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130 Cards in this Set
- Front
- Back
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Etiology
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Cause
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Pathognomonic
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Adjective meaning "characteristic of a particular disease"; lesions or clinical signs that are indicative of a specific etiology
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Hormonal hyperplasia
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- under influence of endocrine stimulation
- "as needed" increase in functional capacity of tissue - e.g. female repro tract under influence of estrogen |
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Compensatory hyperplasia
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occurs following loss of cells or in response to chronic mechanical factors (e.g. physical load on bone, traction applied to skin)
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Physiologic hypertrophy
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[hypertrophy occurs in terminally differentiated, non-dividing cells]
- occurs due to increased functional demand on a tissue - e.g. skeletal muscle (endurance exercise = increased number and volume of mitochondria; resistance exercise = increased contractile apparatus), adipocytes, cardiac myocytes |
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Limiting factors of hypertrophy
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- diffusion distance from nearest capillary
- may not function as well |
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Visible features of hyperplastic or hypertrophied cells
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- enlarged (increased intracellular components)
- basophilic cytoplasm (increased rER for protein synthesis) - enlarged nucleolus (upregulated ribosome production) - enlarged nucleus (sometimes due to polyploidy) - pale chromatin (dispersed for transcription) |
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Atrophy
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- acquired condition
- reduction may be via reduced size and/or number - atrophy of cells may be accompanied by atrophy of intracellular matrix (e.g. bone matrix) - imbalance between protein synthesis and degradation |
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Phagosome-lysosome pathway
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- degradation pathway mostly for membrane/cell surface material and phagocytosed material
- digested by acid hydrolase enzymes in lysosomes |
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Ubiquitin-proteasome pathway
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- degradation pathway for cytosolic and nuclear proteins
- proteasome: 26S cylindrical organelle that performs ATP-dependent destruction of proteins marked with ubiquitin |
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Autophagic vacuoles
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- membrane-bound vacuoles in cytoplasm of cells
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Residual bodies
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- autophagic vacuoles that persist indefinitely
- contain digestion-resistant material - e.g. lipofuscin granules |
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Metaplasia
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- divergent differentiation in stem cells (not a change in differentiated cells!)
- reversible - usually one epithelial cell type for another or one mesenchymal cell type for another - epithelial examples: columnar --> squamous in chronic respiratory irritation or Vit A deficiency; squamous --> columnar/glandular in distal esophagus in Barret's esophagus - mesenchymal examples: formation of bone, cartilage, or adipocytes in abnormal places |
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Pneumoliths
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- example of mesenchymal metaplasia
- small foci of metaplastic bone |
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Endocardiosis
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- example of mesenchymal metaplasia
- nodular, myxomatous metaplasia of normally fibrous cardiac valves |
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Categories of accumulated substances
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- normal cellular constituents in excess (e.g. water, lipid, protein, carbohydrate)
- exogenous abnormal substances (inorganic material, material related to infections such as viruses) - endogenous abnormal material (products of abnormal synthetic pathway) - pigment |
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Mechanisms by which substances accumulate in cells
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- diminished metabolism or removal
- genetic or acquired defects in metabolism - cell lacks the machinery to digest or transport abnormal exogenous substance |
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Renal tubular proteinosis
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- proximal tubular accumulation of protein droplets
- associated with glomerular protein loss - excess protein is absorbed from tubular filtrate (pinocytosis) by proximal tubular epithelial cells |
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Russell bodies
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accumulations of immunoglobulin precursors in the ER of plasma cells
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Hyaline change
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- microscopic change: a homogeneous, glassy, pink appearance to cells
- not indicative of a specific disorder - may occur in protein accumulation or smooth ER hypertrophy |
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Lipofuscin
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- non-digestible lipid and phospholipid that is complexed with protein
- result of chronic membrane turnover and recycling - not injurious to cells - histologically: grey-brown, granular, cytoplasma - may be seen grossly as yellow-brown discoloration |
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Melanin
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- the only endogenous brown-black pigment
- fine, granular |
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Melanosis
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deposition of melanin in unusual locations (species-dependent)
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Hemosiderin
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- hemoglobin-derived pigment
- yellow-brown, coarse, irregularly granular - inert storage form of iron (stored as ferritin in complex with the apoferritin protein) - common in spleen, bone marrow, sites of prior hemorrhage |
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Bilirubin
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- bright yellow pigment
- accumulates due to hemolysis, hepatic dysfunction, biliary obstruction - visible grossly and histologically |
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Dystrophic pathologic calcification
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- occurs in localized areas of necrosis
- two steps: initiation and propagation - initiation: calcium accumulates and binds to exposed or altered large molecules --> formation of microcrystals - propagation depends on calcium/phosphorus concentration ratio and the local presence of inhibitors or facilitators |
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Metastatic pathologic calcification
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- occurs in healthy tissues due to systemic hypercalcemia
- common causes: paraneoplastic PTH production, hypervitaminosis D, renal failure with compensatory secondary hyperparathyroidism, destruction of bone by neoplasia - most commonly affects acid-losing tissues, e.g. gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins |
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Replicative senescence
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- cells lose their ability to divide
- occurs after a fixed number of replications - due to incomplete replication of telomeres (chromosome ends) during cell division --> telomere shortening - when telomeres shorten past a certain point, the cell cycle ceases - telomerase (maintains telomere length): high levels in germ cells, low levels in stem cells, ABSENT in somatic cells |
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Dysplasia
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- abnormal growth and development of cells
- can be disordered development during fetal growth or disorganized proliferation of epithelia secondary to chronic inflammation/irritation |
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Steroid hepatopathy
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- glycogen accumulation in cells caused by glucocorticoids (glycogen synthase activity)
- midzonal hepatocytes appear swollen; liver dysfunction, increased liver enzymes |
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Introns vs. Exons
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- introns: not coded into protein
- exons: coding sequences |
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Aneuploidy
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Abnormal number of chromosomes
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Down's syndrome
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third copy of chromosome 21
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Klinefelter syndrome
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male with at least one extra X
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Chronic myelogenous leukemia
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parts of chromosomes 9 and 22 switch places (translocation)
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Isochromosome
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a chromosome that has lost one of its arms and replaced it with an exact copy of the other arm
(the chromosome lined up at right angles to how it was supposed to during mitosis) http://www.med.uni-jena.de/fish/sSMC/formis1.jpg |
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Polyploidy
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- 3 or more of each type of chromosome
- common in flowering plants - found in some fish and amphibians - lethal for humans |
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Uniparental disomy
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- receiving 2 copies of a chromosome or only part of a chromosome from one parent only (no copies from the other parent)
- frequently clinically silent; tend to be clinically significant if genes that undergo genomic imprinting are involved |
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Genomic imprinting
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- alleles from each parent are differently expressed
- DNA modification before fertilizing - methylation inactivates gene - e.g. random inactivation of one X chromosome in calico/torties |
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Familial hypercholesterolemia
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- defect in plasma membrane receptor for LDL (LDL cannot be internalized)
- cholesterol in LDL needed for feedback of cholesterol synthesis |
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Sickle cell anemia
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- inheritance of 2 copies of HbS (normal is HbA)
- when HbS unloads its oxygen, it sticks together and forms long rods inside RBCs, which makes them rigid and inflexible, shorter lifespan - carriers have enough normal hemoglobin, no clinical signs, have increased resistance against malaria |
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Malignant hyperthermia
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- unregulated release of calcium from sarcoplasmic reticulum --> excessive muscle contraction
- congenital defect in ryanodine receptor (Ca release channel in SR) - humans, dogs, horses: autosomal dominant - pigs: autosomal recessive |
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Congenital Erythropoietic Porphyria
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- defect in hemoglobin formation (RBC precursors, called normoblasts, produce excess type I porphyrin), deficient activity of uroporphyrinogen III
- red/brown staining of teeth, bones, urine; photosensitization legions - cattle, humans: autosomal recessive - pigs, cats: autosomal dominant |
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Heteroplasmy
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- presence of more than one type of organelle genome (mitochondrial DNA or plastid DNA) in a cell or individual, i.e. wild-type and mutant
- mitochondria segregate passively when cell divides, so the proportion of mutated mitochondria varies in different cells |
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Amyloids
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- insoluble fibrous protein aggregates
- 95% fibrillar protein, 5% P component (glycoprotein) - non-branching fibrils, indefinite length, can appear singly, in bundles, or in interlocking meshwork - 2 most common fibrillar proteins are amyloid light chain (AL) and amyloid associated (AA) |
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Primary amyloidosis
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- AL fibrils consisting of immunoglobulin light chains
- secreted into circulation by neoplastic plasma cells (multiple myeloma) - deposits found subendothelially in many organs; fibrils are small and can pass through glomeruli - associated w/ immune dyscrasia |
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Secondary amyloidosis
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- AA fibrils
- associated with chronic inflammation; also some viral infections, cancer, familial Mediterranean fever - serum amyloid A (SAA) is produced in liver in response to IL-1, IL-6, TNF-alpha - SAA is then cleaved to AA, which forms beta-pleated sheet structure |
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Peroxisomes
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- radiodense organelle surrounded by single trilaminar membrane
- synthesize plasmalogens (phospholipid), cholesterol, bile; beta-oxidation of LCFAs; gluconeogenesis; breakdown of hydrogen peroxide - disorders diagnosed by low plasmalogen, high LCFA levels in blood |
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Gangliosidosis GM1
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- defect/deficiency in beta-galactosidase
- abnormal storage of lipids in CNS and PNS cells (particularly affects nerves) - cerebellar dysfunction, corneal clouding |
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Gangliosidosis GM2
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- defect in beta-hexosaminidase
- accumulation of lipids in CNS - almost all are fatal |
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Globoid Cell Leukodystrophy
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- a form of sphingolipidosis
- deficiency of galactosylceramide B-galactoside (a galactocerebrosidase) - accumulation of galactosylsphingosine and galactosylceramide --> demyelination in both CNS and PNS - autosomal recessive - affects young animals, Cairn and West Highland terriers, polled Dorset sheep |
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Glucocerebrosidosis (Gaucher's Disease)
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- glucocerebrosidosis
- defect in activity of glucosylceramidase - most common lysosomal storage disease in dogs - autosomal recessive |
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Chediak-Higashi syndrome
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- most prominent lysosomal-related organelle disorder
- autosomal recessive - cattle, killer whales, persian cats, Aleutian mink, beige mice, white tigers? - partial albinism/hair color dilution, increased susceptibility to bacterial infection, interstitial pneumonia, bleeding diathesis (predisposition) |
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Four types of gene therapy
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- insert normal gene to compensate for nonfunctional gene
- replace abnormal gene with normal gene - repair abnormal gene through selective reverse mutation - change regulation of gene pairs |
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Ischemia
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- total loss of blood supply to a tissue
- can be due to blocked arterial flow or reduced venous drainage - glycolysis cannot continue |
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Hypoxia
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- decrease in oxygen
- can be due to low environmental oxygen, poor circulation, interference with normal oxygen deliver, heart failure, reduced transport of oxygen (anemia; CO poisoning), blockage of cellular respiratory enzymes (cyanide toxicity) - glycolysis can continue for some time |
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Hydropic degeneration
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- aka cell swelling
- due to loss of water flow regulation across cell membrane |
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Steps of reversible cell injury
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1) Depletion of ATP
2) Mitochondrial damage 3) Influx of intracellular Ca and loss of Ca homeostasis 4) Accumulation of oxygen-derived free radicals 5) Defects in membrane permeability |
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Sources of free radicals
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- absorption of radiant energy (ionizing radiation)
- enzymatic metabolism of exogenous chemicals - byproducts of normal metabolic processes (cellular respiration; also superoxide release by neutrophils during inflammation) - transition metals (iron, copper) - nitric oxide (can act as free radical / be converted to highly reactive nitrogen species) |
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Effects of reactive oxygen species
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- lipid peroxidation of membranes (free radicals attack double bonds of unsaturated FAs --> peroxides)
- oxidative modification of proteins (oxidation of AA side chains, formation of protein-protein cross-linkages, oxidation of protein backbone) - lesions in DNA (free radicals + thymine --> single-stranded breaks) |
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Control of effects of reactive oxygen species
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- antioxidants (Vit A, C, E; glutathione)
- iron- and copper-binding proteins (keep free metals from reacting) - free-radical scavenging enzymes (catalase, superoxide dismutase, glutathione peroxidase) |
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Pyroptosis
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- a form of programmed cell death associated with antimicrobial responses during inflammation
- requires direct activation of caspase-1 and subsequent secretion of IL-1 and IL-18 - important during microbial infections, regulating metabolic processes, mucosal immune response |
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Inflammasome
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- multiprotein oligomer induced by exogenous or endogenous signals, like pathogen-associated molecular patterns (molecules associated with pathogens recognized by immune system)
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Hemochromatosis
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- large amounts of iron absorbed from GI tract
- iron is stored in parenchymal tissue, e.g. liver - iron storage exceeds capacity and cell ruptures - iron also overruns ferritin system and Fenton rxn - mynah birds, lemurs, Salers cattle |
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Ischemia-reperfusion injury
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hypoxic tissue is reoxygenated, producing lots of reactive oxygen species that cause tissue damage
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White muscle disease
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- concentration of free FAs increases in plasma (e.g. fresh pasture is high in linoleic acid)
- increased formation of free radicals, overruns antioxidant system |
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Bacterial meningitis
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- neutrophils attracted to bacteria in meninges
- leukocytes produce reactive oxygen and nitrogen intermediates - membranous and DNA damage |
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Karyolysis
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- nuclear change in necrosis
- loss of chromatin basophilia due to DNAse |
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Pyknosis
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- nuclear change in necrosis
- nuclear shrinkage, increased basophilia |
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Karyorrhexis
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- nuclear change in necrosis
- fragmentation of pyknotic nucleus |
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Coagulative necrosis
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- gross and cellular architecture retained
- usually due to hypoxia or acute toxicity - classically seen in kidney, muscle, liver - necrotic tissue eventually lyses, is phagocytosed |
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Liquefactive necrosis
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- loss of gross or histological recognition
- only type of necrosis in brain - typical of focal bacterial/fungal infections |
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Caseous necrosis
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- amorphous granular debris composed of fragmented cells, resembles cottage cheese
- enclosed in granulomatous rxn - mycobacterium and related organisms - necrotic debris often calcifies |
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Fat necrosis
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- grossly evident white areas due to saponification (base hydrolysis of TGs)
- due to pancreatic enzyme release - released TGs combine with calcium to form deposits - can also result from trauma or idiopathic |
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Gangrenous necrosis
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- results from invasion and putrefaction of necrotic tissue by saprophytic bacteria (feeds on dead matter)
- dry: develops in extremities that have undergone coagulation necrosis due to ischemia; multiplication of bacteria is limited. Examples- frostbite, fescue toxicity - wet: develops in tissues that retain moisture and warmth after necrosis occurs. Examples- aspiration pneumonia, penetrating wounds |
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What do apoptotic cells look like histologically?
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- round
- intensely eosinophilic cytoplasm - dense nuclear chromatin fragments |
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Caspases
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cysteine proteases that cleave at aspartic acid residues
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What do apoptotic cells express on their surface for recognition by macrophages?
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- phosphatidylserine (in the outer layers of their plasma membrane)
- thrombospondin |
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Death receptors
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- cell surface receptors of the TNF receptor family that contain a cytoplasmic domain called the death domain
- best known: type I TNF receptor and Fas (CD95) |
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Extrinsic pathway of apoptosis initiation
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- when Fas is crosslinked by FasL (membrane-bound), 3+ molecules of Fas come together, and their cytoplasmic death domains become a binding site for the adapter protein FADD
- FADD binds inactive form of caspase-8, which becomes autocatalytic, allows pro-caspase-8 molecules to activate each other |
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Inhibition of extrinsic pathway of apoptosis initiation
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FLIP protein can bind pro-caspase-8 but cannot activate it
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Intrinsic pathway of apoptosis initiation
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- as mitochondrial membrane permeability increases, cytochrome c leaks out into cytosol, binds protein called Apaf-1, and this complex activates caspase-9
- if cell is deprived of growth signals, anti-apoptotic molecules (Bcl-2 and Bcl-x) are lost from mitochondrial membrane, and replaced with pro-apoptotic molecules (Bak, Bax, Bim) - other proteins (e.g. apoptosis inducing factor) enter cytoplasm to bind to/neutralize apoptosis inhibitors |
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Execution phase of apoptosis
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- caspase-8 and 9 activate caspase-3, 6, and 7
- they cleave cytoskeletal and nuclear matrix proteins - caspase-3 activates cytoplasmic DNAse - eventually cells are phagocytosed (dying cells secrete soluble factors that recruit macrophages) |
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How do viable cells avoid engulfment by macrophages (when their neighbors are undergoing apoptosis)?
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they express certain cell molecules such as CD31
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Erythema multiforme
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- autoimmune skin disease
- multilevel apoptosis due to circulating antigen-antibody complexes that bind to receptors on keratinocyte cell surface and activate extrinsic pathway of apoptosis initiation - dogs, cats, horses |
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DNA-damage-mediated apoptosis
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- p53 accumulates when DNA is damaged (e.g. exposure to radiation or chemotherapeutic agents) and arrests the cell cycle to allow for DNA repair
- if repair not achieved, p53 stimulates production of Bas, Bak, Apaf-1 |
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Apoptosis induced by TNF
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- TNF binds to TNFR1
- TNFR1 associates with the adapter protein TRADD - the complex binds FADD and leads to apoptosis |
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Hyperemia
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- active, arteriole-mediated process causing excess blood in vessels
- if physiologic: in response to tissue demand (e.g. exercise, blushing) - if pathologic: disturbance in blood flow (e.g. inflammation, infection, trauma, metabolic disease) |
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Congestion
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- passive, venous-mediated process causing excess blood in vessels
- may cause edema, hemorrhage - often seen with cardiac or pulmonary disease - if localized, probably torsion - if generalized, probably heart failure - hypostatic: due to gravity |
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Diapedesis
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- minor form of hemorrhage
- minor leakage through endothelial gaps - inflammation, toxins |
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Rhexis
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- more severe hemorrhage
- tearing of blood vessels |
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Petechiae
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cutaneous hemorrhages less than 1-2 mm diameter
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Ecchymoses
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cutaneous hemorrhages larger than 1-2 mm diameter (up to 2-3 cm)
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Purpura
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diffuse petechial or ecchymotic hemorrhages over many body surfaces
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Causes of widespread hemorrhage
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If petechiae/ecchymoses:
- diffuse vascular damage - platelet depletion/dysfunction If body cavity hemorrhage: - coagulopathy (hereditary or secondary to Vit K depletion) |
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Infarction
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regional ischemic necrosis of tissue secondary to thrombosis
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Coping mechanisms for external blood loss
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- acute vasoconstriction
- chronic hematopoiesis |
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Coping mechanisms for internal blood loss
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- resorption of some blood through vessel walls
- most blood recycled through fibrosis, erythrophagocytosis, recycling of heme / globin |
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Mechanism of reperfusion injury
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During ischemia:
- ATP is broken down all the way to hypoxanthine - Ca release activates proteases that convert xanthine dehydrogenase to xanthine reductase When circulation is restored: - xanthine reductase metabolizes hypoxanthine and oxygen to urate, hydrogen peroxide, and superoxide free radical - ferric iron (3+) turns superoxide into hydroxyl radical |
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Endothelium anticoagulant factors
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Secreted:
- PGI2 and NO: inhibit platelet aggregation, cause vasodilation - ADPase: degrades ADP (adenosine diphosphate, which stimulates platelet aggregation) - protein C / protein S: degrade coagulation factors V and VIII - tPA (tissue plasminogen activator): activates plasmin to digest fibrin Membrane-associated: - thrombomodulin: binds thrombin, activates Protein C - heparin-like molecules (glycosaminoglycans): cofactors for antithrombin III activation |
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Endothelium procoagulant factors
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- PAF (platelet activating factor): recruits and activates platelets
- vWF (von Willebrand's factor): allows platelet binding to collagen to form primary hemostatic plug - TF (tissue factor; membrane bound): initiates extrinsic coagulation pathway to form secondary hemostatic plug - tPA inhibitor (aka plasminogen activator inhibitor, PAI): inhibits fibrinolysis (clot degradation pathway) [- glucocorticoids, if present in excess: cause vasoconstriction and decrease production of NO and prostacyclin] |
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PGI2
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- secreted endothelium anticoagulant factor
- inhibit platelet aggregation, cause vasodilation |
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NO
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- secreted endothelium anticoagulant factor
- inhibit platelet aggregation, cause vasodilation |
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Protein C / Protein S
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- secreted endothelium anticoagulant factors
- require Vit K to be activated - Protein C requires thrombomodulin (endothelial receptor for thrombin) and Protein S to be activated - break down V and VIII |
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Tissue plasminogen activator (tPA)
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- secreted endothelium anticoagulant factor
- activates plasmin to digest fibrin |
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ADPase
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- secreted endothelium anticoagulant
- degrades ADP (adenosine diphosphate), which stimulates platelet aggregation |
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Thrombomodulin
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- membrane-associated anticoagulant factor
- binds thrombin, activates Protein C |
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Heparin-like molecules
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- aka glycosaminoglycans
- membrane-associated endothelium anticoagulant factors - cofactors for antithrombin III activation |
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Platelet activating factor (PAF)
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- endothelium procoagulant factor
- recruits and activates platelets |
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Von Willebrand's Factor (vWF)
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- endothelium procoagulant factor
- allows platelet binding to collagen to form primary hemostatic plug - large multimeric (linked by disulfide bonds) glycoprotein produced by endothelial cells and platelets - some is secreted and bound to subendothelial collagen, some is stored in endothelial cytoplasmic granules, some circulates in complex w/ factor VIII - platelets bind to exposed vWF using GP1B receptors |
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Tissue factor (TF)
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- aka tissue thromboplastin, coagulation factor III
- only coagulation factor not activated by proteolysis - initiates extrinsic coagulation pathway to form secondary hemostatic plug - small, single-chain, hydrophobic transmembrane protein; part of cytokine receptor family - organized in dimers on endothelial cell membranes (active site hidden), complexed with factor VII |
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Plasminogen activator inhibitor (PAI)
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- aka tPA inhibitor
- endothelium procoagulant factor - inhibits fibrinolysis (clot degradation pathway) |
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3 types of platelet granules
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- alpha granules: largest, most numerous; membranes contain P-selectin; granules contain coagulation factors (fibrinogen, factor V, factor VIII, vWF), growth factors, adhesion molecules, chemokines
- dense bodies/granules: contain ADP, calcium, magnesium, serotonin (major inflammatory mediators) - lysosomes: contain hydrolytic enzymes |
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ADAMTS-13
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plasma metalloproteinase that degrades overly large vWF multimers
(to prevent formation of large, potentially dangerous platelet plugs) |
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Platelet adhesion
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platelets bind to exposed vWF (on endothelial cells) using GP1B receptors
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Activation of platelets
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- can be activated by binding to subendothelial extracellular matrix or by exposure to activating factors (ADP, thrombin, TXA2, thrombospondin, epi, PAF)
- activating signal transduced from platelet surface --> Ca messenger system --> release of Ca - generalized conformational change: extension of pseudopods, secretion of granules |
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Platelet secretion (following activation)
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- release contents of their storage granules: promotes platelet aggregation, fibrin generation, vasoconstriction, inflammation, repair
- synthesize and release newly formed mediators such as TXA2 (stimulates platelet aggregation, vasoconstriction) - undergo conformational change to expose platelet phospholipid complex (Platelet Factor III) |
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Platelet recruitment and aggregation
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- mediated by granule contents: PAF, TXA2, ADP (dense granules), serotonin (dense granules)
- fibrinogen binds to GPIIbIIIa |
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Non-enzymatic coagulation factors
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I, V, VIII
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Coagulation factors that require Vit K to be formed by liver
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- carboxylation of glutamic acid residues in order to bind Ca++
- II, VII, IX, X (* same as those that need Ca to be activated!) |
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Coagulation pathway components that need Ca to be formed
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7a, 9a, 10a, 2a, also stabilized fibrin
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Intrinsic pathway of coagulation cascade
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- platelets or subendothelial collagen (negatively charged) or HMWK activate XII
- XIIa --> XIa --> IXa - IXa + VIIIa --> Xa (then common pathway) [intrinsic pathway also stimulates kinin, fibrinolytic, and complement pathways (latter 2 via plasmin)] - XIIa --> kallikrein --> bradykinin (comes from HMWK) |
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Extrinsic pathway of coagulation cascade
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- primary mechanism for activation of coagulation
- membrane disruption splits factor III dimer, exposing its active site, which activates the complexed factor VII - VIIa can activate common and intrinsic pathway [TF is regulated by Tissue Factor Pathway Inhibitor (TFPI); it inhibits IIIa activity, i.e. activation of X and IX] |
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Common pathway of coagulation cascade
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X --> Xa
Xa + Va --> IIa IIa activates I and XIII Ia and XIIIa form stabilized fibrin [Platelets crosslink via fibrin] |
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Clot contraction
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- aka clot retraction or syneresis
- after fibrin cross-linking, secondary hemostatic plug contracts to form an irreversibly fused mass (gel) of platelets |
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PTT test
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- activated partial thromboplastin time
- measures intrinsic system (XII, XI, IX, VIII, X, V, II, I, PK, HMWK) |
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PT test
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- prothrombin time
- measures extrinsic system (I, II, V, VII, X) |
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Thrombin
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- aka factor IIa; serine protease
- multiple binding sites for anticoagulants, Na (binds to protein C --> thrombin is inactive), fibrinogen - positive feedback/amplification: forms Va, VIIa, VIIIa, XIa (generates more thrombin) - makes Ia and XIIIa (stabilizes clot) - recruits/activates platelets - stimulates endothelial cells and macrophages via protease-activated receptors (PARS): increased expression of leukocyte adhesion molecules (e.g. P-selectin), secretion/expression of vasoactive substances and growth factors * at high concentrations, inhibits Va and VIIIa (via Protein C): negative feedback loop to regulate coagulation |
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Factor XIIIa
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- crosslinks fibrin polymers by linking lysine and glutamine residues
- also needs calcium |
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Cell-based model of coagulation
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Initiation:
- circulating VIIa binds TF on surface of cell - small amounts of Xa, IXa, and thrombin (IIa) produced Amplification: - thrombin activates platelets, cleaves vWF-VIII complex, generates Va, VIIIa, XIa Propagation: - activated coagulation factors aggregate on activated platelets and produce a lot of Xa - Xa and Va then produce abundant thrombin [Xa is inhibited when separated from platelet surface complex] |
