Exam 1 Flashcards
Mechanisms and Morphology of Cellular Injury, Adaptation, and Death
Learning Objectives
What is pathology?
The study of disease from all perspectives. It includes etiology (cause of disease), pathogenesis (how a particular disease develops to give morphologic diagnosis), morphologic (gross and histologic) changes in cells/tissues/organs.
What does it do?
What does it target?
Where does it go?
Some times morphologic (appearance) it is same as clinical diagnosis
General pathology: focuses and cells and tissues injury and mechanisms of response
Systematic: involves the organs and entire organism
Gross morphological changes: anatomic pathologist
Clinical pathologists: lab work, urine, chemistry tests.
- Define key pathology terms: Pathology,Lesion, Pathogenesis, Morphologic diagnosis, Etiology (etiologic agent) Etiologic diagnosis, Prognosis. Use a pathology report to identify important information regarding the patient.
- Describe the differences between cytology and biopsies
- Identify the microanatomy and function of the cell and organelles. Describe the sequelae associated with damage to these structures.
- Describe the gross, microscopic, and ultrastructure features of reversible and irreversible injury/cell death.
- Identify the causes of injury to cells and cellular responses to injury (including: hypoxia, cell swelling, degeneration, hyperplasia, metaplasia, dysplasia, hypertrophy, anaplasia, atrophy
- Summarize the causes and preventions of reperfusion injury and free radical injury leading to cell death.
- Identify and describe the process and features of necrosis and apoptosis. Identify the type of necrosis in gross and microscopic lesions.
- Compare, contrast and diagnose antemortem changes and postmortem changes. 10.
- Identify and diagnose the type of cellular accumulations in gross and microscopic lesions and their accompanying pathogenesis.
Identify and describe the necessity, importance of, (necropsy) procedure, limitations of and
ancillary testing methods used when doing a necropsy
The normal cell
1. What are some targets for pathogenic organisms and toxicities?
- Cell membrane and organelles. The function of individual organelles depend in great part on the biochemistry of their membranes and intracellular matrix.
Cytocavitary System
-Cell membrane phospholipid bilayer barrier, enzymes, and receptors that determine its function.
-Plasma membrane (first line of contact with harmful substances).
-Transmembrane proteins
-Ligand-receptors (first messengers). Autocrine, paracrine, endocrine signals.
-Cytoplasm, cytoplasmic receptors and Nucleus, nuclear receptors control gene expression.
-Glycoprotein and lipoprotein transmembrane receptors. Each its own intracellular biochemical pathway.
**Notch signaling pathway: embryonic development. Neural tissue, blood vessels, heart, pancreas, mammary glands, T lymphocytes, hematopoietic lineage, and others.
-Parvovirus, coronavirus disrupt this pathway injuring enteric crypt cells, lack of secretory or absorptive enterocytes during healing.
-Second messenger system: Calcium, cAMP, inositol triphosphate, diacyglycerol, arachidonic acid, and Nitric Oxide (NO). They translate first messages.
-Cytosol: cytomplasmic matrix = gel portion of cytoplasm that surrounds organelles.
-Nucleus: DNA, RNA, mRNA production.
-Nucleolus: non-membrane bound structure within the nucleus that forms around chromosomal loci of the Ribosomal RNA (rRNA). Contains RNA polymerases.
-Rough ER: main function is protein synthesis. Translation of mRNA attached to rER then Golgi for further processing. Basophilic.
-Ribosomes: Facilitate the synthesis of proteins in cells. Translate mRNA into polypeptide chains.
-Golgi complex: processing and packaging of immunoglobulins. Process and packed into vesicles to be released into cytosol or plasma membrane for export. If big = eosinophilic stain. (H&E: hematoxylin and eosin).
-Smooth ER: synthesis of lipids, steroids, carbohydrates. Metabolisms of toxins. Hepatocytes have abundant smooth ER, eosinophilic and finely vacuolated cytoplasm.
-Mitochondria: dynamic, large in athletic horses. Major function is generation of ATP through oxidative phosphorylation. Involved in apoptosis, signaling, cell differentiation, and cell growth.
-Vaults: newly discovered
-Lysosomes and Peroxisomes: contain digestive enzymes, endocytosis or phagocytosis. Peroxisomes Beta-oxidation of FAs and degradation of by catalase hydrogen peroxide produced.
-Cytoskeleton: network that regulates the movement and shape of organelles, cell division, and biochemical pathways.
-Cellular inclusions: composed of molecules that accumulate as metabolic by-products or result of cellular injury. Can be intranuclear or cytoplasmic inclusions caused by viruses, bacteria, etc.
Causes of cell injury
a. Morphologic Lesions: structural observations. Need to correlate lesions with biochemical causes, damage may or may not have apparent morphological alterations.
b. Causes are the etiological agents that disturb cellular homeostasis.
- ATP depletion
- Permeabilization of cell membrane
- Disruption of biochemical pathways
- Damage to DNA
**More often there is an interplay of all these mechanisms. Anything that decreases oxygen and nutrients supply to the cell or that damages mitochondria directly halts oxidative phosphorylation, leading to rapid depletion of ATP. Switch to anaerobic glycolysis, ATP ion pump malfunction. Calcium homeostasis lost and phospholipases, proteases, nucleases, activated = damage membranes.
Responses can be
- Adaptation: increased efficiency or productivity
- Degeneration: diminished functional capacity
- Death: DNA damage, permanent growth arrest, or malignant transformation.
Oxygen Deficiency
-Hypoxia: decrease in O2 supply. Result from cardiac or respiratory failure, reduction of vascular perfusion (Ischemia), reduced transport from erythrocytes (anemia or CO toxicosis), or inhibition of respiratory enzymes in cell (cyanide toxicosis).
Physical agents
-Trauma, temperature extremes, radiation, electric shock. Directly or indirectly damage of blood supply.
-Cold: vasoconstriction
-Heat: denature enzymes
-UV light: ionizes atoms or molecules, Reactive oxygen species. DNA damage
Infectious Microbes
-Replicate once they gained cellular entry
Nutritional Imbalances
-Deficiencies or excesses
-Starvation = atrophy of cells
-Caloric excess = metabolic disturbances, disease
-Predisposition or vulnerability to infectious organisms.
Genetic Derangement
-Purebred: increased inherited diseases
-Section II more info
Workload imbalance
-Hypertrophy: meet demand by growing in size
Chemical Drug, and Toxins
-Alter homeostasis, within or outside of tolerable limits. Binding receptors, inhibiting or inducing enzymes, altering metabolic pathways, increasing member permeability, etc.
Immunologic Dysfunction
-Failure to respond effectively or through excessive response.
-Hypersensitivity reactions
-Immunodeficiencies
-Autoimmune disease.
Aging
-ROS
-DNA mutations
-Cellular senescence
-Predisposition to neoplasia.
Reversible cell injury
The initial response to perturbation of homeostasis is acute cell swelling.
- Acute cell swelling a.k.a HYDROPIC DEGENERATION. If not stopped = cell lysis and death.
-Hepatocytes, renal tubular or epithelial cells = hydropic degeneration
-SKIN keratinocytes = BALLOON DEGENERATION.
-CNS = Cytotoxic Edema
Mechanism acute cell swelling
-Na/ATPase pump controls cell volume: normally 3Na out, 2K in. Influx of Na, Ca, and water. Loss of K, Mg = electrolyte imbalance. Water diffuses passively across osmotic gradient normally. But electrochemical gradient lost.
Resulting from Hypoxic Injury
-Hypoxia: decrease delivery of oxygen. Mitochondrial oxidative phosphorylation diminished.
-Ischemia: reduce oxygen and nutrients and reduce removal of waste.
-Anaerobic metabolism starts: Glycolysis = short term survival.
-Damage cell = lose microvilli, bulges, vacuolation, dispersion of organelles, decreased PH, production of heat due to accumulation of lactate.
Free radicals modify phospholipids
-Carbon Tetrachloride: cell membrane injury.
-Membrane attack complex (MAC): form a pore or channel that disrupts lipid bilayer. C5b complement begins enzymatic cleavage.
Morphology of Acute cell swelling
Gross appearance
-Increased volume and parenchymal weight of organs and imparts pallor (deficiency in color).
-Kidney and liver striking lesions of acute swelling.
-Kidney: increased volume, pallor, swollen, with rounded edges and accentuated lobular pattern. Result of acute cell swelling (hydropic degeneration) and necrosis of centrilobular hepatocytes.
-CNS: Cytotoxic edema, increased volume, little effect on color of neuroparenchyma.
Microscopic appearance
-Euchromatic nuclei: Open (uncoiled chromatin). Active in transcription. Basophilic.
-Heterochromatic nuclei: Not open (tightly coiled chromatin). Inactive in transcription. Basophilic
-Diluted cytosol, separated organelles, distended cell appearance. Fine vacuolated appearance.
-Clear cytoplasmic vacuoles = water-distended mitochondria.
-Balloon degeneration typically seen in keratinocytes. Poxviruses classical cause.
-Loss of cilia and microvilli, cytoplasmic “blebs” at apical cell surfaces.
-Renal proximal tubules: swollen epithelial cells impinge on the tubular lumen.
Irreversible cell injury and cell death
Same major mechanisms
-Hypoxia, ischemia, lipid bilayer disruption through MAC (membrane attack complex).
Response depends on
- Type of cell injured
- Susceptibility or resistance to hypoxia and direct membrane injury.
Cell death by oncosis (Oncotic Necrosis)
Cell membrena injury
Free Radical Injury
Severe or persistent injury can overwhelm the cell’s capacity to restore homeostasis. Acute cell swelling can become irreversible.
Oncotic Necrosis: is a process of cell swelling and distinct from cell death apoptosis. The cell loses ability to control electrolytes imbalance and volume. It can be programed like apoptosis (necroptosis).
-Increased Cytosolic Calcium: triggers cellular enzymes. Protein Kinase C, endonucleases, phospholipases, and various proteases.
Paradoxical restoration of blood flow and oxygen supply can exacerbate ischemia cell injury due to oxidative stress formation of ROS. Ischemia-reperfusion injury.
-Intrinsic and extrinsic triggers.
-Group of cells vs. individual (apoptosis).
-Release of cytoplasmic contents into extracellular matrix = INFLAMMATION
1. Initiation 2. Propagation 3. Execution.
Apoptosis: process of cellular shrinkage and fragmentation.
-Marked for phagocytosis
-Contents remain in vacuoles
-Directed by Caspases
-TNF, FasL, DNA damage, Cluster of differentiation 3 CD3, Interferon-y.
Cell membrane injury: Na/K ATPase failure allows Ca in the cell. Exacerbation of damage to mitochondria and other cell membrane damage.
Free Radical: contribute by oncotic necrosis, especially when ischemia is followed by reperfusion. Damage to lipids, proteins, and nucleic acids. Superoxide radical and reactive nitrogen species are highly reactive. Unpair electrons tend to extract H+ from cell membrane polyunsaturated fatty acids.
Coagulative Necrosis
Refers to the denaturation of cytoplasmic proteins
-Cytoplasmic proteins opaque and intense eosinophilic in necrotic cells.
-Hypoxia, ischemia, or toxic injury.
-Cellular acidosis denatures structural and other proteins
-Nucleic acids degraded
Characteristics
-Pyknosis, karyorrhexis or karyolisis
-Most easily recognized in the liver, kidney, myocardium, or skeletal muscle.
-Cell outlines temporarily preserved and tissue architecture
Gross appearance
-Pale tan to pale grey
-Often sharply demarcated from normal color of adjacent viable tissue and solid (no crumbling, sloughing, liquefaction, or other obvious loss of structure).
Infraction
-Typically begins as coagulative necrosis, especially in tissue such as kidney.
-Scaffolding provided by tubular basement membranes maintains tissue structure.
-Tissue with loss of its blood is blanched, but within minutes blood flow is restored. Macrophages remove blood (acute hemorrhage) and infract tissue becomes pale and sharply demarcated by a red rim, attributed to hyperemia hemorrhage and acute inflammation.
Liquefactive Necrosis
-Cells are lysed and the necrotic tissue is converted to a liquid phase.
-Typically final stage of necrosis in parenchyma of the brain or spinal cord.
Gross appearance
-Malacia in spinal cord and brain tissue
-Initial translucency of affected tissue
-Yellowing, swelling, softening of tissue.
-Liquefaction progresses with arrival of macrophages to phagocytize myelin debris and other components of necrotic tissue.
-Debris-laden gitter cells.
-Part of pyogenic (pus-forming) bacterial infection and suppurative (neutrophil rich) inflammation at the center of abscesses.
Gangrenous Necrosis
Wet and dry
-Type of necrosis that tends to develop in the distal aspect of extremities.
-It can be designated as wet or dry
-If the bacteria present produces gas toxins then wet to gas gangrene ensues.
- In the lungs wet gangrene is often sequel to lytic necrosis.
Gross appearance
-Red-black and wet tissues
-Histologically it resembles liquefactive gangrene by accompanied by more numerous leukocytes especially neutrophils.
Dry Gangrene
-Results from decreased vascular perfusion and or loss of blood supply.
-It is a form of infraction, coagulative necrosis.
-Dry leathery texture to affected tissues
-Arterial thrombosis and frostbite are causes of dry gangrene.
Histologic changes in Necrosis (oncotic necrosis)
-Pyknosis (condensed nucleus)
-Karyrrhexis (fragmented nucleus)
-Karolysis (dissolution of nucleus).
Dead cells intense eosinophilia due to denatured proteins
Caseous Necrosis
-Curdle or cheese-like gross appearance.
-It is an older lesion with complete loss of cellular or tissue architecture.
-Crumbled, granular, or laminated yellow-white exudate in the center of granuloma or a chronic abscess.
-Lysing of leukocytes and parenchymal cells converts necrotic tissue into a granular to amorphous (cell outlines are not visible) eosinophilic substance with basophilic nuclear debris.
-Calcification of the necrotic tissue can contribute to basophilic granular appearance.
Chronic cell injury and cell adaptations
Reversible cell injury with acute cell swelling and irreversible injury with cell death.
Atrophy
diminished number and size of organelles with decreased cell size and tissue mass after it has reached its normal size.
-Different from hypoplasia (tissue or organs that are smaller than normal)
-Atrophy: nutrient deprivation, hormonal causes, decrease workload, disuse, etc.
-Thymus atrophy in severe cases of canine distemper or feline parvovirus.
Hypertrophy
Increase cell size because of increase workload, more organelles.
-Or from accumulation of endogenous or exogenous substances.
Hyperplasia
increased number of cells due to proliferation of cells capable of mitosis
-Example: enlargement of the thyroid gland, iodine deficiency
-Physiological when it is in response to cyclic hormonal stimulations as on endometrial or mammary gland development.
Metaplasia
Change in cell type to another of same germ layer (e.g., ciliated epithelium to stratified epithelium)
Dysplasia
Development of cellular atypia (lacking uniformity). No apparent advantage. Precursor to malignant neoplasia (cancer).
Intracellular accumulations
Lipidosis (steatosis)
Accumulation of lipids within the parenchymal cells. Hepatic lipidosis particularly common.
-Hepatic lipidosis: grossly, results in a swollen, yellow liver, with a greasy texture. Severe lipidosis can alter specific gravity of hepatic parenchyma to the point that slices of it float in formalin.
Sharply defined lipid vacuoles are unstained distend the hepatocellular cytoplasm and displace the nucleus to the periphery of the cell.
Glycogen
-Normally store in hepatocytes and in skeletal muscle.
-Excessive storage in Diabetes mellitus, hyperadrenocorticism, results in hepatopathy.
-Liver grossly: enlarged and pale-brown. Swollen hepatocytes with extensive cytoplasmic vacuoles
-PAS ( periodic acid-Schiff) to demonstrate glycogen histochemistry
Proteins
-Eosinophilic H&E stain
-“Hayline” appearance with H&E stain.
-Pink to orange to red
-Protein losing nephropathy.
Extracellular accumulations
Amyloid
-Yellow, waxy, coalescing nodular deposits mainly of protein and carbohydrate molecules or amorphous deposits.
-Iodine still use, stain black spots.
-Misfolding of soluble and functional peptides or proteins, converting them into relatively insoluble and non functional aggregates.
-Highly organized fibrillar structure in amyloidosis
-Deposits are crystals, collagen.
Apple-green with Congo red stain
-AL amyloidosis in horses, the conjunctiva and skin are affected.
-systemic: Shar-Pei dogs, Abyssinian cats, AA amyloid deposits are typically most abundant in renal medullary interstitium.
Pathologic Calcification
-Deposit of calcium salts, typically phosphates or carbonates in soft tissues.
-Result from elevated serum calcium concentration, metastatic calcification.
-Deposit in necrotic tissue is dystrophic calcification.
-Appearance: chalky white deposits with brittle or gritty texture. May be discolored yellow-brown
**Dystrophic calcification: Loss of ability to regulate Ca balance is critical turning point that converts reversible to irreversible injury.
-Prominent in mitochondria and is basophilic stippling of the dead cell.
-Ca gross lesion in myocardial and skeletal muscle in ruminants ( vitamin E or selenium deficiency) white muscle disease.
**Metastatic calcification: imbalance in calcium and phosphate concentrations in the blood.
-Chronic kidney disease
-H&E subtle basophilic stippling
-Von Kossa: blackens the calcium phosphate or carbonate salts.
Pigments
Exogenous and endogenous substances can alter the color of tissues.
-Carbon (Anthracosis) and other dusts:
Pneumoconiosis: lung disease due to inhalation of dust.
-Appearance: black discoloration, grey-black stippling to the lung. Tracheobronchial lymph nodes gray.
-Carotenoid pigments
Impart a yellow coloration to plasma, adipose, and other lipid laden cells. Not a lesion but a dietary indication.
-Tetracycline: binds to calcium phosphate in teeth and bones. Permanent discoloration to animals’ teeth if during time of mineralization. Yellowish discoloration in bone, teeth yellow to brown.
-Nonhematogenous Endogenous Pigments
Melanin
Pigment responsible for color of hair, skin, iris. Melanosis in oral mucosa.
Congenital melanosis are merely color changes and not lesions, no ill effects to the animal.
-Lipofuscinosis and Ceroid
-Yellow-brown lipoprotein that accumulates as residual bodies in secondary lysosomes, especially in neurons and cardiac myocytes.
-Correlates with age of animal “wear and tear”
-PAS positive: Oil Red O
Hematogenous Pigments
-Hemoglobin
Cyanosis: deoxygenated hemoglobin, blue-purplish discoloration
-Carbon Monoxide
Pink color to the tissues in cases of CO poisoning
-Nitrate Poisoning
Nitrate in ruminants from fertilize fields. Converts hemoglobin to methemoglobin turning the color of blood to chocolate brown.
-Intravascular hemolysis
Hemoglobinuria turns renal parenchyma a darks red to gunmetal blue. Browner discoloration of kidney from myoglobinuria from injured skeletal muscle fibers in the urine.
-Hemosiderin
Free iron is toxic to cells catalyzes the formation of ROS. Ferritin binds free iron and stores it in nontoxic form. Intracellular protein, but serum concentrations correlates with iron stores. Macrophages with ferritin (hemodiderin) are converted to Golgen Brown. Prussian blue detects it. Should not be in liver, indication of congestion.
-Hematoidin
Bright-yellow crystalline pigment derived from hemosiderin within macrophages, but it is free iron. Deposited in tissues of hemorrhage.
-Bilirubin
Normally gets recycled and becomes component of bile. Hyperbilirubinemia results in yellowing of tissues, jaundice or icterus.
Yellow discoloration of icterus best seen in adipose tissue, intima of the great vessels, sclera.
-Porphyria
Heme synthesis disorders results in deposition of porphyrin pigments in tissues. Congenital disease results in pink teeth, discoloration of dentin in teeth.
Morphologic Appearance of Post Mortem Changes
-Postmortem Changes are result of autolysis
-Antemortem cells follow biochemical events that result in morphological changes and takes time to develop.
-Intestines autolyze within minutes after somatic death. Can looked like lesions, such as loss of microvillous brush border, rounding, attenuation, and detachment from basal membrane.
-Brain and spinal column are quick to autolyze. Dark neurons is a postmortem change.
-Skeletal muscle is not so quick to autolyze. Retains ability to contract, rigor mortis commences 1-6 hours
-Livor mortis or hypostatic congestion: red and purple discoloration of the skin on the side which the animal died and was laying. Results from pressure points that prevents blood flow to those areas. Gravitational pooling of blood on the dependent side of the carcass. It becomes permanent once the blood clots. Useful finding in forensic pathology.
-Postmortem clot vs. antemortem clot: Smooth shiny surface and lack of lamination or attachment to endothelial surface of vessel. Avian adipose tissue=’chicken fat clot’
-Color changes to autolyzed carcass: Reddish discoloration in endocardium and intima of large vessels. Pink-brown discoloration from hemoglobin leaving lysed erythrocytes.
-Pseudomelanosis: blue-green to black discoloration of tissues, along the digestive tract, by iron sulfide deposits due to reaction bacteria and iron.
-Gas forming bubbles in digestive tract, bloating carcass
-Pressure on organs postmortem “imprints”
Morphologic Appearance of Post Mortem Changes
-Postmortem Changes are result of autolysis
-Antemortem cells follow biochemical events that result in morphological changes and takes time to develop.
-Intestines autolyze within minutes after somatic death. Can looked like lesions, such as loss of microvillous brush border, rounding, attenuation, and detachment from basal membrane.
-Brain and spinal column are quick to autolyze. Dark neurons is a postmortem change.
-Skeletal muscle is not so quick to autolyze. Retains ability to contract, rigor mortis commences 1-6 hours
-Livor mortis or hypostatic congestion: red and purple discoloration of the skin on the side which the animal died and was laying. Results from pressure points that prevents blood flow to those areas. Gravitational pooling of blood on the dependent side of the carcass. It becomes permanent once the blood clots. Useful finding in forensic pathology.
-Postmortem clot vs. antemortem clot: Smooth shiny surface and lack of lamination or attachment to endothelial surface of vessel. Avian adipose tissue=’chicken fat clot’
-Color changes to autolyzed carcass: Reddish discoloration in endocardium and intima of large vessels. Pink-brown discoloration from hemoglobin leaving lysed erythrocytes.
-Pseudomelanosis: blue-green to black discoloration of tissues, along the digestive tract, by iron sulfide deposits due to reaction bacteria and iron.
-Gas forming bubbles in digestive tract, bloating carcass
-Pressure on organs postmortem “imprints”
-Postmortem bloat or emphysema
Sequela to Oncotic Necrosis
-Most tissue: band of Hyperemia (hemorrhage and acute inflammation) bring leukocytes to the site and encircles the tissue.
-Influx of macrophages that become gitter cells in CNS.
-Leukocytes and macrophages phagocytize and lyse necrotic tissue converting coagulative necrosis to liquefactive necrosis and hastening the removal of damaged tissue.
-The liver is not prone to infraction because of its high regenerative capacity and rich dual blood supply.
-Renal infracts are seldom repaired and usually replaced by scar (fibrous) tissue.
-Focal epithelia necrosis that results in ulcerations can be repaired by hyperplasia or adjacent normal cells without scarring if the defect is small.
-Adipose tissue is ill equipped to replace necrotic fat lobules.
Morphologic Appearance of Apoptosis
- Cell death is in the process of condensation and fragmentation of the nucleus (pyknosis and karyorrhexis) with bebbling of the plasma membrane to form membrane-bound apoptotic bodies that contain nuclear fragments, organelles, and condensed cytosol. Inflammation does not occur.
Autophagy
House keeping cell survival mechanism, cells consume their own damaged organelles.
Necrosis of epithelium
-Epidermis or corneal epithelium and lining epithelium (mucosal epithelium of respiratory tract, digestive or reproductive)
-Causes exfoliating or sloughing of dead cells resulting in erosion of the epithelium or with full-thickness necrosis, in ulceration.
-Trauma (herpesvirus) and loss of blood supply are causes.
Heterophagy
Other cell phagocytizes another cell.
Extracellular accumulations, Gout
-Deposition of sodium urate in tissue.
-Primates, birds, and reptiles.
-Urate crystals in the articular and periarticular tissues and elicit an acute inflammatory response. Neutrophils and macrophages aggregates of urate crystals called “Tophi.”
Extracellular accumulations, Gout
-Deposition of sodium urate in tissue.
-Primates, birds, and reptiles.
-Urate crystals in the articular and periarticular tissues and elicit an acute inflammatory response. Neutrophils and macrophages aggregates of urate crystals called “Tophi.”
-Acircular crystals.
-high protein diets, Vitamin A deficiency.
Extracellular accumulations, Cholesterol
-Cholesterol crystals elicit granulomatous inflammation.
-Acircular, needle-shaped clefts in histologic sections. Pale yellow nodules in the choroid plexus of the lateral 4th ventricle in horses.
-Form where there is necrosis or hemorrhage.
Extracellular accumulations, Cholesterol
-Cholesterol crystals elicit granulomatous inflammation.
-Acircular, needle-shaped clefts in histologic sections. Pale yellow nodules in the choroid plexus of the lateral 4th ventricle in horses.
-Form where there is necrosis or hemorrhage.
Heterotopic Ossification
-Formation of bone tissue at extraskeletal site.
-Appears grossly as hard spicules or nodules.
Chapter 2 Vascular disorders and Thrombosis
Diagnose and describe the mechanisms of edema.
Describe the macro and micro anatomy of the circulatory system
Describe and diagnose transudates and exudates
Describe the expected findings in heart failure, including the pathogenesis of extracardiac lesions.
Describe Virchow’s triad. Diagnose emboli and thrombi, infarcts, including their types
Identify hyperemia, congestion, and hemorrhage in tissues/organs.
Identify the type of shock in a patient.
Describe the responses to vessel injury and how it contributes the initiation of platelet plug formation and to the initiation of coagulation.
Summarize the composition and physiology of platelets, including platelet adhesion, activation, secretion and aggregation.
Explain how von Willebrand factor and fibrinogen plasma proteins are needed for platelet function and how activated platelets promote coagulation.
Summarize the classical model of coagulation pathways, including the nature of the various coagulation factors.
Describe why vitamin K is essential for normal coagulation.
Summarize how the cell based model of coagulation better represents the in vivo process of coagulation than the classical model. (See Textbook)
Explain how the major anticoagulants inhibit coagulation.
Describe how fibrinolysis is activated and inhibited
Describe the types of hemorrhage expected with various hemostatic defects.
Summarize the pathogenesis of thrombus formation in arteries and veins and diseased that may induce thrombosis in animals.
Circulatory System
- Heart (central pump)
- Blood distribution (arterial) network
- Blood collection (venous) network
- System for exchange of nutrients and waste products between blood and extravascular tissue (microcirculation a.k.a microvasculature).
- Lymphatic network of vessels that parallel the veins contributes by draining fluid from extravascular spaces into the blood vascular system.
- Systemic circulation and Pulmonary circulation. Left (systematic) to right (pulmonary) right to left.
Anatomy of arteries and veins
Microcirculation: arterioles, metarterioles, capillaries, and postcapillary venules.
Arteries
-walls are thick and consist predominantly of smooth muscle fibers for tensile strength and elastic fibers for elasticity.
a. Tunica intima: endothelium, basement membrane, internal elastic lamina.
b. Tunica media: smooth muscle, collagen, reticular and elastin fibers.
c. Tunica adventitia: connective tissue, vasa vasorum (microvessels), lymphatic vessels, nerve fivers.
Veins
-Composed mainly of collagen, elastin, and smooth muscle.
a. Tunica intima: endothelium, basement membrane
b. Tunica media: smooth muscle, collagen, reticular, and elastic fibers.
c. Tunica adventitia: modest connective tissue, vasa vasorum (microvessels), occasional nerve fibers.
Arterioles
Major resistance vessels, relative narrow lumens. Extrinsic Sympathetic innervation regulate contraction and dilation.
Capillaries
Site of nutrient and waste product exchange between blood and tissue.
Most numerous vessels in the system. Slow rate of blood flow.
Thin one endothelial cell wall layer. Facilitate diffusion.
a. Continuous capillaries: brain (BBB), muscle, lung, bone. 02 and Co2 exchange
b. Fenestrated capillaries (filtration): Renal glomeruli, intestinal villi, endocrine glands, Ciliary process of the eye, Choroid plexus.
c. Discontinuous capillaries (sinusoidal): liver, spleen, lymph nodes. Passage of large molecules.
Venules
-Similar to capillaries but have thin layers of muscle.
Lymphatic vessels
-Are distensible, low-pressure vessels that require lymphatic valves and contraction by muscles that surround them to facilitate return of fluid.
Endothelium that covers circulatory system
What are some characteristics of normal endothelium?
What happens if activated by oxidative stress, hypoxia, inflammation, infectious agents, tissue injury, or similar events?
*A single layer of endothelium lines all components of the circulatory system, forming a dynamic interface between blood and tissue.
-Physical barrier between intravascular and extravascular spaces
-Critical participant in fluid distribution, inflammation, immunity, angiogenesis, and hemostasis.
Normal endothelium
-Antithrombotic
-Profibrinolytic
-Help maintain blood in the fluid state
If activated it produces and releases numerous substances with a wide range of roles in physiology and pathology.
Microcirculation, Interstitium, and Cells
-Interstitium is the space between cells and microcirculation, where the exchange of fluid, nutrients and waste products occurs.
Components
-ECM extra cellular matrix: Type I collagen, adhesive and absorptive, framework where cells reside.
-Cell basement membranes: Type IV collagen
-Adhesive glycoproteins: serve are sites for attachment, and receptor.
Fluid distribution and Hemostasis
Water = 60% of BW
Intracellular = two-thirds
Extracellular = one-third, divided 80% interstitium and 20% plasma.
-Capillary wall is semipermeable: lipid soluble can pass easily, large proteins need transport within vesicle. Prevents albumin and other plasma proteins from moving.
-Local stimuli can cause endothelial cells to contract to widen interendothelial pores and allow passage of larger molecules. Composition of plasma and interstitium very similar except for large proteins.
-Water distribution mainly determined by osmotic and hydrostatic pressure differentials, formula for it.
-Large non-permeable suspended proteins such as albumin that do not move between the spaces, largely contribute to the difference in osmotic pressure between plasma and interstitium.
-In microcirculation osmotic pressure and hydrostatic forces remain constant and favor intravascular retention of fluids. However, net filtration of fluid at the end of capillary bed occurs into the interstitium. Overall there is a constant flow of fluid absorption and filtration, which allows exchange of nutrients and waste products. Interstitium provides a fluid buffer to either increase or decrease plasma volume to ensure effective circulatory function.
Abnormal Fluid Distribution
Alteration in any of the factors that regulate normal fluid distribution between interstitium and plasma and cells can lead to pathologic imbalances between these compartments.
Imbalance between Intracellular and Interstitial compartments
-Example: Alterations in plasma volume and inflammation can result in fluid shifts.
-Hypervolemia: excess plasma volume, results in movement of additional water into interstitium and ultimately into the cell causing cell swelling.
-Hypovolemia: flow of water in the opposite, decrease of water in interstitium and opposite direction than hypervolemia direction resulting in cell shrinkage.
-Osmotic imbalance in cell can cause cell membrane damage or failure of energy dependent pump resulting in cell swelling.
Imbalance between Intravascular and Interstitial Compartments (EDEMA)
-Accumulation of interstitial fluid due to
1. Increased microvascular permeability
2. Increased intravascular hydrostatic pressure
3. Decreased intravascular osmotic pressure
4. Decreased lymphatic drainage.
Causes of edema
Vascular leakage associated with inflammation
Infectious agents
-Viruses (e.g., influenza, caninine adenovirus, etc.)
-Bacteria (e.g., Clostridium spp.)
-Rickettsia (e.g., Anaplasma phagocytophilum, Rickettsia ricketsii, Ehrlichia ruminantium).
Immune mediated
-Type III hypersensitivity (e.g., feline infectious peritonitis, purpura hemorrhagica).
Neovascularization
-Anaphalaxis (e.g., Type I hypersensitivity)
-Toxins
-Clotting abnormalities (pulmonary embolism, disseminated intravascular coagulation)
-Metabolic abnormalities (dibetes mellitus, encephalomalacia by thiamine deficiency)
Increased intravascular Hydrostatic Pressure
-Portal hypertension (right-sided heart failure, hepatic fibrosis)
-Pulmonary hypertension (left-sided heart failure, high altitude disease).
-Localized venous obstruction ( gastric dilation and volvulus, intestinal volvulus and torsion, uterine torsion or prolapse, venous thrombosis).
-Fluid overload (iatrogenic, fluid retention with renal disease).
-Hyperemia (inflammation, physiologic).
Decreased Intravascular Osmotic Pressure
-Decreased albumin production (malnutrition, severe hepatic disease, debilitating diseases)
-Excessive albumin loss (gastrointestinal disease-protein losing enteropathy) or parasites Haemonchosis or trichostrongylosis, renal disease-protein losing nephropathies, severe burns.
-Water intoxication (salt toxicity, hemodilution caused by sodium retention)
