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253 Cards in this Set
- Front
- Back
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Pathologic cause of atrophy
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Canine hypoadrenocorticism, Addison's
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Mechanism of atrophy
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Cell death: necrosis or apoptosis; autophagy (phagosome/lysosome) or ubiquitin/proteasome pathway
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Residual bodies?
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undigested material from autophagy (e.g. lipofuscin)
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Russell bodies?
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Accumulated protein in ER of plasma cells; renal tubular proteinosis
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Hemosiderin?
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Hb-derived pigment; ferritin complexed with apoferritin; in spleen, bone marrow, and liver
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Mitochondrial disease presentation?
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Myopathies and multisystemic disorders.
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Neurological symptoms of inherited mitochondrial disease?
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abnormal eye movements, cerebral ataxia, seizures, peripheral neuropathy, leukodystrophy
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Muscular presentation of mitochondrial disease?
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muscle weakness, respiratory distress, lactic acidosis
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Cardiac presentation of mitochondria disease, other?
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concentric cardiomyopathy, hepatic liver failure with steatosis, cirrhosis
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Mitochondrial myopathies in...?
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horses, cattle, Old English sheep dogs, Aussex spaniels, Leigh disease in dogs
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Endolysosome functions
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membrane trafficking, protein transport, autophagy, signal transduction, immune system, protein modificaiton, tissue development and malignancy
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Types of lysosomal storage disease?
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Based on major stored material: MPS, sphingolipidosis, lipidosis, glycoprotein, glycogen storage disease, mucoliposis, GM1 and GM2-gangliosidosis
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Infantile Tay-Sachs
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mutation in alpha-chain of Beta-hexosaminidase A leads to accumulation of GM2
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Defects in glycoproteins and oligosaccharide degradation
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Mutation in deficient hydrolase activity in 7 out of 8 steps - accumulation of glycolipids, also oligosaccharides
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Defects in glycosphingolipid degradation
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ceramide (2HC chains: 1 sphingosine and 1 FA and carbohydrate chain).
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Drug-induced lysosomal storage disease (phospholipidosis)
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1) inhibit lysosomal phospholipase; 2) inhibit lysosomal enzyme transport; 3) enhance PL and CH biosynthesis
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Sphingolipid activator proteins (Saposin A B C D) functions
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Required for maximal breakdown of sphingolipids by specific lysosomal hydrolases. No B leads to GM1. No A leads to GM2. Storage disorder even though corresponding enzyme is normal.
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Misfolding proteins leading to storage disease
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PolyQ, Huntington's, neurodegenerative
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Amyloidosis
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buildup of amyloid (starch-like diverse protein group) - looks eosinophilic, hyaline under LM
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Special stain for Amyloid
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Congo red, polarized light --> red green birefringence
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Structure of Amyloid
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90% fibrils (A1-Amyloid light chain and AA-amyyloid, Prealbumin), 10% glycoprotein P
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Amyloid deposition look
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Enlarged organs, pressure atrophy, altered tissue function - can be systemic or localized
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Primary amyloidosis, AL (amyloid light chain) protein
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monoclonal B cell proliferation; AL fibril protein; overproduction of Ig light chains; in urine
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Secondary amyloidosis (chronic inflammation); AA (amyloid-associated) protein
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Cytokine secretion like IL01, acute phase reaction, Beta-2 amyloid protein in cerebral plaques and Alzheimer's
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Systemic amyloidosis
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Systemic amyloidosis deposits occur extracellularly between parenchymal cells and their blood supply
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Chronic deposition amyloidosis
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Between glomerular endothelial cells and podocytes alter filtering leads to large proteins in urine (renal amyloidosis, proteinuria, nephrotic syndrome, renal failure, uremia)
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Amyloidosis Mechanism
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Mostly amyloid derived from soluble precursor in circulation. Increased level of serum precursors, or genetic defect. Conversion of soluble precursors to insoluble form.
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Storage Disease in Lab
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HPLC for undegraded substrates, enzyme assays, skin biopsy, stain, PCR
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Hypoxia
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Decrease O2 for cell function; results in anemia; glycolysis can continue for some time
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Ischemia
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total loss of blood to tissue; vascular occlusion i.e. atherosclerosis; glycolysis can't continue
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Hydropic degeneration
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Main expression of cell injury; loss of water flow regulation across membrane due to reduced activity of Na/K pump
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With O2, OP stops, less Na/K pump, accumulation of Na in salt, cell swelling, more AMP activates anaerobic glycolytic enzymes... then...?
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Mitochondrial permeability transition (KEY EVENT) - damaged by Ca2+, oxidative stress, PL breakdown, pore
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Mitochondrial permeability and leakage of proteins leads to...?
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Ca2+ can influx and ROS gets into cell. Activates many enzymes leading to cellular degradation. Accumulate free radicals from reducing molecular O2.
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Effect of ROS (superoxide, hydrogen peroxide, hydroxyl anion)
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Membrane peroxidation, unstable and reactive peroxides, rupture cell membrane, oxidative modification of proteins, DNA damage
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Control of ROS
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Antioxidants, Fe and Cu binding proteins (Transferrin, Ferritin, Lactoferrin, Ceruloplasmin), Free radical scavenging enzymes (Catalase, SOD, Glutathione peroxidase)
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Final important aspect of cell injury: defects in membrane permeability...
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Decreased membrane PL leads to rupture; activated proteases degrade cytoskeleton; lipid breakdown products; rupture of lysosomes and release of enzymes triggers "wave of cell death"
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Histological changes in cell injury
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cell swelling (hydropic degeneration), fine lacy cytoplasm "moth eaten", fatty change, plasma membrane blebbing, loss of microvilli, dilation of ER
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Necrosis
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Highly eosinophilic (denatured cytoplasmic proteins), cells can calcify, enlarged cell size, leaky and damaged plasma membrane, inflammation, many affected
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Apoptosis
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Reduced cell size, always shrinking; intact plasma membrane; cytoplasm intact and apoptotic bodies; no inflammation; isolated cells
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Karyolysis
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Loss of chromatin basophilia due to DNase actions
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Pyknosis
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Nuclear shrinkage and increased basophilia
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Karyorrhexis
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fragmented pyknotic nucleus
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Coagulative Necrosis
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Gross and cellular architecture retained; due to hypoxia or acute toxicity; classically in kidney, muscle, and liver
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Dry gangrenous Necrosis
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Type of coagulative necrosis, dryness limits multiplication, ischemia from frostbite or fescue toxicity
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Liquefactive Necrosis
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Focal bacterial or fungal infections; loss of gross of histological recognition; only type in brain
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Caseous Necrosis, subtype of Liquefactive Necrosis
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Grossly amorphous granular debris; TB or related bacteria; often necrotic debris calcifies
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Fat necrosis, subtype of Liquefactive Necrosis
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Due to pancreatic enzyme release; released TGs combine with Ca2+ to form deposits (saponification, white areas); also from trauma
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Wet gangrenous necrosis, subtype of Liquefactive Necrosis
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invasion and putrefaction of necrotic tissue by saprophytic bacteria, retains moisture and warmth; i.e. aspiration pneumonia
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Examples of physiologic apoptosis
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Embryogenesis, hormone-dependent involution, cell deletion, death of host cells, elimination of self-reactive lymphocytes, cell death via cytotoxic T cells
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Pathologic processes involving apoptosis
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Radiation, anti-neoplastic drugs, viruses, duct ligation, cell death in tumors
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Apoptotic cell appearance
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More orderly & isolated shrunken cells, chromatin condenses, cytoplasmic blebs and apoptotic bodies, phagocytosis by macrophages
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What drives the apoptotic process?
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Caspases, endonucleases, expression of phosphatidylserine and thrombospondin
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Apoptosis Flow Chart
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Initiation phase: either extrinsic pathway (Fas/FasL & Caspase-8) or Intrinsic Pathway (Cyt C, Apaf-1, Caspase-9) to Execution Phase (Caspase 3, 6, 7)
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Intrinsic pathway blocking of apoptosis
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BCL2 in outer membrane of mitochondria can be released into cytosol to block Cyt C binding pores up.
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Pro-apoptotic members of Apoptosis
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BIM, BAX, BID, BAK (BIM & BID bind with high affinity to other BCL2 family members to increase apoptosis)
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Hyperemia
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Active, arteriole-mediated excess blood in vessels; can be physiologic due to increased tissue demand or pathologic due to disturbed blood flow, i.e. inflammation
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Congestion
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passive, venule-mediated excess blood in vessels, e.g. hepatic chronic passive congestion "nutmeg liver"; pulmonary congestion
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Hemorrhage
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Escape of blood from the CV system; can be diapedesis or rhexis
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Types of hemorrhage
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Focal or widespread (systemic cause, petechiae, body cavity hemorrhage is coagulopathy)
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Hemorrhage leads to
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Hypoxia, Hypovolemic shock, loss of function, Tissue death/ischemia; e.g. Pericardium cardiac tamponade
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Acute hemorrhage
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Vasoconstriction in attempt to stop bleeding; platelet plug and activation of clotting cascade
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Chronic hemorrhage
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Compensate for blood loss by making new RBCs, WBCs - extra medullary hematopoiesis; up regulate Hypoxia-Inducible Factors
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3 primary components for hemostasis (blood in fluid state and rapid formation of localized hemostatic plugs!)
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Blood vessels (endothelium and underlying CT), platelets, and pro- and anticoagulant plasma proteins
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General Control of Hemostasis/Thrombosis (4)
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1. Restrict coagulation cascade to PL surface; 2. Remove procoagulant factors by phagocytes & hepatocytes; 3. Maintain continual BF; 4. Endothelial pro/anti-coagulant properties
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Anticoagulant factors PGI2 and NO
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Inhibit platelet aggregation, cause vasodilation
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Anticoagulant ADPase
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Degrades pro-coagulant ADP
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Anticoagulant Protein C & S
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Degrade coagulation factors V & VIII
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Anticoagulant tPA
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Activates plasmin to digest fibrin
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Anticoagulant Thrombomodulin
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Binds thrombin and activates Protein C
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Anticoagulant Heparin-like molecules (GAGs):
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Cofactors for Antithrombin III activation
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Procoagulant PAF
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Recruits and activates platelets
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Procoagulant vWF
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Allows platelet binding to collagen to form primary hemostatic plug
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Procoagulant TF (III)
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starts extrinsic coagulation pathway to form secondary hemostatic plug
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Procoagulant tPA inhibitor
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Inhibits fibrinolysis (clot degradation pathways)
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Steps of Vascular Injury and Clot Formation (4)
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1. Vasoconstriction
2. Formation of Primary HP 3. Formatin of Secondary HP 4. Thrombus Formation and Clot Lysis |
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Step 1: Vasoconstriction
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Prevent more blood loss. Loss of endothelium exposes sub endothelial collagen and TF and vWF come along. Endothelial release of endothelia leads to reflex vasoconstriction.
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Step 2: Primary Hemostatic Plug
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Platelets adhere to vWF to form primary HP. Platelets do shape change, release granules (ADP, TXA2) into cytoplasm to recruit more platelets to the site.
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Step 3: secondary Hemostatic Plug
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Aggregate of platelets, coagulation cascade activated and TF released. Exposure of negatively-charged matrix (intrinsic). Polymerize fibrin.
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Step 4: Thrombus Formation and Clot Lysis
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Release of tPA (fibrinolysis) and Thrombomodulin (blocks coagulation cascade) leading to Plasmin.
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Main players of Step 2 of Primary HP (3)
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Platelets, vWF, granule contents (TXA2, PAF, ADP, Serotonin); Fibrinogen binds to GpIIbIIIa
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Activating factors for platelets:
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ADP, thrombin, TXA2, thrombospondin, Epi, PAF
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3 types of granules
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Alpha granules, dense bodies, lysosome
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vWF
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multimeric glycoprotein produced by endothelial cells and platelets; some bound to sub endothelial collagen, some circulating in complex with coagulation fVIII; aids platelet adhesion to vessels all by binding to ECM
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vWF disease symptoms
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Continuous bleeding, with normal Hct/platelet/WBC levels/chem/clotting tests; urinalysis = hematura
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ITP diagnosis
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Immune-mediated thrombocytopenia; clotting test normal except for BMBT; low CBC count 20,000
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Main players of Secondary HP
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Thrombin, Fibrin, Plasma proteins, Platelets, Ca2+, PL Surface
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Thrombin Formation and Fibrin Cleavage - Coagulation Cascade parts
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Extrinsic pathway main initiator, intrinsic pathway amplifies process - joining at Factor X
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Common pathway
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Starts at Factor Xa; Factor Xa and V make Thrombin (IIa) from Prothrombin (II). Thrombin causes formation of Fibrin.
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Factor II (Prothrombin) function, intrinsic pathway needs it from extrinsic pathway
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Made by common pathway, amplifies Intrinsic pathway (Factors XII, XI, IX, VIII + HMWK, PK)
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Intrinsic pathway
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Activate fXII, prekallikrein, HMWK upon contact with negatively-charged sub endothelial collagen; activate factors XII, XI & PK leading to cleave X to Xa; stimulates fibrinolytic, kinin, and complement inflammatory pathways!
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TF(III) + fVII + Ca2+ leads to?
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Activate fVIIa. Leads to Common (X) and Intrinsic (XI) pathways. Common ends with polymerization of fibrin (Ia) by Thrombin (IIa) and Fibrin-stabilizing factor (XIIIa)
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Platelets' Ca2+ function
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Links vitamin-K dependent factors to platelet PL; platelet PL membranes accelerate the activation of coagulation factors (PF3, IP3)
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Enzymatic factors, controlled by ATIII, circulate as proenzymes
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Contact factors: XII, XI, PK
Vitamin-K dep: II, VII, IX, X (PT/PTT) Clot-stabilizing factor: XIII |
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Non-enzymatic factors, acute phase proteins controlled by Protein C
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Limit coagulation cascade; I, V, VIII
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Intrinsic Pathway Abnormalities diagnosis
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Via PTT; Factors XII, XI, IX, VIII, X, V, II, I, PK, HMWK (NOT TF or VII)
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Intrinsic Pathway Abnormalities due to?
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Hemophilia A/B, Rodenticide, mild vWD
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Extrinsic Pathway Abnormality indicated by?
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PT; Factors I, II, V, VII, X
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Extrinsic Pathway Abnormalities due to?
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Rodenticide, hereditary fVII deficiency, DIC
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Prolonged PT; Normal PTT
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Liver disease, decreased vitamin K, decreased/defective fVII
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Normal PT; Prolonged PTT
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Decreased/defective fVIII/IX/XI, vWD, lupus anticoagulant present
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Both PT & PTT Prolonged
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decreased/defective fI/II/V/X, severe liver disease, DIC, Rodenticide
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Normal PT & PTT
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normal hemostasis, but can be normal with mild deficiencies
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Vitamin K in 2 different spots - Rodenticide?
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Factor VII has shortest half-life; with rodenticide toxicity all vitamin-K dep factors will be gone, but Factor VII will be gone first (PT elevated first)
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Thrombin
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36kD enzyme from cleaving Prothrombin; multiple binding site Na+ determines if inactive (binds to anticoagulant Protein C) or active
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Thrombin function
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Make fibrin from fibrinogen. Some vasoconstriction. Activate fV, VII, VIII, XI to generate more fibrin. Also fXIII to stabilize clot. Recruit and activate platelets, increases neutrophil adhesion.
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Fibrin forming phases
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Proteolysis (Fibrinogen with Thrombin to make Fibrin); Polymerization (fibrin monomer to polymers to urea-soluble fibrin); Stabilization (urea-soluble fibrin with fXIII and Ca2+ to cross-linked fibrin)
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Cell-Based Model centered on TF-bearing cells and platelets
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Initiated by circulating fVIIa binds TF on surface cell to make Xa, IXa, and Thrombin. Thrombin amplifies by activating platelets, cleaving vWF-fVIII complex to make Va, VIIIa, XIa; Propagation by activated coagulation factors aggregating on activated platelets; produce lots of Xa; Xa and Va produce thrombin; Xa inhibited when separated from platelet surface complex
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Overview of Secondary Hemostasis
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Adhesion & Stimulation (vWf to GpI; Thrombin, TXA2, ADP onto clot); Secretion & Conformational change; Coagulation Cascade (fibrinogen to fibrin); Aggregation (cross-link); Retraction (conformational changes tighten secondary HP)
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Formed Thrombus & Antithrombotic Effects, deals with:
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ATII, Protein C, Plasmin, FDPs, TFPI
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Antithrombin (ATIII)
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80% of plasma anticoagulant activity; major inhibitor of Thrombin (IIa) & Xa, also IXa, XIa, and XIIa; active on endothelial surfaces; irreversibly binds to Thrombin; catalyzed by heparin 2000x; lost in glomerular disease; Heparin-Thrombin CANNOT inhibit Fibrin-Bound Thrombin!
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Protein C
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Major inhibitor of Va & VIIIa (negative feedback to Thrombin); Vitamin K dependent; activated by Thrombomodulin (IIa) with Protein S
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Plasmin
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2 functions: fibrinolysis, inhibition of fibrin polymerization; activates Kinin & Complement pathways; activated by Plasminogen activators (tPA, uPa)
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Types of Plasminogen activators
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tPA made by endothelial cells, most active when bound to fibrin, clots secrete tPA, plasmin chops up fibrin and gets rid of clot; uPA made by many cells especially macrophages; less susceptible to inhibition than tPa; also bacteria-derived PA (inhibited by alpha-2-antitrypsin & PAIs)
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TFPI
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TF Pathway Inhibitor: inhibits extrinsic pathway
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FDP
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Fibrin Degradation products - results from plasmin digestion of fibrin; bind to thrombin; weak anticoagulants D dimers; specific for lysis of fibrin
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Phagocytes in Anticoagulation
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Degrade and digest clots after injection
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General Clot Formation and lysis
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Vasoconstriction, activate platelets and form primary HP, activate coagulation cascade and form secondary HP, thrombus formation and clot lysis; all overlap and processes going on simultaneously; pathologic sequelae; diagnostic tests; clinical presentations; breed predispositions
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Virchow's Triad leading to pathological thrombosis
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Altered blood flow, endothelial damage, hyper coagulability
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altered blood flow: turbulence and stasis
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Increased contact between platelets and endothelium, activation of endothelial cells, impaired clearance of clotting factors, less anticoagulant factors around
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Altered blood flow examples
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Immobilization, shock, congestive heart failure, polycythemia, hyper viscosity, GDV, aneurysm, diarrhea, DV thrombosis, heart disease, vessel obstruction, recumbency
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Endothelial damage - MOST IMPORTANT INFLUENCE in Triad
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Exposure of sub endothelial collage, release of TF, alteration of endothelial properties
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Alteration of endothelial properties examples
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E. coli and hemolytic uremic syndrome in people, rat with polyarteritis nodosa, immune-mediated disease, vitamin E/Se, DIC, Alabama rot of greyhounds
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Hypercoagulability - sticky platelets, no fibrinolysis
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Anticoagulant deficiency (Protein C, ATIII), Enhanced platelet activity (diabetes, heartowrm, neoplasia), metabolic abnormalities (Cushings increases clotting factors, hypothyroidism, diabetes), congenital and acquired disorders leading to increase or decrease in fibrinolysis, ATIII loss in renal protein loss in chronic glomerular disease, glomerular disease, sepsis, DIC, pancreatitis
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Examples of Thrombosis
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Heartworm: turbulent blood around, chronic intimal proliferation, abnormal endothelial surface, hyper coagulability; hypertrophic cardiomyopathy: thick LV, blood backs up to LA, dilate and stretch; clot in LA, embolism, saddle thrombus
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Fate of Thrombosis
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Fibrinolysis/dissolution (chronic thrombi more resistant), embolism, propagation, organization
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Factors associated with thrombosis
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Pulmonary thrombosis/thromboembolism, hypoxemia (V/Q mismatch), atelectasis, edema, CV compromise
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Infarction
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Regional ischemic necrosis of tissue, secondary to thrombosis
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Susceptibility of infarction depends on (3)
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metabolic demands of tissue, vascular supply, cardiac output
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Red vs. white infarction
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Red: venous occlusion, spongy, collateral circulation, reestablished blood flow to a previously-occluded organ; vs. White: arterial, solid organs, all drained out, end-arterial circulation of spleen, heart, kidney
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Ischemic injury: less ATP with ischemia leads to...
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Loss of Na+ pump, swelling, increased anaerobic glycolysis, lactic acid buildup & acidification, detachment of ribosomes, reduces protein synthesis, lipid deposits
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Reperfusion injury
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Restoring blood flow, more O2, ROS. Ischemia's loss of ATP leads to HX. HX with Ca2+ causes XO. mito damage. Once circulation is restored, HX gets converted into uric acid. Also makes ROS. damage to cell. Also loss of defense mechanisms, inflammation can increase cytokine production for more free radicals, complement system activation due to deposited IgM.
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Primary hemostatic disorders (platelets)
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Defect in platelet arm of coagulation - petechiae, ecchymosis, gingival bleeding, prolonged bleeding, hematuria, melena, hyphemia, measure with BMBT
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Causes of primary hemostatic disorder
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thrombocytopenia (decreased production of platelets from toxicity, disease, neoplasm, sequestion by spleen, increased platelet consumption with disease); bone marrow toxicity cattle bracken fern and phenylbutazone in horses
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vWD
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inherited, vWf decreased/absent; variable severity; platelet #s and intrinsic function normal
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Glanzmann's Thrombasthenia
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Platelet weakness - deficiency in fibrinogen receptor (IIb/IIIa) in G. Pyrenees, Otterhounds
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Other platelet defects, defect in platelet aggregation - what's Chediak-Higashi syndrome?
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Less platelet ADP storage, mink/cattle/Persian cats/whales
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Examples of primary hemostatic disorders in LA
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Horses: EVA, EIA, Ehrlichiosis, purpura hemorrhagica, HS or immune-mediated; Ruminants: malignant catarrhal fever (MCF), bluetongue (BT), pigs with classical and african swine fevers
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Evaluation of primary hemostatic disorder
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Significant low platelet count, anti platelet Ab assays if ITP; more than 4 min BMBT (increased with vWD, DIC, thrombocytopenia, uremia, scurvy, platelet function defects (i.e. Glanzmann's); BMBT normal with secondary hemostatic coagulation factor issues; platelet aggregation; clot retraction
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vWF assay
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Diagnose vWD & differentiate from Hemophilia A (vWF carrier protein for fVIII)
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Secondary hemostatic bleeding disorder
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Hematomas, bleeding in body cavities, delayed bleeding from venipuncture sites
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Causes of secondary hemostatic disorder
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defect in fibrin polymerization, liver disease leading to less plasma coagulation factors and inhibitors, congenital abnormalities of clotting factors, inherited vitamin K deficiency
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Congenital abnormalities of clotting factors by pathway
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Intrinsic pathway (XI, IX, VIII), Common pathway (I, II, X), Hemophilia types: A with VIII, B with IX, C with XI
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Inherited Vitamin K deficiency, can be acquired
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Rambouillet sheep, Devon Rex cats, most common secondary coagulation disorder, impaired activation of fII, VII, IX, X, Protein C & S by liver (redox cycle of K interrupted)
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Acquired Vitamin K deficiency
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Anticoagulant rodenticides containing vitamin K antagonists; LA eating dicoumarol on mold-tainted feed, especially sweet clover
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Diagnostic tests for secondary hemostatic disorders (first rule out platelets with count & BMBT)
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PT, PTT< ACT, TCT, FDPs, ATIII assay, PIVKA
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PT
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Extrinsic and common pathway; hereditary fVII deficiency, vitamin K deficiency, DIC, <30% to prolong
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PTT
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Intrinsic and common pathway; hereditary fXII/XI/IX/VIII deficiency; vWD (fVIII deficiency); vit K defic; DIC; heparin therapy - <30%
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ACT = activated clotting time
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Intrinsic & common <5%
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TCT = thrombin clotting time
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Hypofibrinogenemia - also in DIC, can be hereditary
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Mixed hemostatic disorder - best example DIC - always SECONDARY to process
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primary physical lesion: thrombotic occlusion of small and mid-sized vessels' resultant hypoxia and metabolic derangement; TF release, multi systemic organ failure
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Primary processes in DIC
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Sepsis (gram negative), Trauma, Neoplasia, Vascular disorders - widespread abnormal self-perpetuating activation of BOTH clotting & fibronolysis!
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Uncontrolled thrombin generation in DIC
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Driven by TF/VIIa; probably from release of TF from cytokine-stimulated mononuclear cells
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DIC other symptoms
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Decreased/depletion of coagulation inhibitors like ATIII and TFPI; decreased fibrinolysis by increased PAI; RBC sheared leading to increased thrombin leading to increased plasmin and fibrinolysis
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Review of DIC
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Fibrin thrombin; platelet aggregation; thrombocytopenia; massive tPA release; excess inflammation & cytokines; more TF release; altered fibronolysis; impaired anticoagulant pathways; thrombin inactivated by excess FDPs; multisystemic infarction; RBC lysis - massive TF release - no single test
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Endothelium lining functions in acute inflammation (4)
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Blood flow through capillary beds; intravascular coagulation status; leukocyte adhesion; leukocyte transmission
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PT
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Extrinsic and common pathway; hereditary fVII deficiency, vitamin K deficiency, DIC, <30% to prolong
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PTT
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Intrinsic and common pathway; hereditary fXII/XI/IX/VIII deficiency; vWD (fVIII deficiency); vit K defic; DIC; heparin therapy - <30%
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ACT = activated clotting time
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Intrinsic & common <5%
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TCT = thrombin clotting time
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Hypofibrinogenemia - also in DIC, can be hereditary
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Mixed hemostatic disorder - best example DIC - always SECONDARY to process
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primary physical lesion: thrombotic occlusion of small and mid-sized vessels' resultant hypoxia and metabolic derangement; TF release, multi systemic organ failure
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Primary processes in DIC
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Sepsis (gram negative), Trauma, Neoplasia, Vascular disorders - widespread abnormal self-perpetuating activation of BOTH clotting & fibronolysis!
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Uncontrolled thrombin generation in DIC
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Driven by TF/VIIa; probably from release of TF from cytokine-stimulated mononuclear cells
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DIC other symptoms
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Decreased/depletion of coagulation inhibitors like ATIII and TFPI; decreased fibrinolysis by increased PAI; RBC sheared leading to increased thrombin leading to increased plasmin and fibrinolysis
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Review of DIC
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Fibrin thrombin; platelet aggregation; thrombocytopenia; massive tPA release; excess inflammation & cytokines; more TF release; altered fibronolysis; impaired anticoagulant pathways; thrombin inactivated by excess FDPs; multisystemic infarction; RBC lysis - massive TF release - no single test
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Endothelium lining functions in acute inflammation (4)
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Blood flow through capillary beds; intravascular coagulation status; leukocyte adhesion; leukocyte transmission
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5 classic signs inflammation
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rubor, calor, tumor, dolor, functio laesa
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sequence of events acute inflammation (6)
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1. transient vasoconstriction
2. vasodilation 3. increased BF 4. increased vascular permeability 5. hemoconcentration 6. leukocyte trafficking (leukocyte margination, firm adhesion, extravascular emigration) |
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3 barriers of leukocyte to trafficking
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Endothelial cell, endothelial cell BM, Pericyte
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types of capillaries
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Continuous (CNS, TJs, with caveolae), fenestrated (kidney, liver, spleen), and intermediate
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Starling's Equilibrium: balance of filtration and absorption pressure across a capillary wall - 3 requirements
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1. intact functional blood vessels
2. intact functional lymphatics 3. protein concentration |
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4 measurable forces in Starling's Equilibrium
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1. plasma hydrostatic pressure (30 to 17)
2. tissue osmotic pressure (10) 3. tissue hydrostatic pressure (-8) 4. plasma osmotic pressure (-25) |
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Plasma hydrostatic pressure, i.e. BP
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Pushes fluid out of tissue on arteriolar side, pushes it into tissue on venous side.
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Tissue osmotic pressure
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Pushes fluid out, glycoproteins suck water, move fluid from intravascular to extravascular space
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Tissue hydrostatic pressure
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Draws fluid INTO vessels
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Plasma oncotic pressure
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Albumin draws fluid INTO vessels
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Causes of edema! (4)
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1. Increased vascular permeability
2. Lymphatic obstruction 3. Increased plasma hydrostatic pressure 4. Decreased plasma oncotic presure |
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Increased vascular permeability
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Acute inflammation, fluid leaks out, not as much reabsorbed at venular end due to mild tissue damage, severe tissue damage, perivascular fluid overwhelms capacity of regional lymphatics, edema
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Lymphatic obstruction
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Excess fluid into vessels, most commonly surgical; transection of lymphatic vessels; edema
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Increased plasma hydrostatic pressure
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Due to venous obstruction, thrombus, heart failure - more fluid OUT of vessels, less reabsorbed on venous end
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Decreased plasma oncotic pressure
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Less fluid INTO vessels, renal los, decreased synthesis (chronic liver disease), more fluid leaving arteriolar side, less reabsorbed venular end, lymphatics overwhelmed; edema
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Mast cell in acute inflammation
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Histamine, Heparin, Proteases; Fc-gamma receptors for IgE and C5a; degranulation; anaphylaxis
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Macrophages/Monocytes/DCs
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In tissues everywhere, surface Fc & C3b receptors for phagocytosing opsonized bacteria; have pathogen recognition receptors (TCRs, mannose receptor, NOD, etc); most important in acute inflammation is pro-inflammatory IL1 & TNF-alpha = Type II endothelial actiation
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Neutrophils - first line of defense
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Acute tissue damage, eliminate invading bacteria; myeloperoxidase; primary granules; oxygen-dep or indep (both macrophages and neutrophils)
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O2 radical system
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Of neutrophils and macrophages
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Myeloperoxidase-halide system
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Of neutrophils and macrophages - use H2O2 and 2Cl- to make HOCl (bleach)
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Secondary granules - O2 independent
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Lysosyme (hydrolyze bacterial cell wall); Cathepsin G and definsins (protease against bacteria), Lactoferrin (interfere with bacterial respiration)
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Eosinophils - against extracellular parasites
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Fight against parasite infection; receptors for IgG, IgE, and C3b; MBP, eosinophilic cation protein; eosinophilic peroxidase; allergies asthma, rhinitis, conjunctiviits
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Basophils - mast cells of the blood
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also have Fc-gamma and IgE receptors; heartworm; cros-link IgE to degranulate, release histamine too
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Platelets stop leaks
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Alpha-granules PF4/antiplasmin, dense granules ADP & serotonin; bind to areas of blood vessel damage where BM has been denuded, release granules
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How Platelets contribute to Inflammation (5)
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1. Vasodilation, increased vascular permeability (serotonin, TXA2)
2. Adhesion molecules (P-selectin) 3. Chemokines (MCP1) 4. Leukocyte activation (CD40L) 5. Activate clotting cascade with fIV and Fibrinogen |
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Inflammatory mediators sources
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From plasma proteins (inactive, inflammation, proteolytic cleavage), or from cells (granules of His or serotonin, de novo PGs, LTs, cytokines)
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Vasoactive amine Histamine
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Type I endothelial activation, vasodilation, H1R = NO, H2R = relax smooth muscle; increased vascular permeability (PAF), adhesion molecules
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Vasoactive amine Serotonin
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Type I endothelial activation, vasodilation via SM relaxation, increased vascular permeability, adhesion molecule
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Vasoactive amine NO
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eNOS: at rest vasodilation and reduced leukocyte adhesion to endothelium
iNOS: macrophages make excess NO, to peroxy-nitrite |
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Plasma proteases complement system mediators
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C3a, C3b, C5a
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C3a
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activate mast cells for His release, vasodilation, increased vascular permeability, weak leukocyte chemotaxis, adhesion, LT production
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C5a
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activate mast cells for His release, vasodilation, increased vascular permeability, leukocyte chemotaxis, LT production
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C3b
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opsonization
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Kinin cascade
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fXIIa gets kallekreine to bradykinin (vasodilator causing pain, contracts visceral smooth muscle). Kalekrein activates complement cascade (C3C) and feedsback on XII to XIIa
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Plasmin of clotting cascade breaks down fibrin to connect to complement?
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Fibrin breakdown into FDPs that increase permeability and chemotaxis
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Activates complement cascade
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Thrombin, kallekreine, and plasmin
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Arachidonic acid metabolites
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Breakdown PLs with PLA2 to make arachidonic acid
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PLA2 inhibited by?
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Inhibited by corticosteroids (no AA formation)
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COX
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COX1 constitutive; COX2 inducible, elevated during inflammation - make PGG2 from AA to PGH2
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PGH2 into either PGI2 (vasodilation, block platelet agg) or TXA2 (vasoconstrictor, platelet agg)
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Specific COX2 inhibitor only blocks it (NSAIDs block both), best choice to knock down enzyme without inflammation, without producing PGs (less ulcers, cytokines, renal damage)
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5-LO takes AA to make 5-HPETE (chemotaxis)
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HPETE can make LTs that are important in asthma; LTB4 only glycosanoid that is chemotactic and activates neutrophils
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LTs
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vasoconstriction, increased vascular permeability, bronchospasms (think asthma)
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LTs into Lipoxins LXA4 & LXB4
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inhibit neutrophil chemotaxis and adhesion, while promoting that of monocytes and platelets!
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PAF, Platelet Activating Factor
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made by Neutrophils, basophils, monocytes/macrophages, endothelial cells and platelets; stimulates leukocyte adhesion, chemotaxis, degranulation, short-lived
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What stimulates PAF production?
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C5a, thrombin, Ag binding to surface-bound IgE
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High PAF
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Platelet activation and aggregation, vasoconstriction, bronchoconstriction
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Low PAF
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Vasodilation, increased vascular permeability
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Cytokines
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SMW proteins, involved in acute reps inflammation - produced by most all nucleated cells, appropriate receptor, pro or anti-inflammatory, target cell can have multiple cytokine reeptors
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Tip of inflammation cascade
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TNF-alpha and IL-1 made by macrophages and DCs, activate endothelium ate site of inflammation for Type II endothelial activation (autocrine, paracrine, endocrine)
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Type II endothelial activation on body, TNF-alpha and IL-1
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RA, psoriasis, MS, IBD - brain, liver and CV system (lower BP, circa shock, neutrophilia), adrenal (ACTH, corticosteroids), macrophages & DCs (cytokines, phagocytosis, upregulate costimulatory molecules, ROS)
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IL-8
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made by endothelial cells, stored in preformed Weibel Palade bodies, can be made by other cells, Neutrophil recruitment and activation, wave of neutrophil influx into acutely inflamed tisue
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IL-6 (suppresses IL-8, increase MCP-1)
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made by macrophages, lymphocytes, fibroblasts, and SM cells - transition from neutrophilic to mononuclear cell infiltrate; acute phase response in liver
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IL-23
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made by DCs; activate Th17 leukocytes to make IL-17
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IL-17
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Stimulate leukocytes to make GCSF and IL-8 by endothelium, feedback, neutrophil chemotaxis
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Histamine
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Made by mast cells and basophils, vascular leakage, no chemotaxis
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Serotonin
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Made by platelets, vascular leakage, no chemotaxis
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Bradykinin
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Made in plasma, vascular leakage, no chemotaxis; Pain
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C3a
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Made in plasma, vascular leakage, chemotactic to mast cells
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C3b
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Made in plasma, no vascular leakage, no chemotaxis; Opsonization
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C5a
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Made in plasma, vascular leakage, chemotactic to leukocytes; leukocyte adhesion and activates mast cells
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PGs
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Made by leukocytes and mast cells; Potential vascular leakage, Vasodilation, pain, fever
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TXA2
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made by platelets; vasoconstriction and platelet aggregation
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LTB4
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Made by leukocytes and mast cells; chemotactic to neutrophils, adhesion and activation
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LTs
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made by leukocytes and mast cells; vascular leakage; vaso- and bronchoconstriction
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O2 species
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Made by leukocytes; vascular leakage; Endothelial, tissue damage
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PAF
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Made by leukocytes and mast cels; Vascular leakage; Chemotactic; Bronchoconstriction
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IL-1 & TNF-alpha
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Made by Macrophages; Endothelial activation and fever
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Chemokines
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made by many cells; chemotactic to leukocytes, activate htem
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NO
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Made by macrophages and endothelium; Vasodilation and cytotoxicity
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Endocytic pattern recognition receptors
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Innate immune response cells; macrophage mannose receptor and scavenger receptor
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TLR4
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Expressed on cell surface of extracellular bacteria, from LPS from gram negative cell walls, viral glycoproteins, also in plasma membrane of endosomes (intracellular pathogen), TLR4 & CD14
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NOD family
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intracellular recognition of peptidoglycan muramyl peptide leading to cell activation and cytokine production
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RNA helicase
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Cytosolic proteins; intracellular recognition ds viral RNA; leading to cell activation and cytokine production
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MBL
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Made by liver, binds to mannose residues on bacteria
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Surfactant proteins A & D
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clear organisms by alveolar macrophages, clear naked DNA/RNA, mice w/o = SLE
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Adjuvants
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Bacteria from it stimulate macrophages to deliver co-stimulatory signal to T cells recognizing non-bacterial antigen; proliferate T cells specific for non-bacterial protein
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Leukocyte Trafficking
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1. Capture
2. Rolling 3. Slow Rolling 4. Arrest 5. Adhesion, Strengthen, Spreading 6. Intravascular crawling 7. Transcellular Migration 8. Paracellular Migration |
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1 & 2 - Capture and Rolling
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Selectins, bind to PSGL1
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3 - Slow Rolling
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Integrins (Beta-2 integrins most important, bind with ICAM-1 and ICAM-2; intermediate)
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4 - Arrest
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Chemokines; stimulate cell activation and promote firm adhesion of leukocytes at inflammation sites
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5 - Adhesion, Strengthening, Spreading
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Integrin clustering & signaling (high affinity LFA-1 molecules)
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6 - Intravascular Crawling
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Chemokine gradient; signals through ICAM-1 promote further endothelial activation
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8 - Paracellular Migration
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5min; between adjacent endothelial cells; molecular zipper of adhesion molecules
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7 - Transcellular Migration
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20%; <1min; common for TJs and CNS; caveolae
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PGI2 & NO endothelial function in health - quiescent tissue
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PGI2: induced by COX-1 expression; NO to relax vascular smooth muscle, prevent platelet & leukocyte adhesion
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Mild tissue damage: Type I endothelial activation
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His, rapid, short-lived, No protein synthesis, vasodilation, increased vascular permeability; NO, PGI2, IL-8
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Severe tissue damage: Type II endothelial activation
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Slower, protein synthesis, longer-lasting, TNF-alpha and IL-1, endothelial activation, Bradykinin, FDPs, C3a and C5a, PGI2, serotonin, TXA2, less NO, balance of PGI2 and TXA2
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Multiple places to BLOCK leukocyte homing with specific drugs
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Block selections, chemokine receptors, integrins
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