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219 Cards in this Set
- Front
- Back
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Which has a higher specific gravity (protein concentration), exudate or transudate?
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exudate
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Which inflammatory cytokines induce endothelial activation?
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IL-1 and TNF
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Which chemical mediators are involved in redistribution of Weibel-Palade bodies?
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Histamine and thrombin
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What features found on endothelium and leukocytes aid in transmigration?
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CD31 (PECAM-1)
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What are some endogenous chemoattractants involved in chemotaxis?
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C5a, leukotriene B4, cytokines (e.g. IL-8)
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What are the features that interact in:
Rolling Adhesion Transmigration |
Rolling - Selectins and sialylated oligosaccharides
Adhesion - Integrins to ICAM-1 Transmigration - PECAM-1 (CD31) |
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What is the most effective bactericidal mechanism in PMNs?
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H2O2-MPO-halide system
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What enzymes are found in the azurophilic granules of leukocytes that aid in oxygen-independent bacterial killing?
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Lysozyme
Acid hydrolases BPI |
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What enzymes are found in the specific granules of eosinophils that aid in oxygen-independent bacterial killing?
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MBP
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What enzyme is defective in CGD? What does this disrupt?
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NADPH oxidase -- oxidative burst
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What is an acquired defect resulting in leukopenia?
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Bone marrow suppression due to chemo or radiation
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What are some acquired (non-genetic) diseases that may cause a defect in leukocyte adhesion and chemotaxis?
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DM, malignant neoplasm, sepsis, chronic dialysis
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What types of cell has both specific and azurophil granules?
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PMNs
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What type of cell only has azurophil granules?
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Monocyte
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What does IL-8 do?
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attract PMNs (and basophils)
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Which cells secrete histamine?
What is the stimuli that cause them to release histamine? What are the effects of histamine? |
Mast cells, basophils, platelets
Physical injury, immune rxns, C3a and C5a, neuropeptides, cytokines IL-1 and IL-8 Dilation of arterioles, increased permeability of venules during acute inflammation |
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What cells release serotonin?
What stimuli cause them to release serotonin? What are the effects of serotonin release? |
Platelets and neuro-endocrine cells
Platelet aggregation and PAF Dilation of arterioles, increased permeability of venules |
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What are the 4 major systems of plasma proteins activated by Factor XIIa (Hageman)?
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Kinin cascade
Clotting cascade Fibrinolytic system Complement cascade |
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What relationship do inflammation and coagulation have on each other?
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They promote each other
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What do C3a and C5a do?
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Cause histamine release from mast cells and thus increase vascular permeability
C5a is also chemotactic for PMNs |
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What does C3b do?
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Acts as an opsonin, promotes phagocytosis
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What common effect do prostaglandins and leukotrienes have?
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They both increase vascular permeability
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What opposite effect do prostaglandins and leukotrienes have?
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Prostaglandins lead to vasodilation
Leukotrienes lead to vasoconstriction |
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Which three cell types produce NO?
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Endothelial cells
Macrophages Specific brain neurons |
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What effect does NO have and how does it exert its effect?
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Relaxes vascular smooth muscle
Paracrine method |
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What does the hypothalamus secrete in response to IL-1 and TNF that cause fever?
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Prostaglandin E2
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Which genetic disorder related to the immune system is characterized by neutrophils with giant granules due to problems with lysosome fusion?
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Chediak-Higashi syndrome
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What is the mechanism of hypertrophy?
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increased synthesis of structural proteins
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Describe denervation atrophy.
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When the nerve supply to a tissue is interrupted it may atrophy (e.g. can happen in skeletal muscle without periodic activation of NMJ)
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What are two mechanisms of atrophy
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Ubiquitin-proteasome pathway (increased protein degradation)
increased number of authophagic vacuoles (looks for residual bodies) |
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Which are reversible between neoplasia, dysplasia, metaplasia?
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Dysplasia and metaplasia
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What are myelin figures? What process are they found in?
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Phospholipids from damaged cell membranes seen in cells undergoing necrosis
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Is karyolysis seen in necrosis or ischemia?
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Necrosis (irreversible)
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Are blebs and pyknotic nuclei seen in ischemia or in necrosis?
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Ischemia (reversible)
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What are two key features of necrosis?
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Enzymatic destruction of cellular contents
Disruption of plasma membrane |
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What event may lead to coagulative necrosis?
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Ischemia
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What are the two components of purulent exudate (pus)?
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Neutrophils
Dead cell fragments |
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What type of infections is liquefactive necrosis seen in?
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Bacterial infections that involve toxins (S. aureus, S. pyogenes, C. perfringens)
Bacterial or fungal infectiosn with an intense inflammatory response ischemic-hypoxic death of cells in CNS |
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What type of inflammation is involved in caseous necrosis?
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Granulomatous inflammation
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What diseases cause caseous necrosis?
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TB
Some fungal infections |
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What are three features of a caseating granuloma?
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Central acellular nucleus
Multinucleated giant cells Peripheral zone of lymphocytes and macrophages |
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What are some things that can cause non-caseating granulomas?
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Tattoo ink or inhaled dust
Hypersensitivity rxns Brucella M. leprae Cat-scratch (Bartonella Sarcoidosis |
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What are some of the cellular-level effects of depletion of ATP due to hypoxic ischemia halting oxidative phosphorylation?
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Reduced Na,K-ATPase activity on PM
Switch to anaerobic glycolysis Compromised Ca2+ pump (influx of calcium) Decreased protein synthesis due to detachment of ribosomes Misfolding of proteins Potential for damage to mitochondrial and lysosomal membranes ER and cellular swelling, loss of microvilli (where applicable), blebs, clumping of nuclear chromatin, decreased protein synthesis, lipid deposition |
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What are two substances that can be released from mitochondria due to injury or dysfunction?
Which causes necrosis and which causes apoptosis? |
H+ leaks from mitochondrial permeability transition pore - leads to necrosis bc can't make ATP
Cytochrome c leaks and causes apoptosis |
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What are the two sources of cytosolic Ca2+ after injury?
What is one significant effect this has? |
From outside the cell through the damaged plasma membrane
Released from organelles ---Opens mitochondrial permeability transition pore |
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What is the most potent and damaging ROS?
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OH*
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What are 4 ways to generate ROS?
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Normal metabolism
Radiant energy (UV light) Inflammation Metals |
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What are three molecules that ROS react with?
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Fatty acids
Proteins DNA |
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What are 3 antioxidant enzymes that degrade free radicals?
What else does? |
SOD
Glutamine peroxidase Catalase Vitamins A, C, E |
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What is the Fe storage protein?
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ferritin
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What is the Cu storage and transport protein?
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seruloplasmin
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What are two features that make reversible injury progress to irreversible injury?
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inability to fix or reverse mitochondrial dysfunction
severely disrupted membrane functions |
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What is the key thing that tissues are deprived of that differentiate ischemia from hypoxia?
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Glucose
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What are two clinical interventions to try to limit irreversible ischemic injury?
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Restoration of blood flow (although controversy with ischemia-reperfusion therapy)
Induce hypothermia |
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What is the enzyme involved in reperfusion therapy and the end product?
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Xanthine oxidase
toxic OH* |
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What is the most common cause of discontinuation of drug therapy?
What do we order to monitor this? |
toxic hepatocyte injury
get LFTs |
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What are two organs commonly affected by direct toxic injury?
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kidney and GI
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What enzyme mediates the indirect conversion of a drug from a harmless to a harmful form (indirect toxic injury is the result)
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cytochrome p450
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Do infectious agents and chemical or physical agents typically cause necrosis or apoptosis?
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necrosis
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What is the most important feature for identifying histologically a cell that is apoptosed vs. necrosed?
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Whether the PM is intact (and whether there is swelling)
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What is involved in the intrinsic pathway of apoptosis?
The extrinsic? |
Mitochondria
Death receptors |
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What protein family regulates intrinsic apoptosis?
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Bcl-2 family
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What protein family regulates extrinsic apoptosis?
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caspase
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What protein inhibits the extrinsic pathway of apoptosis?
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FLIP (binds and inactivates caspase-8, is used by some viruses to give them more time to replicate in their host cell before it dies)
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What protein inhibits both the intrinsic pathway of apoptosis and the execution phase common to both?
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XIAP
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What are three ways that cells wanting to undergo apoptosis attract macrophages?
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PS on outer membrane
Express thrombospondin Coat with antibodies and C1q |
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What apoptotic pathway does p53 promotes death by in cells with DNA damage?
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Intrinsic
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Why does the cell undergo apoptosis in Alzheimer's and Parkinson's?
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Accumulation of misfolded proteins in ER activates caspases
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What are three mechanisms of pathologic apoptosis?
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Misfolded proteins
Bcl-2 overexpression Too little or too much apoptosis (too little in cancer, autoimmune dxs, too much in neurodegenerative dxs, viral infections bc of CD8 T cells) |
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What is autophagy and when is it useful?
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When the cell digests its own cytoplasmic components
Useful in situations of nutrient deprivation |
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What pigment is associated with residual bodies?
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Lipofuscin (lipid-derived granules that resist digestion by autophagy)
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What are three substances that may accumulate intracellularly?
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Normal cellular consituents (lipids - steatosis, cholesterol - atherosclerosis, xanthoma, cholesterolosis)
Abnormal substance ( Pigment |
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What are two diseases associated with protein accumulation due to alpha-1-antitrypsin deficiency?
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cirrhosis
emphysema |
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What are Mallory bodies in hepatocytes made from?
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cytokeratin intermediate filaments
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Which pigment is associated with hemochromatosis (which often progresses to cirrhosis)?
Which is associated with ochronosis (alkaptonuria)? |
Hemocidarin
Homogentisic acid |
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What are two forms of pathologic calcifications? Describe the difference.
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Dystrophic calcification is deposition in dead tissue despite normal serum levels of calcium.
Metastatic calcification is deposition in normal tissue due to hypercalcemia. |
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What is a disease associated with dystrophic calcification?
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Aortic stenosis (calcification around valves of heart leading to aorta)
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What is a histological sign of metastatic calcification? What pathologies is this seen in?
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Psammoma body (concentric layers)
Seen in thyroid papillary carcinoma and brain meningioma |
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Why do normal somatic cells undergo senescence?
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Because they lack telomerase so their telomeres shorten.
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What is the difference between regeneration and repair?
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Regeneration involves the replacement of cells and tissues in which normal structure is restored.
Repair is when cells/tissues are restored and there is fibrosis (scar formation) and normal structure is not restored. |
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What are two factors that determines whether injury will result in regeneration or repair?
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The capacity of injured cells for regeneration (they are either labile, quiescent, or permanent with respective decreasing capacity for regeneration)
If the extracellular matrix was damaged or is intact (if damaged, then will get repair rather than regeneration) |
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What is a labile cell?
What are three examples? |
A cell with unlimited capacity for regeneration.
Skin, GI tract, hematopoietic cells |
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What is a quiescent cell?
What are three examples? |
A cell with limited capacity for regeneration
Most internal organs (liver, kidney, endocrine) Mesenchymal cells (fibroblasts, smooth muscle, vascular) |
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What is a permanent cell?
What are three examples? |
A cell with little to no capacity for regeneration
CNS neurons Skeletal muscle cells Cardiac muscle cells |
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What are four types of stem cells, from highest abililty to differentiate further to lowest?
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Totipotent
Pluripotent Multipotent Somatic |
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What are niches?
What are four examples of cells found in niches? What are niche cells? |
Environments where somatic stem cells reside
Bulge stem cells in skin next to hair follicles Crypt cells in the intestine Oval cells in the canals of Hering in the liver Corneal stem cells under the limbus Cells that are not stem cells that protect stem cells |
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Where are the two checkpoints in the cell cycle?
Where is the restriction point? |
Checkpoints at G1/S and G2/M
Restriction point in G1 |
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What is the restriction point in the cell cycle?
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Rate-limiting step after which normal cells are committed to divide
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What is the role of cyclins and CDKs in the cell cycle?
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The concentration of them varies throughout the cell cycle to (when complexed with CDKs) aid in the transition to the next phase of the cycle by phosphorylating important proteins like Rb
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What are CDKIs?
What happens when they are mutated? |
CDK inhibitors that bind to CDKs to inhibit progression to the next phase of the cell cycle
When mutated, get uncontrolled division and higher chance of neoplasm |
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How is hyperplasia accomplished in most adult solid organs?
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Recruitment of quiescent cells from G0 into G1
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What disease results from mutation of p16 (which is a CDKI for CDK4)?
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familial malignant melanoma due to less regulation at G1/S checkpoint
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What are six important growth factors?
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EGF (epidermal)
PDGF (platelet-derived) FGF (fibroblast) VEGF (vascular endothelial) TGF-beta (transforming) HGF (hepatocyte) |
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Which growth factors are mitogenic for fibroblasts?
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EGF, PDGF, FGF, TGF-beta
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Which growth factor stimulates granulation tissue formation?
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EGF
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Which growth factor stimulates angiogenesis, wound contraction, matrix degredation?
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PDGF
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Which growth factor stimulates angiogenesis, wound contraction, matrix deposition?
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FGF
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Which growth factor inhibits epithelial proliferation and stimulates fibroplasia and angiogenesis?
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TGF-beta
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Which growth factor increases cell motility and promotes cell scattering in embryogenesis?
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HGF
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What are five important signal transduction pathways?
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MAP-kinase
PI3-kinase IP3 cAMP JAK/STAT |
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What type of receptor is acted upon by growth factors and causes transduction through the PI3 kinase, MAP kinase, and IP3 pathways?
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Tyrosine kinase receptors
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What type of receptor is acted upon by chemokines, histamine, serotonin, hormones, or many drugs and causes signal transduction through the cAMP pathway?
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G protein receptors
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What receptor is acted on by cytokines and causes signal transduction through the JAK/STAT pathway?
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Receptors without tyrosine kinase activity
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What is the process by which growth factors cause a cell to go into G1 from G0?
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Growth factor binds to receptor with tyrosine kinase activity which dimerizes, causes auto-phosphorylation, and attracts a bridge protein that through RAS phosphorylates a GDP, then initiates the MAP kinase cascade through RAF (MKKK->MKK->MK) which causes cytoplasmic effects and phosphorylates transcription factors that make proteins to put cell back into cell cycle
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What are transcription factors?
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Proteins that, upon phosphorylation by kinases, regulate cell proliferation.
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What are two growth-promoting transcription factors?
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cMYC, cJUN
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What is a cell-cycle-inhibiting transcription factor?
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p53
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What happens in the cell cycle of remaining hepatocytes after partial hepatectomy that results in compensatory hyperplasia?
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Early genes cause cytokines (TNF, IL-6) to bind to activate signal transduction pathways in priming stage.
In proliferation stage, HGF, TGF-alpha, and adjuvants cause cells to go from G0 to G1, esp during 24 hours-36 hours post surgery (c-fos, c-jun, c-myc involved). Then in G1 bclx gene does anti-apoptotic functions to carry them through it, and mdm3 and p53 genes get it through G1/S. In growth inhibition, after one or two replications the cells go back to G0 because of TGF-beta and activin. |
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What are the two anatomic components of the ECM?
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Interstitial matrix and basement membrane
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What are the three groups of macromolecules in the ECM?
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Fibrous structural proteins for strength and recoil (collagen, elastin)
Adhesive glycoproteins to connect the cells and ECM (fibronectin, laminin) Gel proteins to provide resilience and lubrication (proteoglycans, hyaluronan) |
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What are the five major functions of the ECM?
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Mechanical support
Control of cell growth (binds to integrins) Modulation of differentiation (via integrins) Storage of regulatory proteins (growth factors) Provides scaffolding for regeneration |
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What are the three components of the basement membrane?
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Type IV collagen
Laminin Proteoglycan |
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What are three components of interstitial matrix?
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Fibrillar collagens
Elastin Proteoglycan and hyaluronan |
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What is required for hydroxylation of the pro-alpha chain of collagen in order to get a stable procollagen triple helix?
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Vitamin C
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What are cross-linked adjacent collagen molecules that increase tensile strength?
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Fibrils
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Where is type I collagen typically found?
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Hard and soft tissues (ubiquitous)
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Where is type II collagen typically found?
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Cartilage, intervertebral discs, vitreous
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Where is type III collagen typically found?
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Hollow organs, soft tissues
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Where is type V collagen typically found?
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Soft tissues, blood vessels
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Where is type IX collagen found?
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Cartilage, vitreous
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Where is type IV collagen found?
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Basement membranes
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Where are some sites where elastin is abundant?
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Skin, lungs, uterus, aorta, ligaments
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What are the two components of elastic fibers?
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Elastin (core protein)
Fibrillin (microfibrils that form scaffolding) |
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What is the genetic mutation in Marfan's syndrome?
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Fibrillin of elastic fibers, which leads to aortic dissection and detachment of the lens of the eye
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What are two adhesive matrix glycoproteins? What is their function?
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Fibronectin (binds to cells and matrix proteins)
Laminin (polymerizes to collagen IV in basement membrane) |
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What do integrins do?
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Connect cells to ECM proteins or cells to other cells -- attached to internal cytoskeleton, have a transmembrane component, and cytoskeleton filaments external to cell
-response to mechanical forces |
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What are cadherins?
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Calcium-dependent adherence proteins that connect the plasma membranes of similar cells (zonular adherens and desmosomes), regulate migration of keratinocytes, and are involved in regeneration of the epidermis
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What are catenins?
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Cells that link cadherins to actin in the cytoskeleton. They, along with cadherins, regulate motility, proliferation, and contact inhibition
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What are two gel proteins?
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Glycosaminoglycans and hyaluronan
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What is the structure of glycosaminoglycans?
What is the structure of hyaluronan? |
Repeating dissacharide polymers with sulfate residues that are linked with a protein to form proteoglycans
Repeating disaccharides formed at cell membrane by hyaluronan synthase, not linked to a core protein |
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What do glycosaminoglycans do?
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Regulation connective tissue structure and permeability
Function as integral membrane proteins that can modulate binding of growth factors |
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What does hyaluronic acid do?
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Binds to receptors that regulate proliferation and migration (such as CD44 on WBCs to promote recruitment), binds H2O to form a gel for resisting compressive forces and to lubricate joints
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Why is fibrosis necessary in tissue repair?
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To fill in the gaps that cannot be replaced by regenerating cells
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What are the five major processes involved in tissue repair by fibrosis?
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Induction of inflammation to remove dead or damaged cells
Formation of new blood vessels Migration and proliferation of fibroblasts Scar formation Connective tissue remodeling |
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What are two mechanisms of angiogenesis?
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1-sprouting new blood vessels from pre-existing vessels (involves vadodilation with NO, VEGF, proteolysis of BM by metalloproteinases, migration of ECs, proliferation of ECs behind migrating front of cells, maturation of ECs, recruitment pericytes and smooth muscle cells to support new vessel
2-angioblast-like endothelial-precursor cells (EPCs) are recruited from bone marrow, homing to site of angiogenesis |
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What is the Notch pathway?
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promotes branching of new vessels (VEGF) and prevents excess vessel formation (DII4, which activates genes to downregulate responsiveness to VEGF in stalk cell)
---involves the tip cell and the stalk cell right behind it |
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What are the three phases of fibrosis?
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1 - migration and proliferation of fibroblasts: macrophages, endothelial cells, and platelets secrete GFs (TGF-beta, PDGF, EGF, FGF, IL-1, TNF)
2 - Deposition of Extracellular Matrix - fibroblasts become more synthetic, collagen synthesis begins 3 - Maturation and Remodeling - remodeled, decreased vascularity and fibroblast proliferation, more collagen deposition and cross-linking to give tensile strength |
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What is the most important GF promoting fibrosis?
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TGF-beta
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What are the differences between granulation tissue and mature fibrosis?
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Granulation tissue have more vascularity and less collagen
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What do matrix metalloproteinases do?
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degrade ECM components
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What are the three phases of wound healing?
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Inflammation (clot formation, chemotaxis)
Proliferation (re-epithelialization, angiogenesis and granulation tissue, provisional matrix) Maturation (collagen matrix, wound contraction) |
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Deposition of what leads to increased wound strength?
How long until the would is 70-80% of normal? |
Collagen type I (NOT type II)
3 months |
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What are the four systemic factors that increase wound healing?
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Nutrition (profound effect due to deficiencies in protein and vitamin C deficiency)
Metabolic status (DM delays healing bc of lack of insulin) Circulatory status (atherosclerosis or venous stasis slow healing) Steroid hormones (inhibit early inflammatory response) |
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What are the five local factors that influence wound healing?
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Infection (most important cause of delay in healing)
Mechanical (may break edges) Foreign bodies Anatomic location (areas with lots of vascularity heal faster) Type of wound (sharp, controlled wounds heal faster than large deep wounds) |
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What is wound dehiscence?
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Separation of wound edges due to mechanical forces
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When does wound ulceration occur?
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With inadequate blood supply
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What happens when there is excessive wound repair?
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Keloid (hypertrophic scar) which means there was too much collagen and not enough metalloproteinases (see thick collagen bundles in the dermis)
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What happens when there is excessive granulation tissue?
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Proud flesh - this is good because there are lots of blood vessels and fibroblasts
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What are the major causes of edema?
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lymphatic obstruction
sodium retention (kidney disorders) increased hydrostatic pressure reduced plasma osmotic pressure |
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What are two causes of increased hydrostatic pressure?
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impaired venous return (DVT, CHF)
arteriolar dilatation (heat, neurohumoral dysregulation) |
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What are two causes of decreased colloid osmotic pressure?
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albumin loss (nephrotic syndrome)
decreased albumin synthesis (liver disease, protein malnutrition) |
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What is anasarca?
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Generalized, severe edema with widespread tissue swelling
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Is exudate or transudate due to increased hydrostatic pressure and decreased plasma osmotic pressure?
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Transudate
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What is hyperemia and congestion?
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Increased blood volumes
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What causes hyperemia? Congestion?
|
Hyperemia is an active process caused by arteriolar dilatation, leading to increased blood flow.
Congestion is a passive process that involves decreased blood flow from tissue, leading to increased blood volume there. |
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What is an example of hyperemia?
Of congestion? |
Blood-shot eyes seen in conjunctivitis
Pulmonary congestion when left ventricle has reduced output (blood backs up into pulmonary circulation) |
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What are three causes of hemorrhage?
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Capillary damage
Rupture of artery or vein Hemorrhagic diathesis (because of a clotting disorder) |
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What are three types of hemorrhages based on size, from smallest to largest?
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Petechiae (1-3mm)
Purpura (3-10mm) Ecchymosis (>1cm) |
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What are three names for hemorrhages based on location?
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Hemothorax (remember, with edema this was HYDROthorax)
Hemopericardium Hemoperitoneum Hemarthrosis (blood in joint) |
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What are the three physiologic components that maintain hemostasis?
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Endothelium
Platelets Coagulation cascade |
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What are the two types of granules found in the cytoplasm of platelets?
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Alpha granules (fibrinogen, fibronectin, factors V and VIII, PDGF, TGF-beta, vWF)
Dense granules (ADP, ATP, calcium, histamine, serotonin, epinephrine) |
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What are the three stages of platelet involvement in primary hemostasis following vascular injury?
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Adhesion and shape change
Secretion of granule contents Aggregation |
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What is the role of vWF in hemostasis?
|
Acts as a bridge between the platelet surface receptors and exposed collagen (helps anchor them against the flow of blood)
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What is the mutation in Glanzmann thrombasthenia?
|
Gp11b-IIIa, which connects the platelet and fibrinogen (when induced by ADP)
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What is the mutation in Bernard-Soulier syndrome?
|
Gp1b, which connects the platelet to vWF on the subendothelium
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What is the mutation in von Willebrand disease?
|
vWF, which is on the subendothelium and exposed in vascular injury
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What are the three steps in platelet aggregation?
|
1) Thrombin binds to GpIIb-IIIa, thrombin+ADP+TxA2 leads to aggregation of platelets, cytoskeleton of platelets contracts to form secondary hemostatic plug
2- Fibrinogen --> Fibrin with help of thrombin which cements the platelets in place |
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When is platelet aggregation no longer reversible?
|
After thrombin generation
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Between prostacyclin (PGI2) and thromboxane (TXA2), which is anti-coagulative and which is pro-coagulative?
|
Prostacyclin is anti-coagulative and thromboxane is pro-coagulative
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What does aspirin block the synthesis of when it inhibits COX?
|
Thromboxane (TXA2)
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What does the coagulation cascade accomplish, where does it happen, and what holds together the components?
|
It leads to thrombin formation which, among other things, converts fibrinogen to fibrin on a phospholipid surface and is held together by calcium ions
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What lab test measures the effectiveness of the intrinsic pathway of coagulation?
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PTT (partial thromboplasmin time)
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What lab test measures the effectiveness of the extrinsic pathway of coagulation?
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PT (prothrombin time)
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How does the drug Coumadin (Warfarin) work?
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inhibits vitamin-K-facilitated addition of gamma carboxyl groups to glutamin residues on the calcium-containing phospholipid surface (this is required for factors II, VII, IX, and X to bind)
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What are three ways that thrombin affects the coagulation cascade?
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Converts fibrinogen to fibrin
Cofactor in many of the enzymatic rxns Modulates pro-inflammatory activities (induced platelet aggregation, TxA2 production, endothelial cells to express NO, PGI2, tPA, and activates leukocytes) |
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What are three mechanisms that control coagulation?
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Endogenous anticoagulants (antithrombin III, proteins C and S, tissue factor pathway inhibitor)
Fibrinolytic cascade (run by tPA which allows plasmin to come in and break clot) Endothelial cells |
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How does antithrombin III control coagulation?
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Binds to endothelium to inhibit the action of thrombin, and factors IXa, Xa, XIa, XIIa
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What compound does Heparin enhance the action of?
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antithrombin III (it is an anticoagulant)
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How do proteins C and S control coagulation?
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Come from vitamin K-dependent proteins and inhibit factors Va and VIIIa
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How does tissue factor pathway inhibitor (TFPI) control coagulation?
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It is produced by the endothelium and inactivates tissue factor-factor VIIa complexes
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What is Virchow's triad?
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A description fo the three factors that contribute to thrombosis, which are Endothelial injury, Abnormal blood flow (turbulence, stasis), and Hypercoagulability/Thrombophilia.
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Why does disruption of laminar flow predispose to thrombosis?
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Because it leads to stasis in the veins, and brings platelets in closer contact with the endothelium
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What are the four most common genetic hypercoagulable states?
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Mutation in factor V Leiden (factor Va becomes resistant to cleavage by protein C, 50 fold increase in chance of venous thrombosis with homozygous, 5 fold with hetero)
Mutation in prothrombin gene (elevated prothrombin levels, 3 fold increase in risk of venous thrombosis) Mutation in THF reductase gene (elevated homocysteine levels) Increased levels of factors VII, IX, XI, or fibrinogen |
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What are some secondary hypercoagulability risk factors for thrombosis? (increased risk)
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Prolonged bed rest
MI Atrial fibrillation Tissue damage Cancer Prosthetic heart valves DIC Heparin-induced thrombocytopenia |
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What are some secondary hypercoagulability states that put someone at decreased risk for thrombosis?
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Cardiomyopathy
Nephrotic syndrome Hyperestrogenic states (pregnancy) OCP use Sickle cell anemia Smoking |
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What is catastrophic antiphospholipid syndrome?
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An aggressive form of anti-phospholipid antibody syndrome where there is widespread small vessel thrombi, multi-organ failure, and 50% mortality
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Where to arterial thrombi usually originate? Venous thrombi?
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Arterial thrombi often originate at sites of turbulence or endothelial injury
Venous thrombi often originate at sites of statis |
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Where do occlusive arterial thrombi often occur? Venous thrombi?
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Occlusive arterial thrombi often occur in the coronary arteries, then the cerebral and then the femoral arteries, respectively
Venous thrombi very often occur in the lower extremities |
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How does the growth of arterial thrombi differ from that of venous thrombi?
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Arterial thrombi grow retrograde from where they attach while venous thrombi grow in the direction of blood flow (towards the heart) and often break loose
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What are four potential outcomes of thrombosis?
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Propagation (accumulation of more material)
Embolization (dislodges and moves -- very dangerous) Dissolution (fibrinolysis - tPA aims to do this) Organization and recanalization |
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What are five types of emboli?
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Pulmonary
Systemic thromboembolism Fat and marrow embolism Air embolism Amniotic fluid embolism |
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What do most pulmonary emboli look like?
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In small arteries, silent, become organized. Frequently there are many small ones (shower effect)
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What is a saddle embolism and what is the typical outcome?
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Embolism at the bifurcation at the main pulmonary artery. Sudden death results.
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What is a paradoxical embolus?
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An embolus that passes through the interarterial or interventricular defect that gets into systemic circulation
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What are two disorders that result from intracardiac mural thrombi?
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Systemic thromboembolism (often leads to infarction in the legs)
MI, rheumatic heart disease |
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When do fat and marrow emboli often occur?
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After fracture of long bones, soft tissue trauma, or burns
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What are the signs and symptoms of fat embolism syndrome?
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After severe fractures, get tachypnea, tachycardia, irritability, occlusion of pulmonary circulation or cerebral circulation, anemia, thrombocytopenia, restlessness
Free fatty acids are released from fat globules |
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What happens in decompression sickness?
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In deep sea divers, gas bubbles in circulation coalesce to form frothy masses that obstruct vascular flow
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What are common outcomes of amniotic fluid embolism?
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80% mortality
of those that survive, 85% have permanent neurological deficit |
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What is a red infarct?
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An infarct resulting from a venous occlusion (RBCs are main component) which happen in loose tissues with dual circulation.
Common sites are the lungs, ovaries, and small intestine |
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What is a white infarct?
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An infarct due to an arterial occlusion in a sold organ with end-artery circulation.
Common sites are the heart, kidney, and spleen. |
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What are the four main factors that determine the development of an infarct?
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Nature of vascular supply (is there an alternative blood supply?)
Rate of occlusion development (better if happens slowly) Vulnerability to hypoxia (how quickly does the organ get irreversible damage due to this? brain: 3-4minutes, heart: 20-30minutes, fibroblasts: many hours) Oxygen content of the blood (if in someone who is anemic or cyanotic, worse outlook) |
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What is a septic infarct?
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An infarct that arises from an embolism of vegetative matter from heart valves. Usually this turns into an abscess because microbes seed this tissue.
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What is shock?
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Systemic hypotension due to reduced cardiac output or reduced circulating blood volume.
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What are the three most common types of shock?
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Cardiogenic (less cardiac output due to pump failure....MI, ventricular rupture, arrythmias, cardiac tamponade, pulmonary embolism)
Hypovolemic (loss of blood or plasma volume due to fluid loss) Septic (vasodilation and peripheral pooling of blood as an immune reaction to infection) |
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What are two less common types of shock?
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Neurogenic (loss of vascular tone and peripheral pooling due to anethetic accident or spinal cord injury)
Anaphylactic (systemic vasodilation and increased vascular permeability, IgE-mediated) |
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What is the most common cause of death in ICUs in the U.S.?
What is the most common trigger? |
Septic shock leading to multi-organ failure
Gram+ bacteria |
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What are the five major factors in the pathophysiology of septic shock?
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Inflammatory mediators (activation of leukocytes due to TNF, ILs, prostaglandins, activation of complement cascade and factor XII)
Endothelial activation and injury (due to inflammatory mediators and microbes, makes it more permeable and dilated) Metabolic abnormalities (insulin resistance, hyperglycemia, adrenal insufficiency due to DIC) Immune suppression (TH1-->TH2 shift, IL-10) Organ dysfunction (decreased delivery of oxygen to tissues, less utilization of delivered nutrients, mainly occurs in kidneys, liver, lungs, and heart) |
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What is the standard of care for treatment of septic shock?
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Antibiotics
Insulin therapy for hyperglycemia Fluid resuscitation Corticosteroids to correct adrenal insufficiency |
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What are the three stages of shock from best to worst prognosis?
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Non-progressive phase (compensatory mechanisms active, vital organs perfused)
Progressive phase (tissue hypoperfusion, worse imbalances - acidosis) Irreversible phase (widespread cellular injury, ischemic bowel, shutdown of kidneys, death) |
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What vital organ is rarely affected by septic shock?
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The lungs (dual blood supply)
Heart and brain hit the worse with coagulative and liquefactive necrosis, respectively |
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What does nitroglycerin do?
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It is a vasodilator - angina is often due to decreased blood flow and that is why it works
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What three platelet receptors signal cascades that activate more platelets?
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ADP receptor
Thromboxane receptor Thrombin receptor |
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What receptors are involved in mechanical adhesion to change the degree of stickiness of the platelets to the endothelium wall?
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vWF receptor
fibrinogen receptor |
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What morphological feature gives the platelets tensile strength to overcome the pressure gradient?
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actomyosin filaments
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What are eptifibatide and abciximab?
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Drugs that act as GPIIb-IIIa antagonists (prevent fibrinogen from binding to platelet surfaces, linking them together)
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What do thromboxane and ADP do?
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Platelet aggregation
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What drug inhibits PDE?
What effect does this have? |
Dipyridamole
increases cAMP (because PDE converts cAMP to AMP), which has an anti-aggregatory effect because PKA (protein kinase A) inhibits platelet aggregation (we're not sure how) |
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What drugs inhibit the ADP receptor?
What effect does this have? |
Clopidogrel, ticlopidine
Is anti-platelet because maintains high cAMP |
