84

transudate edema fluid

Back 84

-protein-poor (< 3 gm/dL) fluid which has a specific gravity <1.012
-develops from imbalances in the normal hemodynamic forces and is frequently seen with congestive heart failure (increased intravascular hydrostatic pressure, etc), liver disease (decreased albumin synthesis, obstruction to portal venous flow, etc), renal disease (excessive loss of albumin, excessive salt retention, etc), and GI disorders (protein malabsorption, protein-losing enteropathies, etc).

Front 85

EXUDATE edema fluid

Back 85

- protein-rich (> 3 gm/dl) fluid which has a specific gravity >1.020. It generally is the result of endothelial damage and alteration of vascular permeability and is seen with inflammatory/immunologic disorders, etc.

Front 86

VASCULAR CONGESTION characteristics

Back 86

-refers to decreased blood flow in veins, venules, and capillaries usually due to impaired venous drainage. -results in a bluish discoloration of tissue (cyanosis) due to accumulation of reduced (oxygen depleted) hemoglobin
-edema is a common accompaniment of congestion

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VASCULAR HYPEREMIA characteristics

Back 87

-refers to increased blood flow through dilated arteries, arterioles, and capillary beds
-results in increased warmth and redness (erythema) in affected tissue
-an active, reflexive mechanism (neurally and/or chemically mediated) designed to allow greater blood flow to areas of inflammation, to tissues needing more oxygen, or as a mechanism of heat dissipation
-When associated with inflammation, hyperemia is followed by localized edema resulting from increased vascular permeability.

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HEART FAILURE characteristics

Back 88

-clinical condition manifested by numerous signs and symptoms that arise when the heart is no longer able to maintain normal cardiac output
-signs and symptoms are generally due to hypoxic and congestive effects on organs and tissues other than the heart itself.

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LEFT-SIDED HEART FAILURE characteristics

Back 89

-occurs when the left ventricle is unable to maintain adequate cardiac output
-As a result, the hydrostatic pressure within the left side of the heart increases and is transmitted "backward" into the pulmonary venous circulation
-the clinical manifestations of left heart failure are primarily pulmonary in origin and include easy fatigability, shortness of breath (SOB) or dyspnea on exertion (DOE), paroxysmal nocturnal dyspnea (PND), orthopnea, and cough.

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RIGHT-SIDED HEART FAILURE characteristics

Back 90

-occurs when the right side of the heart is unable to maintain adequate ventricular output to the lungs
-usually due to the inability to overcome an increase in pulmonary arterial pressures (pulmonary hypertension)
-most frequently the result of pre-existing left heart failure
-increased hydrostatic pressure in the right side of heart is transmitted "backward" into the systemic venous return and clinically results in (see next slide)

Front 91

right-sided heart failure clinical results

Back 91

a. Engorgement and distention of neck veins
b. Passive congestion of the liver
c. Portal hypertension
d. Dependent pitting edema
e. Increased body weight

Front 92

LIVER DISEASE (cirrhosis, hepatocellular damage) effects

Back 92

-may result in decreased synthesis of plasma protein, increased hydrostatic pressure and pooling of blood in portal venous circulation, hepatic lymphatic obstruction, etc.

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RENAL DISEASE (glomerulopathy, tubular dysfunction) effecccts

Back 93

This may result in loss of plasma protein, increased sodium retention, etc.

Front 94

GI DISEASE (starvation, malabsorption, enteropathy) effects

Back 94

This may result in plasma protein deficiencies, etc.

Front 95

INFLAMMATORY/IMMUNOLOGIC DISORDERS (infections, hypersensitivities, etc.)

Back 95

-can result in vascular endothelial damage or increased vascular permeability creating localized exudates.

Front 96

hemorrhage definition

Back 96

refers to active bleeding into extravascular tissues or spaces resulting from disruption of the integrity of vascular walls

Front 97

clinical significance of hemorrhage dependent on

Back 97

1. AMOUNT - A small volume of blood loss may be insignificant, a large volume of blood loss may be fatal.
2. LOCATION - A large hemorrhage into soft tissue may be insignificant, a small hemorrhage into the brainstem may be fatal.
3. RATE OF LOSS - Chronic blood loss allows compensatory mechanisms to develop and is tolerated better than acute blood loss.

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hemostasis characteristics

Back 98

-refers to the body's intrinsic ability to slow down or stop hemorrhage
-accomplished by forming an intravascular blood coagulum (thrombus) as the result of a complex interaction between the vascular wall, the blood platelets, and the circulating coagulation and anticoagulation factors
- vs. blood clot which refers to the formation of an extravascular blood coagulum or a postmortem intravascular coagulum formed only from the plasma coagulation factors

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vasoconstriction characteristics

Back 99

(occurs immediately)
-walls of arteries, arterioles, and large veins contain a smooth muscle layer which, on injury, contracts, decreasing the diameter of the vessel lumen and reducing blood flow
-helps stop bleeding from minor trauma
-Venules do not have a muscular layer- do not constrict to any great extent.

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platelet plugs characteristics

Back 100

(occurs in minutes) - Platelets are small cytoplasmic fragments of larger cells called megakaryocytes (found in the bone marrow)
-contain granules carrying specific chemical mediators that aid in thrombus formation and are released into the circulating peripheral blood (150,000 - 350,000/μL)
-When endothelium of a vessel is injured, the platelets adhere to the area of injury and pile up to block the blood leakage
-helps control bleeding from venules, capillaries, and arterioles.

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COAGULATION characteristics

Back 101

(occurs within several minutes) -involves interaction between the platelets, calcium, and various protein coagulation factors which are primarily synthesized in the liver and are normally present in circulating blood in an inactive state
-initiated by "activation" of one of the inactive factors which, in turn, activates the next factor which activates the next factor, etc. in a "waterfall" fashion

Front 102

coagulation pathways

Back 102

intrinsic
extrinsic

Front 103

intrinsic pathway of coagulation characteristics

Back 103

activated by contact of factor XII with the subendothelial matrix of the damaged vessel wall. The time it takes for blood to coagulate by this mechanism is measured in the laboratory by the partial thromboplastin time (PTT).

Front 104

extrinsic pathway of coagulation characteristics

Back 104

activated by chemicals that are released from injured tissue (tissue thromboplastin) and from platelets. The time it takes for blood to coagulate by this mechanism is measured in the laboratory by the prothrombin time (PT).

Front 105

common pathway of coagulation characteristics

Back 105

-pathways converge on inactive factor X to produce activated factor X (prothrombin activator or thromboplastin) which converts prothrombin, a coagulation protein formed by the liver, to thrombin. Thrombin, an enzyme, catalyzes the conversion of fibrinogen, another coagulation protein made by the liver, into fibrin - an insoluble protein which creates a network of interlacing fibers that traps platelets and blood cells to form a fibrin plug - much like building a dam with sand bags and cement.

Front 106

fibrinolysis characteristics

Back 106

-process that opposes and counteracts coagulation and prevents coagulation of blood in areas where it is not needed
-involves a circulating inactive protein, plasminogen (produced in the liver) which, in the presence of excess thrombin, becomes activated to plasmin. -Plasmin degrades fibrin into smaller protein fragments (which can be measured in the blood) and thereby prevents coagulation from occurring

Front 107

congenital coagulation factor abnormalities

Back 107

hemophilia A
hemophilia B
Von Willebrand disease

Front 108

hemophilia A characteristics

Back 108

-(Factor VIII deficiency) -sex-linked inherited abnormality
-Patients have difficulty controlling bleeding after minor trauma
-Bleeding into joint spaces (hemarthrosis) will, with time, lead to a crippling arthropathy
-Patients will have a normal platelet count, normal PT, and increased PTT.

Front 109

hempohilia B characteristics

Back 109

(Christmas disease, Factor IX deficiency) - This has the same inheritance pattern and similar symptoms but is about 20% as common.

Front 110

Von Willebrand disease

Back 110

-an autosomal dominant inherited disease affecting a coagulation factor produced by the endothelial cells that normally promotes platelet aggregation at sites of endothelial injury
-characterized by easy bruisability and bleeding but with little or no bleeding into joints.

Front 111

acquired coagulation factor abnormalities

Back 111

vitamin K deficiency
severe liver disease

Front 112

vitamin K deficiency characteristics

Back 112

Synthesis of factors II, VII, IX, and X in the liver are dependent on the presence of Vitamin K (a fat soluble vitamin ingested in the diet and synthesized by intestinal flora). Deficiencies may occur in cases of malnutrition, malabsorption, biliary obstruction, or drug therapy.

Front 113

severe liver disease effects on coagulation factors

Back 113

This can impair the hepatic synthesis of factors II, V, VII, IX, X, and fibrinogen.

Front 114

THROMBOCYTOPENIA characteristics

Back 114

-refers to a decrease in the number of platelets and is generally characterized by petechial bleeding from small vessels into the skin, GI tract, mucous membranes, urinary tract, and brain
-Platelet counts below 50,000/μL may impede coagulation while levels below 20,000/μL may result in spontaneous hemorrhage
-may result from decreased platelet production, increased platelet utilization, or increased platelet destruction

Front 115

platelet abnormalities FUNCTIONAL DISORDERS

Back 115

Various diseases result from abnormalities in platelet function rather than abnormalities in platelet numbers. These may be inherited or acquired. For instance, aspirin interferes with the function of platelets.

Front 116

VESSEL ABNORMALITIES (increased vascular fragility) characteristics

Back 116

-generally manifested by petechial hemorrhages into the skin or mucous membranes and usually are not severe, life threatening situations
-As with the other components of coagulation, these disorders may be inherited or acquired.

Front 117

PREDISPOSING FACTORS of thrombosis- VIRCHOW'S TRIAD

Back 117

1. ALTERATION OF VASCULAR ENDOTHELIUM
2. ALTERATION OF BLOOD FLOW
3. ALTERATIONS OF BLOOD COMPONENTS

Front 118

arterial thrombi characteristics

Back 118

-form most frequently in areas of atherosclerotic damage to the vessel wall or, in the heart, over areas of previous myocardial infarction
-Cardiac and aortic thrombi tend to be firmly attached to the underlying vessel wall (mural thrombi) and are generally not occlusive while thrombi in smaller arteries (coronary, cerebral, femoral) may be occlusive
-As arterial thrombi develop (particularly those in the heart and large arteries where there is high blood flow), they tend to develop alternating layers (lines of Zahn) of fibrin and aggregated platelets which grossly gives the thrombus a grey laminated appearance (white thrombus).

Front 119

venous thrombi characteristics

Back 119

-usually form in areas of blood stasis; are typically found in the deep leg veins, superficial leg veins, and less commonly in periprostatic, periovarian, and periuterine pelvic venous plexuses; and are frequently occlusive
-Since they develop in areas of stasis, there is less tendency to develop lines of Zahn and a greater tendency for red blood cells to become trapped in the developing thrombus to grossly create a dark red-blue appearance (red thrombus).

Front 120

CAPILLARY THROMBI characteristics

Back 120

-usually due to local endothelial damage
-generally consist of platelets and fibrin and are not grossly visible.

Front 121

sequelae of thrombosis

Back 121

1. THROMBOLYSIS AND/OR ORGANIZATION
2. CONTINUED PROPAGATION
3. FRAGMENTATION AND/OR DETACHMENT

Front 122

infarction definition

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-This refers to the process of tissue necrosis secondary to an abrupt reduction in tissue oxygenation. Except for the brain (where liquefaction necrosis develops), anoxia results in coagulation necrosis
-usually the result of sudden interference with the arterial blood supply to a tissue but, may be due to obstruction of venous drainage or to conditions that decrease the oxygen carrying capacity of blood.

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infarction clinical significance

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-effects of an infarct depends on the location and size
-small infarct of the myocardium may be clinically insignificant while a small infarct of the brainstem may be fatal
-a large infarct of the cerebral cortex may result only in neurologic deficits while a large infarct of the myocardium may cause sudden death.

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DISSEMINATED INTRAVASCULAR COAGULATION (DIC) characteristics

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-acquired disorder complicating a wide variety of disease states particularly obstetric emergencies, malignancies, sepsis, and major trauma
-coagulation abnormality involving the coagulation factors and platelets
-primary mechanism is activation (by the release of thromboplastic substances into the circulation and/or widespread injury to endothelial cells) of intrinsic and/or extrinsic coagulation pathways in the microcirculation

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EMBOLIZATION characteristics

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-process in which an intravascular free-floating mass (embolus) is carried with the blood flow through the vascular system to a point distant to its site of origin or entry
-vast majority of emboli are fragments of a preexisting thrombus (thromboembolus) but other material such as air, fat, atherosclerotic plaque, amniotic fluid, tumor cells, bone marrow, bacteria, foreign objects, etc can act as emboli if they gain access to the circulation

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SYSTEMIC (ARTERIAL) EMBOLI characteristics

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-80-85% of arterial emboli arise from mural thrombi in the left ventricle or left atrial appendage of the heart but valve vegetation, aortic mural thrombi, fragments of atherosclerotic plaque, etc. may also embolize
-Depending on the size and site of impact of embolus, it may or may not cause infarction
-Major sites of impaction include lower extremities, brain, kidney, and spleen.

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PULMONARY (VENOUS) EMBOLI characteristics

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-third most common cause of sudden death (after myocardial infarct and stroke)
-More than 95% arise from thrombi in the deep leg veins (popliteal, femoral, iliac), travel through enlarging venous channels, through the right heart, and into the pulmonary arteries
-clinical significance depends on the size and number of emboli as well as the general cardiovascular status of the patient

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FAT EMBOLI characteristics

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-most frequently occur after long-bone trauma when marrow fat is exposed to the venous circulation
-Fat emboli larger than 20μ are filtered in the lung while smaller aggregates may pass through the lung and lodge in brain and/or kidneys
-This may give rise, 1-3 days after the trauma, to a potentially lethal clinical syndrome of progressive respiratory distress, CNS impairment (restlessness, confusion, incontinence, and coma) and possible renal dysfunction that is related to the mechanical and chemical effects of fat in the circulation.

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AIR EMBOLI

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-These may originate from abortion procedures, traumatic pneumothorax, Caisson disease, etc. While small air bubbles may block the microvasculature, larger amounts (100 cc) may cause "air lock" in the right heart

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shock basic definition

Back 130

This can simply be defined as the inadequate perfusion and resultant hypoxia of all body tissues

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hypovolemic shock characteristics

Back 131

Acute loss of blood or fluid from the circulation may be due to hemorrhage, burns, vomiting, diarrhea,"third-spacing" (shifting of intravascular fluid to extravascular sites), etc.

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cardiogenic shock characteristics

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The inability of the heart to maintain adequate output may be due to myocardial infarcts, cardiac tamponade, pulmonary emboli, etc.

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vascular shock characteristics

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These forms of shock share a common denominator of pooling of blood in the peripheral vasculature leading to a central "hypovolemia" and hypoperfusion of vital organs

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vascular neurogenic shock characteristics

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The inability to maintain peripheral vascular muscle tone with subsequent peripheral pooling of blood may be due to CNS injury, drugs, etc.

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vascular septic shock characteristics (endotoxic)

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Severe gram-negative bacterial infections may produce endotoxins that cause peripheral vascular pooling. The ensuing shock may also complicate by direct toxic damage to the vessels and by disseminated intravascular coagulation.

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vascular anaphylactic shock characteristics

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Hypersensitivity reactions may lead to widespread vasodilatation (causing peripheral vascular pooling) and increased capillary permeability with fluid loss from the vasculature. Both can lead to hypovolemia and hypoperfusion of vital organs.

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tissue effects for shock

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Depending on the severity and the duration of tissue hypoxia, there may be necrosis of neurons in the brain, renal tubular epithelial cells (acute tubular necrosis), centrilobular hepatocytes of the liver, and mucosal epithelium of the GI tract (ischemic enteritis).

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cardio output effects shock

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Except for early septic shock, the other forms of shock result in a decreased cardiac output which is reflected by a compensatory tachycardia.

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blood volume effects shock

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Whether an actual reduction in blood volume or a "relative" reduction in blood volume from peripheral pooling, this leads to hypotension and a weak, thready pulse. Decreased effective blood volume also stimulates the kidneys to retain sodium and water. This (in addition to acute tubular necrosis) produces oliguria.

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blood flow effects shock

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In hypovolemic and cardiogenic shock, peripheral vasoconstriction leads to cool, clammy skin
-In septic shock, the peripheral vasodilation and increased vascular permeability leads to warm, moist skin
-Increased levels of reduced hemoglobin in the peripheral tissues may cause cyanosis.

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acid/base effects shock

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Lactic acidosis develops as a result of the tissue hypoxia and this leads to restlessness, mental obtundation, and a compensatory hyperventilation

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labile cells characteristics

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-cells which continuously regenerate throughout life to replace other cells that are lost through normal physiological processes (all epithelial surfaces, ducts, lymphoid and hematopoietic tissue, etc)
-continuously in the replicative cell cycle and replacement of damaged cells is relatively rapid.

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PERMANENT CELLS regeneration characteristics

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-cells that do not have the ability to regenerate. -include striated and cardiac muscle cells (there is still a question whether or not these cells can regenerate to a limited degree under special circumstances, but in any case, they cannot regenerate to any clinically significant degree) and neurons (neurons of the peripheral nervous system are capable of regenerating axons along the lines of the destroyed axon as long as the cell body is not damaged, but neurons of the central nervous system cannot regenerate).

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stable cells regeneration characteristics

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-cells which retain the ability to regenerate but do not do so under normal circumstances (hepatocytes, renal tubular epithelial cells, glandular parenchymal cells, endothelial cells, mesenchymal cells, etc)
-are in the G0 phase of the cell cycle and the mechanism(s) by which these cells are stimulated to reenter the G1 phase of the cell cycle and proliferate is not entirely known

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hypotheses for stable cells regeneration

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stimulation by growth factors

loss of contact inhibition

decrease in cellular density

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REPAIR BY COLLAGENOUS SCAR FORMATION characteristics

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repair of injured tissue generally involves, to some extent, the production (by fibroblasts) of collagen to produce a scar (cicatrix) that will replace structurally damaged tissue

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type 1 collagen definition

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predominant collagen in skin, bone, and most organs

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type 4 collagen definition

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major component of subepithelial/endothelial basement membranes

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healing by first intention (primary union) characteristics

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-refers to the repair process involved with surgical incisions where the margins of the wound are closely coapted by sutures or other methods
-very little loss of tissue substance and a minimal amount of inflammatory exudate and necrotic debris

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HEALING BY FIRST INTENTION-clot formation characteristics

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-At first, the increased vascular permeability resulting from the inflammatory response initiated by the tissue injury produces a fibrin-rich exudate which fills the space between wound margins
-dehydrates, it forms a surface scab which seals the wound against invasion by microorganisms.

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HEALING BY FIRST INTENTION- EPITHELIAL REGENERATION

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-Beneath scab, surface epithelial cells from the wound margins begin to proliferate and migrate toward the midline within 24 hours of the injury, and by 48 hours a tenuous single layered epithelium covers the surface of the wound

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HEALING BY FIRST INTENTION- inflammation

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-W/ in the first 24 hrs, polymorphonuclear leukocytes accumulate at the margins of the wound as part of the acute inflammatory response to the tissue injury
-Fibrin strands, formed from the inflammatory exudate and coated by plasma fibronectins, are chemotactic for macrophages and fibroblasts and also act as "scaffolding" to facilitate the influx of these cells to the area of injury.

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HEALING BY FIRST INTENTION- FIBROBLAST ACTIVATION

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-By the second day, fibroblasts from the healthy wound margins are "activated", perhaps by growth factors derived from platelets (PDGF), macrophages (interleukin-1), or damaged tissue
-begin to infiltrate the injured area and alter the composition of the extracellular matrix.

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HEALING BY FIRST INTENTION- NEOVASCULARIZATION

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-Macrophages begin to replace the neutrophils around the third day
-cleaning up cellular debris along the wound margins, they secrete factors which act in concert with the fibronectins secreted by the fibroblasts to promote angiogenesis and neovascularization
-combination of neovascularity, "activated" fibroblasts and mixed inflammatory infiltrate (mostly macrophages) embedded in an edematous ground substance is termed granulation tissue

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HEALING BY FIRST INTENTION- scar formation

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From this point, the fibroblasts continue to secrete collagen and other ground substances. As the inflammatory infiltrate subsides and the collagen becomes more abundant, the fibroblasts undergo apoptosis and the vessels are slowly crowded out to produce a relatively acellular, avascular scar.

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healing by second intention (secondary union) definition

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refers to the repair process involved when there is sufficient loss of tissue to prevent coaptation of the wound margins (abscesses, ulcers, infarctions, etc.).

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wound contracture definition

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-phenomenon that occurs in secondary union
-wound margins cannot be coapted, myofibroblasts at the edges of the wound contract and can significantly reduce the volume of the area that must be filled with granulation tissue and subsequent scar
-wound contraction can occasionally be deleterious in that it may lead to disfiguring scars, "frozen" joints, etc

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DEVELOPMENT OF WOUND STRENGTH characteristics

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-As soon as granulation tissue is established and fibroblasts begin to secrete new collagen, the tensile strength of a wound begins to increase although not in a linear fashion
-Early, type III collagen is secreted, but as the scar matures and the collagen is remodeled, Type I collagen, becomes predominant
-After about 100 days, seventy to ninety percent of the original tissue strength is restored, but a scar is never as strong as the original tissue and, of course, is non-functional in terms of parenchymal function

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EXUBERANT GRANULATION (proud flesh) definition

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refers to the excessive buildup of granulation tissue which protrudes above the surface of the wound and prevents re-epithelialization

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KELOID FORMATION definition

Back 160

-refers to a buildup of excessive amounts of collagen leading to disfiguring scars
-seem to be a genetic predisposition to forming keloid scars
-may be an abnormal response of fibroblasts to growth factors, a delay in fibroblast apoptosis, or a defective communication between fibroblasts and the extracellular matrix

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requirements for all proper wound healing

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adequate blood supply
adequate nutrition
adequate cleansing
protection from trauma

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neoplasia characteristics

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-refers to a "new growth" of abnormal tissue (usually derived from a single cell precursor) that serves no physiologic function and, for the most part, is independent of normal restraints on orderly growth
-that neoplasia is, in essence, a "genetic" disease in that the fundamental cellular changes occur at the level of DNA but that these changes are induced by environmental factors.

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benign vs. malignant neoplasms- cellular morphology

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- Benign neoplastic cells resemble the normal morphology of the cell of origin
-Malignant neoplastic cells are characterized by cellular and nuclear pleomorphism; increased nuclear/cytoplasmic ratio; increased nuclear chromatin which is frequently "clumped" along an irregular nuclear membrane; large nucleoli; bizarre mitoses; loss of cellular orientation; and to some degree, loss of normal functional capacity.

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benign vs. malignant neoplasms- cellular differentiation

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-refers to the extent to which neoplastic cells resemble their cell of origin histologically
-cells of benign neoplasms are well differentiated (i.e., all cells closely resemble the cell of origin), have a normal number of chromosomes, and retain functional capabilities
-Malignant cells often show abnormalities in the number or structure of chromosomes and, within the same tumor, may vary from complete lack of differentiation (anaplasia) to well differentiated

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benign vs. malignant neoplams- RATE OF GROWTH

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-tends to parallel the degree of differentiation of the neoplastic cells
-Benign neoplasias generally show slow growth or may, on occasion, spontaneously regress
-malignant neoplasms tend to grow more rapidly and rarely cease growth or regress

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benign vs. malignant neoplams- Mode of growth

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-Benign neoplasms grow by expansion and tend to compress the surrounding tissue into a "capsule" that separates the tumor from normal tissue. -Malignant tumors grow by infiltration and invasion of the surrounding tissue and are not confined by a capsule.

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benign vs. malignant neoplams- METASTASIS

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-refers to spread of a neoplasm to points that are not contiguous with the primary lesion
-Benign tumors do not metastasize, but all malignant neoplasms have metastatic potential (although they do not all do so).

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In general, metastases occur via:

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LYMPHATIC DISSEMINATION (most common)
HEMATOGENOUS DISSEMINATION
TRANSCOELOMIC SEEDING
TRAUMATIC SEEDING

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CLINICAL EFFECTS OF NEOPLASIA- ANATOMIC LOCATION

Back 169

Both benign and malignant neoplasms may cause significant morbidity or kill patients by virtue of their anatomic position (pituitary adenoma, craniopharyngioma, meningioma, etc)
-Even small tumors may cause sudden death by interfering with vital functions (brainstem, conduction system of heart, etc).

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CLINICAL EFFECTS OF NEOPLASIA- LOCAL EFFECTS

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-Both benign and malignant neoplasms may cause compression of surrounding structures
-Malignant neoplasms are more prone to infarction, necrosis, hemorrhage, ulceration, and infection
-They may also stimulate excessive production of connective tissue (desmoplasia)

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CLINICAL EFFECTS OF NEOPLASIA- SYSTEMIC EFFECTS

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-Some tumors (benign or malignant) may produce hormones or hormone-like substances that can have systemic effects known as paraneoplastic syndromes (hypercalcemia, Cushing's syndrome, Syndrome of Inappropriate ADH Secretion, polycythemia, etc)
-Other effects may relate to hypercoagulability, thrombocytopenia, migratory thrombophlebitis, cachexia, sepsis, electrolyte imbalances, etc.

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transformation of a normal cell to a neoplastic cell- initiation stage characteristics

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-Cell contact with chemical initiators can produce permanent changes in the genetic make-up of a cell. -Initiators react with DNA to cause strand breaks, to alter methylation, or to hinder DNA repair
-Initiators do not stimulate cell division, and initiated cells do not have growth autonomy or readily identifiable genotype or phenotype markers

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transformation of a normal cell to a neoplastic cell- promotion stage characteristics

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-Chemical promoters can induce neoplastic transformation in a previously initiated cell but cannot cause neoplastic transformation in and of themselves in a non-initiated cell
-Instead of altering the DNA, their action seems to induce clonal proliferation of initiated cells by altering the regulation of mitosis and the differentiation and maturation pathways

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transformation of a normal cell to a neoplastic cell- CONVERSION

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Ultimately the cells become converted and are no longer dependent on the promoters for proliferation

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transformation of a normal cell to a neoplastic cell- PROGRESSION

Back 175

Once the neoplastic cells become autonomous, continued genetic mutation confers new attributes to subclones of the neoplastic cells (see clonal evolution and heterogeneity)

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carcinogenic agents- radiation characteristics

Back 176

-Ionizing radiation may directly ionize critical cellular macromolecules or interact with cellular water to produce free radicals that mediate cellular damage by breaking or altering chemical bonds
-ability of ionizing radiation to induce neoplastic transformation, however, appears to correlate best with its ability to induce genetic mutation within the cell.

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carcinogenic agents- viruses characteristics

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-Although not numerous, both DNA and RNA viruses have been found associated with human neoplasia (carcinoma of the uterine cervix, hepatocellular carcinoma, Burkitt's lymphoma)
-Through the process of transduction and insertional mutagenesis, viruses may directly rearrange the structure or alter the expression of the host cell genome

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features of malignant cells

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-an increased rate of stem cell renewal
-no longer inhibited by the presence of neighboring cells (i.e., loss of contact inhibition)
-do not require attachment to a hard surface to proliferate (anchorage independent growth)
-less cohesive (loss of surface cellular adhesion molecules)
-immortal (i.e., cell lines can be kept alive indefinitely)
-develop invasive properties and metastic potential
-transplantability

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proto-oncogenes characteristics

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-a normal cell must contain genetic information that could potentially transform that cell into a neoplastic cell under appropriate conditions. These naturally occurring cellular genetic segments were termed proto-oncogenes and, surprisingly, were found in almost all life forms
-Proto-oncogenes, therefore, have the potential of being converted (through mutation, retroviral transduction, increased expression, etc) to oncogenes that can promote excessive or inappropriate cell proliferation

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MECHANISMS OF ONCOGENE ACTIVATION- STRUCTURAL CHANGES

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- Structural mutations can lead to synthesis of a protein that has aberrant structure and function. This can occur through point mutations, insertions/deletions, or translocations.

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MECHANISMS OF ONCOGENE ACTIVATION- REGULATORY CHANGES

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With regulatory changes, mutations affect the amount of protein product rather than the structure. This can occur through translocation or gene amplification.

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EFFECTS OF ONCOGENE ACTIVATION

Back 182

-Oncogenes may code for large amounts of growth factors to which the cell can respond (autocrine stimulation) or they may impart growth autonomy by deregulating genes that encode growth factors. -may encode for defective receptors that transmit stimulatory signals in the absence of a growth factor, or through overexpression of growth factor receptor sites, they may render tumor cells excessively sensitive to low levels of growth factors that are below the threshold for stimulating normal cells

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TUMOR SUPPRESSOR GENES (ANTI-ONCOGENES)

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-expression of these genes (particularly the growth suppressor genes) serve to protect the cell from the events leading to neoplastic transformation
-protein products of the tumor suppressor genes modulate the activity of proto-oncogenes, oncogenes, or their protein products
-In absence of this regulation, neoplasia may arise

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neoplastic transformation characteristics

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-no single oncogene will transform normal cells into neoplastic cells
-appears that more than one oncogene may be involved, with each oncogene supplying some of the functions required to convert a normal cell into a neoplastic one
-Sequential activation of oncogenes (or suppression of tumor suppressor genes) may be reflected in the gradual transition of normal cells to neoplastic cells through stages of dysplasia or pre-neoplasia

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tumor growth characteristics

Back 185

-propensity of tumor cells to reproduce is a distinguishing feature of neoplasia and may be the result of genetic alterations (oncogene activation, tumor suppressor inactivation, etc) that direct the cell to replicate rather than to continue to differentiate
-most tumors are of monoclonal origin i.e., a single cell from normal or pre-neoplastic tissue becomes neoplastic at a specific level of differentiation and the clonal derivatives of that cell produces the neoplasm

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GROWTH FRACTION (GF) characteristics

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-refers to the proportion of cells within a tumor population that are in the proliferating pool
-rate of tumor growth depends upon the growth fraction and the degree of imbalance between cell production and cell loss. Most tumors have a low GF and proliferation only slightly exceeds cell loss
-growth fraction of a tumor has a profound effect on its susceptibility to chemotherapy

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angiogenesis effects on tumor growth

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-Tumor growth is dependent upon vascularization. -Without it, neoplastic growth will stop at approximately one millimeter diameter due to the limited diffusion capacity of oxygen and solutes. -Angiogenic factors which include fibrinogen and various substances produced by the tumor cells (angiogenin, fibroblast growth factor, etc) promote and control the neovascularization of the expanding cell mass

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Tumor growth- doubling time characteristics

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-As tumor size increases, the time it takes for a tumor to double in volume also increases (i.e., growth rate slows down)
-Even though the doubling time slows down as tumors enlarge, by the time a solid tumor is clinically detected it has already completed a major portion of its life cycle
-earlier a tumor is identified, the greater the chance of successful radiation and/or chemotherapy

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clonal evolution of tumors

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-appears to involve a sequence of oncogene activations that, over time, leads to more highly malignant cells i.e. those that have a survival advantage due to their growth rate, invasiveness, drug resistance, etc
-By the time most malignant neoplasms have become clinically detectable, it is likely that they have evolved several subclones with metastatic potential
-implies that the earlier a cancer can be identified, the less likely it is that more aggressive subclones have developed

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MECHANISMS OF TUMOR INVASION AND METASTASIS

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emerging evidence that oncogene activation is involved in conferring metastatic potential on tumor cells by enabling the cell to attach to, degrade, and penetrate basement membranes and interstitial connective tissue

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tumor specific antigens

Back 191

-refers to antigens that are found on neoplastic cells and not on normal cells
-In animals, each individual tumor induced by a given chemical carcinogen frequently carries its own unique tumor antigen while all tumors produced by a given virus share a common antigen. These tumor-specific antigens can activate host immunologic destruction of cancer cells in animals but whether this occurs in humans to any significant extent is not known.

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GRADING of malignant neoplasms definition

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-microscopic pathologic determination of tumor aggressiveness based on the degree of differentiation of the neoplastic cells and the number of mitoses as an estimate of the rate of growth
-graded from I (low grade, well differentiated) through IV (high grade, undifferentiated

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staging of malignant neoplasms definition

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-a clinical and pathologic determination of tumor aggressiveness based on the size of the neoplasm, the presence or absence of regional lymph node involvement, and the presence or absence of distant metastases
-basis of the TNM (tumor size, node involvement, metastasis) staging system

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Once the mechanical and chemical barriers of the skin and mucous membranes have been breeched, the two major internal defense mechanisms of the body against potentially injurious agents are:

Back 194

inflammatory response and the immunologic response

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POLYMORPHONUCLEAR LEUKOCYTES (GRANULOCYTES) definition

Back 195

white blood cells containing an irregular lobulated nucleus and large cytoplasmic granules

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NEUTROPHILS (POLYS, PMN) characteristics

Back 196

-comprise 50-65% of the circulating white blood cells and have a life span of 3-4 days in the blood and 1-2 days in extravascular tissue
-phagocytize and destroy bacteria and other minute particulate matter, elaborate chemotactic factors, and produce digestive enzymes to degrade and "mop up" necrotic cellular debris
-can also undergo an oxidative burst to produce superoxide free radicals

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EOSINOPHILS characteristics

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-comprise 1-5% of circulating white blood cells and have large eosinophilic cytoplasmic granules
-they can produce major basic protein (MBP) which is toxic to parasites but also epithelial cells
-play a prominent role in parasitic diseases and allergic disorders (Type 1 hypersensitivity reactions).

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BASOPHILS characteristics

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-comprise approximately 1% of circulating white blood cells and have large blue staining (basophilic) cytoplasmic granules which contain MBP and lysophospholipase in addition to serotonin, heparin, and histamin
-carry surface receptors for IgE immunoglobulins and, like neutrophils and monocytes, with the proper stimulus can produce and secrete platelet activating factor (PAF) which can cause vasodilation, increased permeability of venules, and synthesis of arachidonic acid metabolites
-tissue bound equivalent are mast cells

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POLYMORPHONUCLEAR LEUKOCYTES (GRANULOCYTES) subcategories

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NEUTROPHILS (POLYS, PMN)
EOSINOPHILS
BASOPHILS

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LYMPHOCYTES characteristics

Back 200

-small cells (slightly larger than red blood cells) consisting primarily of a round hyperchromatic nucleus with very little cytoplasm
-comprise 30-40% of circulating white blood cells and are key mediators in both the humoral and cell-mediated immune responses
-can synthesize chemical mediators (lymphokines) that are involved in lymphocyte recruitment and proliferation as well as other aspects of inflammation/immunology

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T-lymphocytes (T-cells) characteristics

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-comprise the majority (75%) of circulating lymphocytes in the peripheral blood
-lymphocytes that have been "programmed" by passage through the thymus gland where each T-lymphocyte acquires a unique DNA sequence for its surface T-cell antigen receptor
-they also acquire the ability to recognize the major histocompatibility complex (MHC) antigens of the host in order to identify "self" tissues

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T-helper cells (CD4+) fxn

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These augment antibody production by stimulating B-cell proliferation and differentiation into plasma cells.

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T-suppressor/cytotoxic cells (CD8+) fxn

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-will kill virally infected cells and tumor cells which are perceived as foreign
-also dampen antibody production against a specific antigen by inhibiting B-cell proliferation or by restraining T-helper cell activity

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T-memory cells fxn

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-confer life-long memory of specific antigens so that with re-exposure to that antigen, the time delay needed for processing of the antigen is averted.

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B-lymphocytes (B-cells) characteristics

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-comprise about 15% of circulating lymphocytes and represent lymphocytes that have been "programmed" in the bone marrow
-make up the germinal centers of lymph nodes and also reside in the splenic white pulp
-When faced with an antigenic challenge, these cells, with the help of T-cells, mature into plasma cells capable of producing antibodies (immunoglobulins) directed against that specific antigen, or they become B-memory cells

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Natural killer (NK) cells characteristics

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-comprise about 10% of circulating lymphocytes and have a mixed bag of membrane markers
-fxn is not dependent on antigen stimulation
-directly cytotoxic and act by binding to "foreign" cells and lysing the cell membrane through the action of various secreted lymphokines
-important in transplant rejection, destruction of virally-infected cells, and tumor surveillance

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MONOCYTES characteristics

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-(4-8% of circulating white blood cells)
-major source of tissue macrophages
-When these cells leave the circulation and enter tissue, they are termed histiocytes when they are in the resting state and macrophages when reacting to a stimulus
-act to phagocytize large particulate matter and are also capable of pinocytosis of soluble material
-can be "activated" (by gamma interferon, etc) and "deactivated" (by transforming growth factor B, etc) according to their microenvironment.

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PLATELETS characteristics

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-derived from bone marrow megakaryocytes and enclose electron dense granules that contain vasoactive amines and Ca++; alpha granules that contain platelet derived growth factor and coagulation proteins; and lysosomes that contain acid hydrolases
-also are a source of serotonin.

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ACUTE INFLAMMATION definition

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-defensive action by the host that affords an immediate response to tissue injury
-consists of a well-orchestrated series of chemically mediated vascular, neurologic, and cellular events which rapidly mobilizes host defenses to mitigate the severity of the injury and prepare the tissue for repair

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VASCULAR RESPONSE TO INJURY steps

Back 210

1. vasoconstriction
2. vasodilation
3. permeability changes

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acute inflammation- HEMOCONCENTRATION AND STASIS characteristics

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-As fluid escapes into the surrounding tissue, the concentration of cellular elements remaining inside the vessels increases
-normal laminar flow of blood is disrupted and the red blood cells tend to clump together in the center of the vessel while the white blood cells fall to the outer margins and begin to line the endothelial surface, a process called margination

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acute inflammation- ADHESION characteristics

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-As the blood flow slows down because of the loss of fluid from the vessels, the marginating white blood cells begin to loosely "stick" to, roll along, and ultimately adhere to the endothelial surface, a process called pavementing
-accomplished through the expression of a variety of adhesion molecules on the surface of the leukocytes and venular endothelial cells

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acute inflammation- EMIGRATION (TRANSMIGRATION) characteristics

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-process by which the leukocytes escape from blood vessels (primarily venules) by squeezing between widened endothelial cell junctions, through the basement membrane, and into the perivascular interstitial tissue
-Soon after injury, large numbers of neutrophils escape from the venules to be later followed by monocytes and then lymphocytes

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acute inflammation- CHEMOTAXIS characteristics

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-unidirectional migration of cells toward an attractant, usually a chemical substance, along a concentration gradient
-As the chemotactic gradient increases, Ca++ influx persists and membrane phospholipids are converted to arachidonic acid metabolites
-also degranulation of storage vesicles and formation of free radicals within the leukocytes.

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acute inflammation- AGGREGATION characteristics

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-types of cells that aggregate at a site of injury depends somewhat on the causative agent of that injury and may reflect a sequential release of cell-specific chemotactic factors
-w/ acute inflammation (especially bacterial infection), neutrophils arrive at the site of injury first. -Later, the slower moving macrophages and lymphocytes arrive

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predominant inflammatory cell in viral and rickettsial infections

Back 216

lymphocytes

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predominant inflammatory cell in allergic hypersensitivity reactions and parasitic infections

Back 217

eosinophils may predominate

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PHAGOCYTOSIS definition

Back 218

clearing mechanism for particulate material from the site of injury characteristic of neutrophils and monocytes (macrophages) and involves three stages

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3 stages of phagocytosis

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1. recognition and attachment
2. engulfment
3. killing and/or degradation

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serous inflammation definition

Back 220

-often the result of mild injury and consists of the extravasation of an exudate derived from serum or the mesothelial cells lining body cavities
-Example: cutaneous blisters.

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CATARRHAL INFLAMMATION definition

Back 221

-associated with a profuse secretion of watery or mucoid fluid from a mucous membrane
-Example: runny nose.

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FIBRINOUS INFLAMMATION definition

Back 222

-This results in a fibrin-rich exudate which forms shaggy fibrin strands that may ultimately produce adhesions. -Example: "Bread and butter" pericarditis.

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SEROSANGUINOUS OR HEMORRHAGIC INFLAMMATION definition

Back 223

-occurs with highly virulent or fulminating infections where extensive vascular damage occurs resulting in the extravasation of red blood cells
-Example: meningococcal septicemia.

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SUPPURATIVE (PURULENT) INFLAMMATION definition

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indicates the presence of pus which consists of tissue breakdown products, neutrophils, and in most cases microorganisms. Example: furuncles, carbuncles.

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abcess definition

Back 225

This is a localized collection of pus associated with liquefaction necrosis of tissue.

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EMPYEMA definition

Back 226

This is a localized collection of pus in a natural anatomic cavity (usually pleural cavity).

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GANGRENOUS INFLAMMATION definition

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This implies enzymatic and bacterial decomposition (putrefaction) of necrotic (usually ischemic coagulation necrosis) tissue. Example: Gangrene associated with diabetic peripheral vascular disease

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MEMBRANOUS OR PSEUDOMEMBRANOUS INFLAMMATION definition

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-refers to the formation of "membranes" composed of matted fibrin, mucus, and inflammatory cells on focally necrotic epithelial surfaces
-Example: pseudomembrane of diphtheria or clostridia infections

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SYSTEMIC MANIFESTATIONS of acute inflammation

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may include fever (effects of prostaglandin E2 and endogenous pyrogens such as interleukin-1 and tumor necrosis factor produced and released by activated macrophages), shaking chills, weakness, muscle aching, etc.

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MANIFESTATIONS of acute inflammation laboratory findings

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-usually reflected by an increase in the total number of leukocytes circulating in the peripheral blood (normal = 6,000-8,000/ml. blood) which is called leukocytosis
-Leukocytosis may be accompanied by increased percentage of immature neutrophils in the peripheral blood
-increased hepatic synthesis of "acute phase reactants
-erythrocyte sedimentation rate increases-blood becomes hyper coagulable

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chronic inflammation definition

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-may arise following an acute inflammatory reaction in which the inciting agent is not destroyed or with repetitive bouts of acute inflammation
-or may begin as a low grade, smoldering response to persistent infection by organisms with low virulence (tuberculosis), prolonged exposure to nondegradable but toxic substances (silicosis), or autoimmune reactions (rheumatoid arthritis) without ever showing the classical signs of acute inflammation

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CHRONIC NONSPECIFIC INFLAMMATION characteristics

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-proliferative (fibroblastic) response rather than the exudative response seen in acute inflammation. -Histologically, the inflammatory cells are primarily mononuclear (macrophages, lymphocytes, and plasma cells) rather than the polymorphonuclear cells that are seen in acute inflammation
-overlap with the developing immunologic response to injury

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GRANULOMATOUS INFLAMMATION definition

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-a specific pattern of chronic inflammation which may occur in response to a variety of agents (esp. mycobacteria, foreign bodies, fungi) which are indigestible or have low antigenicity
-may also be seen in various "immunologic" disorders (sarcoidosis, primary biliary cirrhosis, etc).

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immunologic response evoked by:

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-may be evoked by any substance (antigen) which the body perceives as "foreign"
-bility of an antigen to evoke an immune response is determined by its size, shape, solubility, and chemical structure

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IMMUNOLOGIC COMMUNICATION characteristics

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-All cells of an individual have expressed on their cell membrane a set of self antigens termed HLA antigens which enable the cells of the immune system to recognize these cells as normal
-important in immunologic recognition of self, non-self, and virally infected cells

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ANTIGEN PROCESSING characteristics

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-On initial exposure, foreign antigens are first processed by macrophages or other antigen processing cells and presented to the T and B-lymphocytes
-Programming of T-helper cells, T-suppressor/cytotoxic cells, and B cells initiates the immune response
-immunologic cells respond by producing various cytokines (interferons, interleukins, growth factors, necrosis factors, etc) which coordinate and regulate both the humoral and cell mediated immune response

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CELLULAR IMMUNE RESPONSE definition

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-the process in which an antigen evokes the production of "activated" T-lymphocytes sensitized to that specific antigen
-These lymphocytes play a major role in the cell-mediated immune responses such as graft and tumor rejection, delayed hypersensitivity reactions, and immunity to certain microbiologic antigens (TB, fungi, etc.)

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HUMORAL IMMUNE RESPONSE definition

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the process in which an antigen evokes the production of circulating antibodies (immunoglobulins) to that antigen

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IgM antibody definition

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-class of immunoglobulins first formed in response to an antigenic challenge and is comprised of five basic immunoglobulin structural units held together by a short polypeptide chain (J chain)
-effective in agglutinating antigen, activating complement, and lysing cell walls.

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IgG antibody definition

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-smallest immunoglobulin in terms of molecular weight, IgG comprises over 85% of the circulating antibodies and is the only immunoglobulin which can cross the placenta from mother to fetus. -Although several subtypes of IgG with slightly different biologic function exist, a major function is to serve as opsonins to enhance phagocytosis

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IgA antibody definition

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present in the blood but is also secreted onto mucosal surfaces (esp. respiratory and gastrointestinal) as a dimeric structure known as secretory IgA to help protect against mucosal invasion by antigens.

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IgE antibody definition

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This mediates allergic reactions and is found primarily in tissue bound to mast cells in and around respiratory and intestinal mucosa.

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IgD antibody definition

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-comprises a small percentage of circulating antibodies, and its function is largely unknown
-on the surface membranes of B-lymphocytes and may play a role in the development and maturation of the humoral immune system

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ANTIBODY RESPONSE characteristics

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-initial B-cell response to an antigenic challenge causes production of IgM antibodies which first appear after a lag time of several days, reach a peak at about 2 weeks, and then decline
-T-helper cells can enhance the B-cell response and T-suppressor cells can suppress the B-cell response. -T-cells also enable the activated B-cells, during their maturation into plasma cells, to switch from the initial IgM antibody production to IgG antibody production

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IMMUNOLOGIC MEMORY characteristics

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-T and B-memory cells are also produced after the first exposure to an antigen and enable the immune response, upon subsequent exposure to that antigen (the anamnestic response), to react more rapidly and to produce greater quantities of antibody (primarily IgG) and/or "activated" T-cells than occurs with the initial response

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TRANSPLANT/GRAFT REJECTION characteristics

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-involves both humoral and cell-mediated mechanisms
-Hyperacute rejection occurs within hours and is mediated by preformed antibody. This leads to extensive fibrinoid necrosis of small vessels, thrombosis, and acute inflammation
-Acute rejection does not begin until days or weeks have passed and can be mediated by humoral and/or cell-mediated mechanisms

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THYMIC APLASIA (DiGeorge syndrome) definition

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-results from embryologic failure of the thymus (and parathyroid glands) to develop
-persons are unable to develop a T-lymphocyte immune response and thus lack cellular immunity
-antibody production may be impaired as well. -especially vulnerable to viral and fungal infections

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INFANTILE AGAMMAGLOBULINEMIA (Bruton agammaglobulinemia) definition

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-sex-linked recessive disease in which there is failure of B-cell maturation and therefore failure of the humoral immune response
-These persons have very small quantities of immunoglobulin in their serum and are vulnerable to severe bacterial infections

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ALYMPHOCYTIC AGAMMAGLOBULINEMIA (Swiss Type agammaglobulinemia, severe combined immunodeficiency disease) definition

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-autosomal recessive inherited disease in which there is a defect in the lymphocyte stem cell population
-decrease in the number of both T and B-lymphocytes as well as thymic hypoplasia and poorly developed lymphoid tissues
-thus neither a humoral nor a cellular immune mechanism
-Unless bone marrow transplantation is successful, these persons usually die early in childhood from recurrent severe infections

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ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) definition

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-result of lymphocyte (primarily T-helper cell) destruction by the human immunodeficiency virus. -Monocytes and their derivatives (macrophages, microglia, dendritic cells, etc) may also be infected. -interferes with both humoral and cellular immunity
-increased incidence of lymphoid malignancies

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HYPERSENSITIVITY REACTIONS definition

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occasionally the immune response may be injurious to the host. These responses are termed hypersensitivity reactions and can be divided into four categories depending on the mechanism of tissue damage involved

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hypersensitivity reactions- type I (anaphylaxis/atopy) characteristics

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-This occurs most commonly in tissues exposed to external antigens (skin, respiratory tract, GI tract)
-antigen reacts with IgE antibodies that have previously been bound to the Fc surface membrane receptors of mast cells and basophils
-causes the immediate release of histamine and other chemotactic chemicals from the mast cell granules initiating the typical allergic response

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hypersensitivity reactions- TYPE II (cytotoxic/cytolytic hypersensitivity) characteristics

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-circulating antibodies (primarily IgG and IgM) attack antigens that are bound to, or are a component of, another cell's membrane or a component of extracellular tissue (such as basement membrane). -Antigen-antibody interaction promotes destruction of the target cell or tissue component primarily by the activation of complement or by antibody dependent cell mediated cytotoxic reactions.

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hypersensitivity reactions- TYPE III (immune complex disease) characteristics

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-Antigen normally reacts with antibody to form an antigen-antibody (immune) complex which is rapidly cleared from the circulation and tissue spaces by phagocytic cells
-Under certain conditions (usually when the antigen-antibody complexes are small), these complexes may not be eliminated and become deposited in tissue
-promotes vascular permeability, phagocytosis, chemotaxis of inflammatory cells, and lysis of cell membranes

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hypersensitivity reactions- TYPE IV (delayed hypersensitivity, cell-mediated hypersensitivity)

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-after processing by macrophages, antigen reacts not with circulating antibodies, but with specifically "activated" T-lymphocytes
-Macrophages transform into epithelioid cells and the resultant release of cytokines (especially interferon gamma) enhances the inflammatory response to the antigen (delayed hypersensitivity) often resulting in granulomatous inflammation complete with giant cells

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AUTOIMMUNE DISEASE- CLONAL DELETION theory definition

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-holds that T and B lymphocytes that react against self antigens are destroyed during early development of the immunologic system
-If for some reason these lymphocytes reappear or become active later in life, they can induce autoimmune disease.

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AUTOIMMUNE DISEASE- ALTERATION OF TISSUE ANTIGEN STRUCTURE theory definition

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can be secondary to radiation, chemicals, drugs, microorganisms, etc. The altered antigen is then recognized as foreign.

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AUTOIMMUNE DISEASE- CROSS REACTIVE ANTIGENS theory definition

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-structure of some "true" foreign antigens may be very similar to some body tissue antigens
-immune response evoked by the invading antigen may then be fooled and "cross react" with the normal tissue antigens.

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AUTOIMMUNE DISEASE - SEQUESTERED ANTIGEN theory definition

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-Normally, some of the body's tissue becomes isolated from direct circulatory and lymphatic exposure
-When these antigens are removed from contact with the immune system, acquired immune tolerance is removed
-With subsequent exposure to the immune system, often secondary to trauma, the antigens are recognized as foreign and an immune response is evoked.

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AUTOIMMUNE DISEASE -LOSS OF T-CELL REGULATORY FUNCTION theory definition

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-T-suppressor cells may inhibit antibody production against specific antigens
-Loss of this activity may lead to antibody formation directed against native tissue antigens
-T-helper cell activity may be abnormally enhanced resulting in an excess of antibody