Section 1
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What are the 4 types of anatomic pathology
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Section 1
(50 cards)
What are the 4 types of anatomic pathology
Gross Microscopic Developmental (teratology) Molecular
What is autophagy
self-degradative process important for balancing energy sources
What is a thrombus
It is a solid mass of coagulated blood within the vessel, often forms on atherosclerosis plaques (the fibrous cap can rupture exposing collagen and thus induces a clot which can occlude the vessel)
Basophil
2 lobed nucleus, large dark purple granules Can bind IgE Releases histamine, leukotrienes Often increase in number during allergic reaction Thought to be an APC to drive Th2 responses > 0.1% PBMC
Monocyte
Mononuclear, kidney shaped nucleus, large 20-40 hr cirulcaiton time-turns to macrophage in tissue (long lived)- phagocytosis, APC, releases cytokines (TNF-alpha and IL-1) important for inflammation 2-10% of PBMC
where would transitional epithelium be found
bladder, ureters: allows cells the stretch to accomodate changes in volume of urine
Causes of hypoxia
-low PO2 -bleeding -anemia -CO poisoning (CO binds Hb which stops it from releasing O2 to the tissue)
Mucosa structure
The structure will vary along the GI tract depending on the function of the area Oesophagus- needs to be protective so has stratified squamous epithelium Small intestine- absorptive so has villi (simple columnar cells with microvilli and goblet cells
What are the mechanisms of cell injury at the molecular level
- reduced ATP (lack of O2) = loss of energy dependent processes -membrane damage = mitochondria (cell death), lysosomes ( enzymatic digestion), Plasma membrane (loss of cellular contents) -Calcium influx and reactive O2 species causes protein breakdown and DNA damage
What are the layers of the GI tract
1. Mucosa: epithelium, lamina propria, muscularis mucosa 2. Submucosa 3. Muscularis propria- inner circular layer and outer longitudinal layer 4. Adventitia
What colour does H and E stain
H = stains nucleic acids/nucleus blue E = stains elastin, collagen and cytoplasm pink
where would simple columnar epithelium be
in the gut (colon): important for ion transport
Neutrophil
2-5 lobed nucleus, small pink-purple granules Recruited by chemokines (IL-8) to area of damage to phagocytose invaders/damaged tissue. Have complement receptors on surface to detect pathogens 40-70% in blood Die after 24-72 hours in tissue
RBC
pink-red biconcave disc, anuclear Transports O2 and CO2 via Hb
What and an embolism
When part of the thrombus detaches and flows downstream and becomes lodges in a vessel
What are the types of leukocytes
Granulocytes = basophils, eosinophils, neutrophils Monocytes Lymphocytes = B, T, NK cells
What colour does Van Geisen stain
stains elastin black and other connective tissue pink
What are types of connective tissue and there features
Adipose: loose, chicken wire structure, designed to hold lipids Bone: dense and highly organised (osteons), strong and rigid Tendon: elongated fibres to transmit force, flattened cells, high collagen content (pink) Blood: contains lots of cells with different functions
Overall function of epithelium
It covers every exposed surface of the body -protective function against: mechanical damage, fluid loss and invasion of foreign bodies -metabolite function: metabolite exchange and glandular secretion
Where would you find simple squamous epithelium
aveoli: allows for gas exchange
Vein vs Artery
Vein: (low pressure) irregular shape, wider lumen , thinner wall due to less smooth muscle, elastin and collagen Artery: (high pressure) regular shape, smaller lumen and thicker wall due to more smooth muscle, elastin and collagen
What colour does Masson's trichrome stain
Stains collagen blue
What are the types of tissue in the body
Epithelium Connective Muscle Nevous
What does PAS stain
glycogen magenta
What does oil red O stain
lipids bright red and nuclei blue
Eosinophil
2-3 lobed nucleus, large orange-red granules Present in allergic reactions Defence against parasites= toxins in granules (major basic protein, eosinophilic cationic protein and peroxidase) to control parasite infections Phagocyte >1% PBMC
Dendritic cell
Large and have dendrites (long arms) 1-2% PBMC Main APC Phagocytose Potent at activating T cells through antigen presentation
Lymphocyte
Cant differntiate B and T cells from morphology Large nucleus with little cytoplasm, variable shape and size B cell= antibody T cell= CD4- helper cells and secrete cytokines, CD8- induce apoptosis 20-40% PBMC (T cells = 60-80% B cells = 15-30%) NK cells: Large, granular 5-10% PBMC Activated when they detect low expression of MHC-1 and they induce apoptosis (important for viral infection) They recognise antigen presented on CD1d (non-classical MHC) which causes them to produce lots of cytokines
What does adaptation or cell injury depend on
It is a balance between dose intensity (severity of injury) and cell vulnerability (type of cell). Stress on a cell increases demand and a cell may adapt or it can become injured. Cell injury is reversible, leading to adaptation but if the injurious stimuli continues than the cell will die (necrosis) and this is irreversible
homocide vs suicide of cells
homocide= many cells die at once suicide+ one cell
What are the results of ischemia
1. MI 2. Stoke 3. Gangrene e.g frostbite 4. Ulceration 5. Death
In what layer of the BV does atherosclerosis develop
Develops on the endothelium of tunica intima
Layers of BV
1. Tunica Intima: endothelium and supporting tissue 2. Tunica media: smooth muscle 3. Tunica Adventitia: collagen for attachment and strength Internal elastic lamina: seperates intima and media External elastic lamina: seperates media and adventitia
Where would pseudostraitifed columnar, ciliated epithelium be
Structure determines function: Respiratory tract (trachea, larynx): important so cilia can clear mucus that traps foreign material
What is the purpose of path
1. Cause 2. Pathogenesis (mechanism of developement) 3. Structural alteration of cell 4. Consequences of these changes
What is senescence
cells can't divide or grow
Types of epithelia
Squamous- simple/stratified Cuboidal- simple/stratified Columnar- simple/pseudostratified Transitional
what are the types of muscle and there defining features
1. Skeletal: striated, nucleus at ends of cells 2. Cardiac: ICDs, nucleus in middle of cells 3. Smooth: spindle shaped cells
Platelet
small, pale purple-blue fragment with small purple granules Blood clotting
What are the 3 types of microscopes and there magnification
Light micrograph = 300x Transmission electron micrograph (TEM) = 1700x, 2D Scanning electron micrograph = 2600 x, 3D
where would stratified squamous epithelium be
mouth, oesophagus, skin (keratinsed): important for protection
What is necrosis
area of cellular death
What is an infarct
Cellular death due to lack of blood supply (ischemic necrosis) e.g MI, stroke
What does silver stain
nerves black
What is Ischemia and the causes
Loss of blood supply to a tissue due to a blocked blood supply.- hypoxia -vessel blockage (vasoconstriction or atherosclerosis) -Thrombus -embolism
Where would simple cuboidal epithelium be
renal distal tubules, salivary glands: protects from excessive water loss due to semi-permeability, also protects from abrasion
What are causes of cell stress or injury
-chemical -physical -infectious -hypoxia -genetic -nutritional -immunologic
What are the tools of path
Gross= autopsy Microscopic = histology Molecular = cell isolation and culture
What can we use to recognise cell injury
1. Biopsy: can use electron microscopes (SEM, TEM) to look at mitochondrial swelling and rupture 2. Gross changes: autopsy, surgery, clinical 3. Blood tests: cell products released into blood stream (e.g troponin-t is specific to heart muscle and is released during MI) 4. Decrease in cell function: e.g if have liver failure may bleed internally 5. Radiology, US, CT, MRI
Section 2
(50 cards)
What are the 3 lines of defence against pathogens`
First line = skin Second line= innate immunity Third line- adaptive immunity
What are the 5 processes for innate immunity
-activation of compliment cascade -phagocytosis -acute phase proteins -NK cells
what are the basic steps from a cut to a scab
1. Cut penetrates the epidermis barrier and bacteria invade 2. Damaged cells releases PGs, leukotrienes and histamine (chemokines) 3. PGs and leukotrienes = increase vascular permeability Histamine = causes vasodilation 4. Macrophages and neutrophils squeeze through the walls of the BVs 5. Antimicrobial chemicals and clotting proteins seep into the damaged tissue = swelling and causes pressure on nerve endings and pain 6. blood clot forms 7. more phagocytes migrate to the site engulf bacteria 8. accumulation of damaged tissue and leukocytes forms pus 9. undifferentiated stem cells repair the damaged tissue. Blood clot is absorbed or falls off as a scab
What is coagulative necrosis
Type of necrosis where the underlying tissue structure is preserved for several days but cellular detail is lost. This is because both structural proteins and enzymes are denatured so the enzymes cant break tissue down Cells will be anuclear and pinker (eosinophilic) Predominance of protein denaturation. Leukocytes will be recruited to the area and will digest the dead cells by lysosomal enzymes and the cellular debris will then be phagocytosed. It is a characteristic of infarcts in all solid organs except the brain
What is the compliment cascade
a series of 9 major protein at act to clear potentially pathogenic material. 1. opsonisation 2. chemotaxis 3. MAC-cytolysis C3 and C5 are cleaved to C3a + C3b and C5a +C5b. C3b: opsonises microbe which speeds up phagocytosis C3a and C5a: recruits and activates leukocytes and causes degranulation of mast cells (histamine and leukotrienes) C5b-9 forms MAC complex= cytolysis
How does inflammation limit damage
• Kills infective organisms • Removing debris that remains when cells are damaged or die Triggering the immune response (via antigens presented on the surface of macrophages) • Initiating repair (Triggered by cytokines produced by macrophages) • Allowing antibodies, fibrinogen & other proteins into the area
What is blood cancer
It is a group of malignant disorders, where the malignant leukocytes grow and accumulate in the marrow. The effect depends on the type of cell affected. Granulocytes and lymphocytes often spill into the blood = leukemia Lymphoma= lymphocytes occupying lymph nodes Myeloma= plasma cells stay in marrow
How does an antibody activate compliment
C1 binds to antibody and then C4 and C2 bind- C4 and 2 get cleaved which creates enzymes to cleave C3 and 5
What is caseous necrosis
Happens during chronic inflammation Looks cheesy- friable, yellow/white TB The tissue architecture is completely destroyed and no cell outline can be seen, eosinophilic, lysed cells The area of necrosis is often enclosed in a distinct inflammatory border (granuloma)
What is malignant disease
Genetic mutations enhance growth signals and inactivate stop signals, resulting in uncontrolled growth and the cells that dont die will proliferate (clonal proliferation) .When the clone is big enough it can replace normal marrow (bone marrow failure) and infiltrate into other tissues where they replace and destroy normal cells
What is hyperplasisa
It is an increase in the number of cells due to an increase in demand Can happen with hypertrophy Physiological: hormones causing breast growth during puberty and lactation) Pathological: cancer
what are the 3 ways to activate compliment
Classical- antibody Alternative- toxin Lectin-sugar
what is the function of TNF-alpha
-Leukocyte recruitment and activation by up-regulation of adhesion factors (selectins and integrins) allowing WBCs to stick to the surface of endothelial cells and diapedesis out to the area of damage - induces fever -increased synthesis of CRP, fibrinogen and serum amyloid A protein (SAA)
What is necrosis
Necrosis is when cells die due to a pathological process. The cell swells and the nucleus undergoes pyknosis (condensing), karyorrhexis (fragments) and karyolysis (fading). The cellular contents are enzymatically digested and leak out. Necrosis will happen to many cells so is noticeable in the tissue and will produce and inflammatory response
What happens during alcohol abuse to the liver
You get a fatty liver due to steatosis-accumulations of lipid droplets in cytoplasm. Liver becomes large, pale and greasy but does maintain overall structure
What pathway results in the most compliment product produced
Antibody pathway because it produces more enzymes = more C3 and 5 cleaved
What are the causes of acute inflammation
-infections -ischemia -trauma -toxins -burns -extreme cold -ionising radiation
What are the major stem cells for blood cells and what do they differentiate into
Myeloid = monocyte, RBC, granulocytes, megakaryocyte Lymphoid = B + T cells, NK cells
What is acute inflammation
It is a protective response that limits tissue response by: -phagocytosing and killing infective organisms -removing debris that remains when the cells are damaged or die -initiating repair -allowing antibodies, fibrinogen and other proteins into the injured area -Has little specificity -same reaction each time -no memory -innate immunity
What factors determine the pattern of necrosis
It is a balance between protein denaturation (favors coagulative) and enzyme action (favors liquefactive)
What is eosinophilia
Increase in eosinophils IL-5 from T cells, mast cells and macrophages stimulate production -allergic disorder -parasite infection -drug allergic reaction (hypersensitivity) -malignant diseases of myeloid cells
What are the 2 types of cell death
Necrosis Apoptosis
What are the acute consequences of myocardial cell death (MI)
-arrhythmia -loss of integrity causing a rupture -loss of function: those cells can no longer contract to pump blood -thrombus formation: emboli could then travel to the brain causing a stroke
What is the function of IL-1
-increases temp -increases expression of adhesion factors on endothelial cells
What is hypertrophy
Increase in cell size due to an increase in demand or hormones, however there is a limit to this because it will lead to necrosis if the cells get too big. Can be physiological or pathological E.g Heart muscle due to increase in demand such as hypertension Type 2 diabetes: increase in size of adipocytes (obesity)
What is liquefactive necrosis
Transformation of necrotic tissue into a liquid viscous mass. Happens in focal bacterial and sometime fungal infections- the microbes cause accumulation of inflammatory cells and the action of there enzymes digests and liquefies the tissue. The dead inflammatory cells (neutrophils) will look a creamy/yellow colour = pus The pus will eventually be phagocytosed. For an unknown reason, hypoxic death of cells causes liquefactive necrosis in the CNS-->leaves a cavity as the brain cant heal bu scarring
What is lymphocytosis
increase in lymphocytes -infants in response to infection -acute viral infections e.g herpes -childhood infections -malignant disease
what chemical mediators cause vasodilation (redness) during acute inflammation
histamine, NO, PGs
What is neutrophilia
Increase in neutrophils -infection -inflammation -drug-induced -leukemia of the myeloid cell lineage
What are the sites of haematopoiesis
Primary lymphoid tissue = thymus (t cells) Bone marrow (b cells) Secondary lymphoid tissue = lymph nodes spleen tonsils and adenoid (waldeyer ring) gut associated lymphoid tissue (peyer's patch)
What is neutropenia
Decrease in neutrophils -drugs: chemotherapy -infections: common in viral, severe bacterial infections -genetic: esp africa, middle east -bone marrow supression
What is acute leukemia and treatment
Rapid growth of blast cells (progenitor cells) Survival time without treatment is 4-8 weeks Treatment: -chemotherapy -stem cell transplant Children has a good prognosis (80% +) but adults not as good
What is the function of IL-8
It is a chemokine which recruits neutrophils out of the blood to the area of damages tissue/invaders. It is the key drive of neutrophilia
what are the 3 ways DC engulf food
-phagocytosis -pinocytosis -receptor-mediated endocytosis
How do macrophages detect damaged cells
Macrophages live for months and are constantly phagocytosing material. When cells die from necrosis they release proteins which aren't normally present and receptors on the macrophages detect them and become activated = -secrete cytokines: TNF-alpha and IL-1 -secrete chemokine: IL-8
What is metaplasia
It is the reversible (takes a long time to go back to normal) change in adult cell type due to reprogramming to stem cells. When cells are under stress they can be replaced by a tougher type e.g replacement of pseudostratified columnar, ciliated cells with squamous cells in smokers = may have survival advantages for the epithelium but important functions are lost (mucus secretion and cilia)
What is lymphopenia
Decrease in lymphocytes -drug therapy: chemotherapy -AIDs -severe stress
What are the major components of acute inflammation
1. Vascular response: vessel dilation and increased vascular permeability to allow cells to enter the tissue 2. Cellular response: leukocytes emigrate from vessels to the site of infection or injury in tissue
What are the clinical signs of acute inflammation
Swelling (tumor) Heat (calor) Redness (rubor) Pain (dolor) loss of function
What is apoptosis
Programmed cell death Enzymes are activated in the cells which degrade own nuclear DNA and cytoplasmic proteins. 1. nuclear fragmentation 2. cytoplasmic blebs 3. apoptotic bodies 4. phagocytosis Apoptosis normally occurs to 1 or 2 cells at a time and phagocytosis is quick so it doesnt cause and inflammatory response (quiet cell death) Physiological: cell removal during embryogenesis, menstrual cycle Pathological: viral infection, death induced by CD8 cells
What is dysplasia
If metaplasia occurs and the stimulus persists, the epithelium can become disorganised and lose its function (abnormal cell shape and size). These cells can progress to malignancy. Dysplasia itself is reversible but if it progresses to cancer then its not. Cervical and respiratory epithelium are prone to dysplasia and developing carcinomas)
What is ischemic coagulative necrosis/gangrene
Tissue death-Frequently a limb or digit- appears dark/black Can get 'wet gangrene' if there is a superimposed bacterial infection as the bacteria liquefy the tissue
Monocytosis
increase in monocytes -reactive chronic inflammatory state e.g several days of pneumonia, TB -bone marrow cancer
How can we examine blood
Quantitative numerical data Qualitative assessment from blood film and marrow
Features of leukemia
The marrow is usually extensively replaced at the time of diagnosis -Anaemia -Thrombocytopenia (not making platelets) -Neutropenia
Apoptosis vs necrosis
Cell size: swells during N and shrinks during A Nucleus: pyknosis, karyorrhexis, karyolysis for N and fragments during A Plasma membrane: disrupted during N and intact but altered structure for A Cellular contents: enzymatic degestion and leakage for N, intact or released in apoptotic bodies for A Inflammation: yes for N, no for A Necrosis is pathological, whereas apoptosis can be pathologic or physiological
What is haematopoiesis
The process of forming blood cells
Blood differential
The blood contains different amounts of each blood cell- dont need to know exact numbers Platelets>neutrophils>lymphocytes> monocytes> eosinophils > basophils
What is atrophy
Decrease in cell size, the cells aren't dead but they do have diminished function Physiological: reduced hormonal stimulation to breasts and endometrium after menopause Pathological: muscle wastage due to immobility or loss of innervation, unilateral renal atrophy due to impaired blood supply, brain in Alzheimers
What chemical mediators cause heat during inflammatory reaction
TNF-alpha and IL-1
Section 3
(50 cards)
What are the local and systemic effects occuring during acute inflammation
Activation of macrophages= TNF and IL-1 released Local: -vascular endothelium: increases expression of leukocyte adhesion molecules, increases procoagulant activity and decreases anticoagulative activity -leukocytes: activates and causes cytokine production -fibroblasts: proliferation and increased collagen synthesis (repair) Systemic: -fever -leukocytosis -increase in acute phase proteins -decreased appetite -increased sleep
What are the stages of forming a scar
1. Angiogenesis = formation of new BVs to bring nutrients to the tissue and stem cells from bone marrow 2. Fibroblasts migrate and proliferate = lay down collagen 3. Deposition of ECM by fibroblasts- collagen, elastin, proteoglycans, glycoprotiens 4. Remodeling = maturation and organisation of the fibrous tissue to produce the smallest amount of scar tissue with maximal mechanical strength and function
what cells release serotonin
platelets
why is it important that the inflammatory system is connected to the coagulation system
important because when tissue injury causes bleeding there will be inflammation and blood clotting to prevent blood loss
What is grey hepatisation
The lung becomes dry, firm and grey as the RBCs are lysed, while the fibrinosuppurative (suppurative is an exudate containing large numbers of neutrophils ie pus) exudate persists
what cells release histamine
mast cells, basophils, platelets
What is the difference between exudate and transdate
Increased vascular permeability allows fluid to enter the tissue from the BV and this is the transudate, as the BVs open up more, protein and fluid leaks out which is the exudate
Explain factor XII and how the kinin and coagulation system are linked
IMPORTANT = inflammation is linked with coagultion system to stop any bleeding. Factor XII (hageman factor) is a plasma protein that enters into the tissue as part of the plasma exudate during increased vascular permeability. Factor XII is activated by contact with collagen, basement membrane or activated platelets. Activated factor XII the activates other clotting factors setting of a clotting cascade that results in thrombin converting fibrinogen to fibrin. At the same time activated factor XII converts prekallikrein to kallikrein which convets plasminogen to plasmin and HMWK to bradykinin. Plasmin then splits up fibrin. Plasmin also causes compliment activation by converting C3 to C3a and C5 C5a
Melanocytes and Keratinocytes
Melanocytes are found at he basal layer of the dermis and when keratinocytes detect sun at the top they release growth factor causing melanocytes to produce melanin.
Where does the compliment proteins come from
the liver
what cells release cytokines
macrophages, lymphocytes, mast cells
What is ESR
erythrocyte sedimentation rate. Take a blood sample and if there is lots of fibrinogen in the blood it will be converted to fibrin which will cause RBCs to stick together and fall to the bottom of the test tube- measure amount of plasma
Hepatic abscess
Liquefactive necrosis- localised area of hepatic necrosis, with an inflammatory exudate containing lots of neutrophils. The reticulin framework is disrupted = liver cant regenerate so will heal by a scar to replace the dead cells
When does tissue repair happen
It happens early after necrosis and overlaps with inflammation- will have inflammatory cells and exudate at site of damage and also angiogenesis and ECM deposition happening together.
How much strength will scar have in 3 months
70-80% of normal tissue
What chemokine causes chemotaxis of the neutrophils
IL-8
what is red hepatisation
When lung has a liver like consistency and the aveoli are packed with RBCs, neutrophils and fibrin. It will appear red
What are the 2 ways a skin wound can heal
Primary intention = clean incision, closely opposed edges,line of closure fills with clotted blood, dehydration of tissue fluid and blood at surface creates a scab Secondary intention = large tissue defect, more inflammation and granulation tissue, wound contraction by myofibroblasts (makes it less cosmetically pleasing)
What are the ways angiogenesis can happen
Can sprout off pre-existing vessels or from early progenitor cells (EPC) from the bone marrow
where in the bone is haemopoetic tissue found
in the middle of cancellous bone
Hepatic centrilobular necrosis vs liver cirrhosis
HCN = this is when there is necrosis around the central veins of the liver. The supporting reticulin framework remain intact to despite extensive hepatocyte necrosis, the hepatocytes (stable cells) can regenerate and liver will return to normal Cirrhosis = chronic damage to the liver (alcohol toxicity) which destroys the supporting reticulin (disorganised, fibrosis, collagen laid down) = although hepatocytes can regenerate by entering the cell cycle, the liver wont return to normal function because of disruption of the reticulin and the regenerating cells are prone to becoming cancerous
What is scar remodelling
This is done to strengthen the scar. MMPs (matrix metalloproteinases)-collagenase, gelatinase, stromelysins turnover interstitial proteins and line up along line of mechanical stress. MMPs are produced by macrophages, neutrophils, fibroblasts as inactive precursors in response to growth factors, cytokines and mechanical stress.
what chemical mediators cause pain during acute inflammation
Bradykinin and PGs
what are the possible outcomes of acute inflammation
- resolution if injurious stimuli removed -healing by a scar -chronic inflammation
What does thrombin do
It is a key mediator of clotting system because it converts fibrinogen to fibrin which is the mesh like structure to help hold the clot and stop spread of infection. Also has pro-inflammatory effects: increases vascular permeability, endothelial cell activation, leukocyte adhesion and chemotaxis)
What are the 3 types of cells and where do they fit in the cell cycle
Labile cells= always in the cell cycle because constantly diving and dying e.g epithelial cells, hematopoietic cells Stable cells = normally in Go phase (quiescent) but can enter G1 of cell cycle if signaled to e.g liver, kidney, pancreas, smooth muscle, fibroblasts Permanent cells = these cells cant enter the cell cycle so have no capacity for cell division (fixed in Go) e.g heart and brain-can only heal by scarring
why is the coagulation system and fibrinolytic system activated at the same time
We dont want the blood clot to stay for long and the fibrinolytic system is also activated so that fibrin can be broken down by plasmin
What is the timing of events following an acute injury
0-24 hrs- oedema 24-48 hrs- neutrophils 48-72 hrs - macrophages
What is granulation tissue
GT is a hallmark of repair by scarring. It includes angiogenesis (new thin walled delicate BVs) and ECM deposition by fibroblasts 3-5 days after damage Gross = pink, soft, granular There is a gradual accumulation of ECM and results in a dense scar that is remodeled over time
Kinetics of wound healing
0-3 days = inflammation 1-10 = granulation tissue 7-8 = wound contraction starts Collagen accumulation and remodeling doesn't start until inflammation has finished at day 3, otherwise protease enzymes would break the collagen down if it started during inflammation
What to myofibroblasts do
responsible for contracting the would to make it smaller
What is the process of skin cells maturing
they are stratified squamous cells . The cells mature from the basement membrane and move up to gain function. Proliferation only occurs at the basal layer and the cells have a big nucleus and little cytoplasm. As the cells more to the top there nucleus decreases in size and cytoplasm increases = produce keratin = waterproof and protective. When the cells die at the top they leave keratin = white flaky stuff It takes 10 days for cells to move from bottom to top of dermis.
What is fibrosis
This is the process of fibroblast proliferation (collagen) and ECM being laid down within the granulation tissue framework. Growth factors = TGF-B, PDGF (platelet derived GF), EGF (epidermal GF), FGF (fibroblast GF) Cytokines = IL-1 and TNF-alpha Source = activated endothelium and macrophages
what cell release PGs and leukotrienes
all leukocytes, mast cells
What is the process of neutrophils being recruited out of the blood
1. Margination: TNF-alpha and IL-1 released from macrophages increase expression of adhesion molecules on the endothelial wall, margination is the process of neutrophils accumulating at the periphery of the vessel 2. Rolling: Selectins (l-leukocytes, E and P- endothelial_ interact on the neutrophils and endothelial wall allowing neutrophils to bind and detach and thus roll along the wall. 3. Adhesion: Increased expression of integrins (ICAM-1 and VCAM-1) on the neutrophils and endothelial wall due to cytokines allow the neutrophils to adhere to the endothelial wall. 4. Diapedesis: (PECAM) the neutrophils then move through the endothelial cells into the tissue and are attracted to the site of damage by chemokine IL-8
What factors influence inflammation and repair
-Nutrition- protein, Vitamin C -Metabolic status- slower in diabetics -Steroids- slows collagen synthesis -Infection- most important cause of delayed healing -Mechanical factors- excessive movement slows healing -Blood supply- impaired in diabetics
what cells release NO
macrophages
What abberations can inflammation and repair result in
-inadequate scar formation -wound dehiscence: rupture -Ulceration: inadequate vascularisation -hypertrophic scar: keloid, too much collagen -wound contracture- scar can restrict joint movement
How does a scab get pushed up
the granulation tissue fills the wound and the basal layer of the epidermis regenerates to push the scar up.
Tissue repair by a scar
Scar tissue formation/fibrosis = replacing the non-generated cells by connective tissue = loss of parenchyma cells so loss of function of that area
what does bradykinin do
it is a vasoactive mediator = vasodilation and increases vascular permeability, also causes pain- in bee venom
How does a wound heal by primary intention
24 hours = neutrophils and regeneration of basal epithelium 1-2 days = epithelial basal cells grown along cut dermis 3 days = neutrophils gone, macrophages enter, granulation tissue forms 5 days = wound filled with granulation tissue, collagen laid down by fibroblasts bridges the wound and the epidermis will be at normal thickness week 2 = accumulation of collagen, fibroblasts, granulation tissue is less prominent
What is the role of NK cells
They are important during a viral infection and are part of innate immunity. When a virus enters a host cells it can down-regulate MHC-1 expression. NK cell activity is inhibited when they recognise MHC-1 molecules so down-regulation of MHC-1 of the virally infected cells, will allow NK cells will kill them. NK cells are importnat because these virally infected cells with low MHC-1 expression escape apoptosis induced by cytotoxic T cells. NK cells have 2 possible apoptotic pathways: - perforin and granzymes which activated apoptotic enzymes -Fas ligand is a surfce molecule on NK cells which can bind to to Fas surface molecule on the target cell which results in apoptosis. Important that its apoptosis= immunologically silent event so doesnt trigger inflammation
what chemical mediators cause swelling due to increases vascular permeability
histamine, serotonin, C3a and C5a
What are the 2 ways tissue can repair/heal
Regeneration by cells of the same type Replacement by connective tissue (fibrosis) forming a scar
what vessels are affected during acute inflammation
arterioles, capillaries and venules at the site of damage/infection
what are the acute phase proteins and where do they come from
All released from the liver during acute inflammation -fibrinogen -CRP -haptoglobin: molecule that can bind to Hb and stops bacteria from utlilising iron so important for bacterial infection -Serum amyloid protein
what cytokines increase synthesis of CRP, fibrinogen and serum amyloid A protein (SAA)
TNF, IL-1, IL-6
What factors recruit, activate and cause chemotaxis of leukocytes
cytokines: TNF and IL-1 chemokines: IL-8 C3a and C5a
what happens to the skin when people get septicemia due to meningitis
Meningitis can lead to blood infection and this causes rashes on the skin due to the clotting cascade being activated and then the clots being broken down by the fibrinolytic system. It is critical to control clotting in the tissue because if there is too much it can lead to ischemia and loss of limbs
Section 4
(50 cards)
What happens during the inflammatory phase of bone healing
1-2 days: The tearing of the periosteum and soft tissue = haemorrhage and clot formation-fibrin mesh scaffold recruits inflammatory cells, fibroblasts and endothelium (keeps bacteria out to stop infection) and this is the first link between the 2 fragments. Necrosis of bone fragments +/- soft tissue. Degranulated platelets and other inflammatory cells release cytokines to active bone progenitor cells 2-5 days: acute inflammatory response with fluid and cellular exudate and start of granulation tissue (fibroblasts) which forms a scaffold between the fragements--> start of soft callus
What area in the lymph node do B and T cells reside
T cells= in the middle (paracortex) B cells = outer (cortex)
how long does it take to activate cytotoxic cells
7 days- if you get infected by same microbe again, you will have memory cells = quicker for T cells to be activated so can kill of microbes faster
what is MHC restriction
the fact that T cells in an individual can only recognise antigens presented by their own MHC molcules
features of th2 cells
-produce IL-4 and 5 -stimulate production of IgE, activate mast cells and eosinophils -defence against parasites (eosinophils) -role in disease = allergies
what does IgG do
4 types found in all body fluids, only antibody that can cross the placenta to protect the offspring via passive immunisation
what does IgD do
expressed on surface of B cells but not secreted
How do you know if bone is viable
look for the nuclei of osteocytes in the lacunae
How to CD8 cytotxic T cells induce apoptosis
The activated cytotoxic t cell will recognise the specific antigen presented on the virally infected cell via MHC-1. Perforin from the T cell creates a pore in the infected host cell membrane and granzymes then enter through the pore to activate apoptotic enzymes = induces apoptosis.
what is the relative compliment binding efficiency of antibodys
IgM > IgG3 > IgG1 > IgG2
What happens during remodeling of bone
Long term-can be years -reorganisation of woven bone to lamellar (highly organised along lines of stress and stronger) bone by balanced action of osteoclasts and osteoblasts = regain normal shape of bone -happens in response to mechanical stress
What is MHC
it is conserved in evolution and is essential for recognition of antigen. It presents peptides derived from the inside or outside the cell to the immune system. Also called HLA
What happens during the reparative process
7 days: -woven bone (new, disorganised structure) is laid down due to osteoblasts and the ECM laid down encourages mineralisation. -cartilage (chondroblasts) often forms initially and is then is gradually replace by bone. -if there is lack of oxygen then collagen will from = bone ends can reunite Next few weeks: - depends on movement and fixation (rigid- slows healing, too much mvt- slows) -blood clot and necrotic bone cleared by phagocytosis -action of osteoblasts and osteoclasts builds callus to join bone ends--> hard callus
what does IgM do
forms a pentamer in the blood = has low affinity but high avidity because it can bind to the antigen on 10 sites
What is immune surveillance
B and T cells move from the primary lymphoid organs to the periphery and enter the lymphatic system. They continuously move through the lymph nodes and then go back into the blood via the thoracic duct and survey the blood for any pathogens and/or tumor cells
What APC has the largest SA
DC
What are the outcomes of acute inflammation
-resolution -abscess (can be good because it contains the infection) -chronic inflammation (adaptive immunity/innate also in some ways, hypersensitivity reactions) -demoliton (healing) = regeneration or scarring, can happen after acute and chronic inflam
Are antibody's expressed on the cell surface on B cells and secreted
Yes= both have the same specificity for the antigen
What are features of the acquired immune response
-host response to a specific antigen -T and B cells -memory response so each time you get infected by the bacteria/virus the immune response with be bigger and faster = purpose of vaccinations
What are the relative quantities of antibody in serum
IgG> IgA > IgM > IgD > IgE (GAMDE)
What do CD8 cytotoxic cells do
induce apoptosis in target cells
what does IgA do
2 types becomes a dimer to survive in mucous membranes
What is an antigen
-any substance that can bind to an antibody -they generate an immune response -generally complex, high molecular weight, proteins -some can be carbohydrates
What is clonal selection
Only a specific naive cell will recognise the specific antigen and will proliferate. Some will differentiate into memory cells and some to plasma cells which will switch antibody class (aided by cytokines released by t helper cells) to secrete high affinity antibody into circulation.
What is the low affinity antibody that all B cells produce initially
IgM
What are the 2 main APCs
Dendritic cells and macrophages -they are constantly sampling antigen by phagocytosis/pinocytosis/receptor mediated endocytosis and then can present it to T cells in the lymph nodes Act as messengers between the innate and acquired immune response
what do CD4 T helper cells do
secrete cytokines- depends on what one its is- Th1, Th2, Th17
how to antibodys kill microbes
-neutralise -opsonise -antibody dependent cytotoxicity (NK cells recognise the antibody and kill the microbe) -compliment activation leading to lysis, opsinisation and inflammation (C3a and C5a recruit neutrophils)
Structure of an antibody
2 identical heavy chains and 2 identical light chains. The end of each is chain the variable region and this is the antigen binding site. The other ends of the chains is the constant region, defining the subclass of antibody-part that changes when B cells get activated
MHC-I
smaller peptide CD8 cytotoxic T cells expressed on all nucleated cells = facilitates recognition of peptides from viruses by CD8 cells. A, B and C on gene
how long does it take to activate T helper cells
4 days
features of Th17
-produce Il-17 -recruit neutrophils and monocytes -defence against extracellular bacteria, fungi -role in disease = immune mediated chronic inflammatory diseases
what does IgE do
coats mast cells-responsible for allergic reactions. coats parasites
what is compact bone made of
Osteons = concentric bony layers, osteocytes in lacunae, receive blood supply by volkmans canal (between periosteum and haversian) and haversian canal (in the middle of osteons)
How is the B cell response generated
In the lymph node the naive B cell will present the antigen to the activated t helper cell via MHC-11. There is also interaction between CD40 molecule on the B cells and CD40L (ligand) on the t cell. This interaction will cause the t helper cell to release cytokines = antibody class switching from IgM to a high affinity antibody
what areas are there more B cells than T cells (there are more T cells in the body overal)
In mucosal associated tissue -lungs -genitourinary tract -gut -mouth (salivary and lacrimal glands) -mammary gland The B cells will being making IgA as this is the only antibody that can survive in mucus
MHC-II
slightly bigger CD4 T helper cells only expressed on APC-DC, macrophages, B cells DP, DQ, DR on gene
What are the clinical signs of chronic inflammation
Elevated: -CRP -ESR -homocysteine, ferratin, HDL -monocytes -blood glucose Disease specific features
Where are naive B and T cells activated
in the lymph nodes due to macrophages/DC coming to lymph node and presenting antigen
What is a problem you could have with bone healing
-non-union or fibrous union resulting from delayed healing: infection, too much mvt, poor blood supply
What are the 3 phases of fracture healing
1. inflammatory phase 2. reparative phase 3. remodelling phase
affinity vs avidity
affinity is the strength of the interaction between the epitope and the binding site on the antibody. avidity = how many sites the antibody can bind to on the antigen
What are the 2 pathways of the acquired immune response
Humoral = extracellular -B cells will produce antibody to neutralise and opsonise resulting in phagocytosis -antibody also activates classical compliment pathway Cellular = intracellular e.g virus -DC/macrophage will present antigen to helper T cell (CD4) via MHC-II = CD4 cell will release cytokines = proliferation and activation of effector cells = cytotoxic T cells induce apoptosis of infected cells
what is central tolerance
In the bone marrow and thymus, thymic epithelial cells present self antigen on MHC to maturing lymphocytes. The self reactive lymphocytes will have a receptor that binds strongly tot he self antigen = removed by apoptosis. This is the main way the immune system learns to discriminate self from non-self.
features of Th1 cells
-produce TNF-a and IFN-gamma -activate macrophages, stimulate IgG production, drive activation of CD8 T cells -defence against intracellular microbes. -role in disease = immune mediated chronic inflammatory diseases
what is an epitope
-part of the antigen recognised by the antigen combining site of an antibody or T cell receptor -can be a small (8 AAs) linear protein- T cells recognise -can be a globular protein (up to 20 AAs)- B cells recognise
HLA polymorphism
There are many different forms of HLA Certain forms of HLA are associated with certain diseases Matching tissue of donor and recipient = want to match forms of HLA so host immune system wont reject donor organ
How do Dendritic cells prime/activate T cells
In the lymph node, DC will slow down their ability to take up antigen and concentrate on interacting with T cells. The DC is the principle APC for activation of naive T cells. The DC will endocytose the pathogen travel to the lymph node. Here it will increases its surface area and upregulate expression of MHC-II and MHC-1 and costimulatory factors (CD80/86). The DC will present the antigen on MHC-II to the CD4 T helper cell and MHC-I to CD8 T helper cells= signal one. To allow survival and differentiation of the t cells, a second costimulatory signal is needed = interaction of CD80/86 on the DC with CD28 on the t cells. Without this second signal = apoptosis of T cells. T cell activation results in proliferation and clonal selection of the antigen specific t cells. The DC releases cytokines (IL-2) which stimulates the naive CD4 cells to differentiate into different populations. Th1 = release IFN-gamma and TNF-a = drives activation of CD8 cytotoxic T cells. Th2 = releases IL4/5 to activate naive B cells into plasma cells to secrete antibody. The cytokines also cause the CD8 cells to differentiate into effector cells (cytotoxic t cells) and memory t cells. The differentiated effector and memory T cells with then enter circulation and migrate to the site of antigen. The Th cells (Th1 and 17) will recognise the antigen presented on the phagocyte with the ingested microbe by MHC-II = release cytokines = activate macrophage to kill the ingested microbe, recruit neutrophils causing inflammation. The CD8 cytotoxic t cells will kill the infected target cell via apoptosis
what is peripheral tolerance
In lymph nodes. Key to preventing over-reactivity of immune system to environmental antigens. Mature self-reactive lymphocytes that enter the periphery due to escaping central tolerance, are eliminated by peripheral tolerance. It is mostly at the level of the T cells, especially CD4. 1. anergy- T cell activation without the second costimulatory signal induces a state of unresponsiveness. 2. supression by regulatory T cells 3. Apoptosis.
what are the high affinity antibodies
IgG, IgA, IgE
Section 5
(50 cards)
TB and HIV
During HIV- as the CD4 count decreases you become more prone to TB by reactivation or reinfection. Once CD4 is really low you can get infected by atypical mycobacteria
What is type 1 hypersensitivity
often called allergy e.g hay fever, asthma, food allergies, anaphylaxis Upon exposure to allergen the macrophage/DC will engulf the allergen and take it to the lymph node to present it to CD4 T cells--> differentiate to Th2 cells. Th2 cells release IL-4 which causes antibody class switching of B cells to IgE. IL-5 released by Th2 cells recruits eosinophils (toxic granules cause damage). Mast cell have a high affinity for IgE = IgE binds to FcRI receptor in mast cells. On next exposure to same allergen, the cross linking of IgE causes mast cell degranulation. Immediate response (minutes after exposure) = histamine, proteases, chemotatic factor, PGs, leukotrienes = vasodilation, vascular leakage, smooth muscle spasm. Late phase reaction (2-8 hours)= cytokines = leukocyte infiltration, epithelial damage, bronchospasm The dose of of allergen inducing type 1 can be very small such as opening a packet of peanuts
how does TB resist degradation by the immune system
They can survive in macrophages because there cell wall contain mycolic acids = thick waxy wall so resists phagocytosis. Effects on macrophage: -increases pH -scavenges iron -creates a leak in phagasome membrane -prevents phagolysosomal fusion -alters metabolism
What is a granuloma
you get granulomatous inflammation when you fail to completely eliminate the pathological insult. -collagen laid down by fibroblasts- destroys underlying tissue -macrophages -epitheloid cells -langhans cells (macrophages joint together) -CD4 and CD8 T cells -area of necrosis in the middle
local vs systemic reactions for type 3 hypersensitivity
Systemic = immune complex formed in circulation and can be deposited in several organs. -excess antigen gives soluble immune complexes. e.g serum sickness = about 5 days after the injection of foreign antigen specific antibodies will be produced by B cells- the antigen is capable to remaining in ciruclation of a long time so the antibody made will react with the antigen still present to form Ab:Ag complexes-get deposited in BVs in various tissue beds = injurous inflammation Local = immune complexes only in a particular organ -excess antibody can lead to precipitated immune complexes e.g farmers lung, pigeon fanciers disease- fungal spores in hay and birds which get inhaled forming complexes in the lungs.
what is isolated organ TB
TB in particular organs. -meninges = TB meningitis -Adrenals = addison disease - bones = osteomyelitis -fallopian tubes = salpingitis -vertebrae= pots disease -kidney = renal TB
what happens during chronic pancreatitis
fibrosis, lymphocytes, exocrine drainage impaired
what are allergens
allergens are antigens- thousands of them -small soluble proteins or glycoprotiens. -often proteases -dust mite faeces -food components -insect saliva -plant extractions -chemicals -drugs e.g penicillin
where in the lung do the TB bacteria like to be
in the top- may be due to higher oxgyen content
how to recognise the TB
use ZN stain
what is primary progressive TB
-elderly and immunosuppressed -the primary complex can progress to primary progressive TB = erosion into the bronchus evacuates the caseous center causing a ragged, irregular cavity lined by caseous material that is poorly walled off by fibrous tissue. -causes hemoptysis =coughing up blood due to erosion of BVs -lots of bacteria and little immune reaction
symptoms of pulmonary TB
-bad cough lasting 3 weeks or longer -weight loss -coughing up blood or mucus -weakness of fatigue -fever and chills -night sweats
What are type 1 hypersensitivity late phase inhibitors
steroids, indomethacin, cetrizine,
What is type 3 hypersensitivity
Immune complex- Ab:Ag Antibody involved is IgG -Induces compliment activation = attracts polymorphs which release enzymes, produces anaphylatoxins (C3a, C3b) causing mast cell degranulation. -platelet aggregation = microthrombi and vasoactive amine release. -macrophage activation = release of IL-1 and TNF Process: 1. immune complex formation: multiple free antibodys secreted from B cells will bind to antigen in circulation. 2. immune complex deposition: Gets lodged in BVs and neutrophils will try to phagocytose it. 3. immune complex mediated inflammation: Fustrated phagocytosis- polymorphs cant engulf complex because they are too big= neutrophils will secrete degradative enzymes causing inflammation (vasculitis) and destruction of the BV.
what happens during silicosis
silica dust particles are inhaled and deposited in the aveoli--> macrophages phagocytose the dust partilces --> they die and release cytokines --> recruits more macrophages and causes fibroblast proliferation --> collagen deposition and fibrosis
what are treatments for chronic inflammation
• Antibiotics for infections • Gold for rheumatoid arthritis • NSAIDs • Corticosteroids • Immuno-suppressants (e.g. Methotrexate) • DMARDs Disease modifying antirheumatic drugs -Therapies based on pathogenesis • Inhibitors of intracellular signalling • Anti-TNF antibodies in rheumatoid arthritis • Blockade of macrophage and T cell migration • IL-1 receptor antagonist in Juvenile Rheumatoid Arthritis
How many type of hypersensitivity reactions are there
4
what are common examples of type 1 hypersensitivity
-hayfever (annoying) -asthma (severly debilitating) -eczema -food allergy -anapylaxis (fatal)
what are the principles of therapy for TB
-long - 6 months -multiple drugs- 4 -MDR-TB is a significant problem and dangerous- chemotherpay with second-line TB -need to identify contacts and treat them is exposed to prevent them from getting the disease
what is progressive secondary TB
when secondary TB progresses and can then lead to miliary TB via massive hematogenous dissemination
does family history increase percentage of children with atopy
yes- it is increased if 1 parent has it and if both do then there is about a 50% chance that the child will have it
what is a hypersensitivity reaction
over reactive immune response to an allergen on the second and subsequent exposure. Don't have a response on first time exposure.
what are epitheloid cells
these are macrophages that become highly secretory with rough ER in a granuloma
What is the mantoux test
-Identifies people with active, latent or cleared infection -Intradermal injection of purified protein derivative (PPD) -If have been exposed to bacteria your skin will react to form a induration with a diameter 5mm or more after 48-72 hours.
TB granuloma
The TB themselves have no direct mechanism for virulence as they don't secrete toxins. TB infection causes tissue destruction due to chronic inflammation. Granuloma = abundant macrophages, epitheloid cells, langhans cells, lymphocytes, fibroblasts, collagen deposition, caseous necrosis in the middle
what is the most frequent from of extrapulmonary TB
lymphadenitis- usually occuring in the cervical region
What is the arthus skin reaction test
Intradermal injection of an antigen and if you have been previously sensitised you will have circulating antibody = arthus reaction occurs = peaks at 3-8 hrs, get an infiltration of polymorphs and formation of anitbody-antigen complexes.
what will you see on a histology slide for the type 1 immediate reaction and late phase
immediate (wheal and flare) -mast cell degranulation -vascular congestion -edema late pahse -swelling -eosinophils -neutrophils -T cells
what is type 4 hypersensitivity
-T cell mediated: release cytokines such as IFN-gamma and GM-CSF = inflammation and tissue damage. -skin test = infiltration of mononuclear cells peaking at 24-48 hrs (delayed)-mainly Th cells which recruit macrophages. -Called delayed because = when exposed to the antigen, memory T cells will get activated in lymph site which takes 2-3 days Process: Delayed-type -APC will present the tissue antigen to CD4 T cells = release cytokines, CD8 T cells can also secrete cytokines = inflammation and tissue injury. -T-cell mediated cytolysis = in some diseases cytotxic CD8 T cells bind to the antigen on tissues an directly kill the cells
What are the predisposing factors to atopy (genetically predisposed causing allergy)
-more IgE molecules and mast cells (3-4 x) -high affinity Fc receptors for IgE on mast cells -higher IgE levels >1ug/ml is the allergic concentration, <0.5 is the normal -80% have at least 1 affected parent -HLA Dw2 association- may favor a stronger Th2 response - polymorphism in IL-4 promotor region = make more IL-4 leading to elevated IgE production. -environmental pollutants increase incidence of allergies by increasing IgE levels. Pollutants have also been shown to inhibit T cell function and inhibit tolerance induction. -neonates which are still being tolerised to foreign antigens may develop allergies if exposed to pollutants and antigens simultaneously (more allergies in cities)
What are the 3 causes of chronic inflammation
1. prolonged exposure to toxins e.g Silicosis (silica is inhaled in the lungs and cant be phagocytosed, atherosclerosis 2. autoimmunity- immune system attacks self e.g RA, lupus (SLE), scleroderma 3. persistent infections e.g TB (mycobacterium tuberculosis, delayed type hypersensitivity, granulomas, caseous necrosis), syphylis, fungal infection, viruses, parasites
what are examples of repeated acute inflammation
-chronic cholecystitis -alcoholic hepatitis
what are 3 examples of how type 2 hypersensitivity happens
1. oposination and phagocytosis of cell tagged with the antibody and C3b 2. compliment mediated inflammation- the antibody activates compliment causing C3a and C5a to recruit neutrophils. 3. Antibody-mediated cellular dysfunction= antibodys that bind to receptors and can block them or stimulate them. e.g grave disease (antibody for TSH receptor) and MG (antibody for Ach receptor inhibiting binding of NT to the receptor)
what are clinical examples of type 2 hypersensitivity
-incompatible blood transfusion -hyper-acute graft injection -Myasthenia gravis (antibody binds to Ach Nic receptor) -graves disease (antibody for TSH receptor stimulates thyroid hormone release) -acute rheumatic fever -some drug hypersensitivities
Explain the TB graph about time vs immuntity
Primary infection with TB = primary complex with localised caseation. If immunocompetent = the lesions will heal and the TB arent viable. or the TB can remain dormant = latent lesion. Reactivation or reinfection by TB = secondary TB = caseation, cavitation, scarring, airways and vessels get destroyed = cough up blood. Secondary only happens in a small number of cases when the person has poor immunity and cant clear the bacteria
what are the features of chronic inflammation
-duration= weeks, years, whole life -active inflammation= mostly lymphocytic/macrophages -tissue destruction -attempts at repair -may follow acute of be insidious
what is the process of TB infection
Develops in the periphery of th lung = Ghon focus Hilar lymph node also involved and can be calcified Ghon focus + hilar lymph node = primary complex (localised caseous necrosis_
How to find TB in patinets
can be difficult because TB hide away -look directly for mycobacterium TB in sputum or ling washings -need to culture to confirm specificity and drug sensitivity -can use PCR -skin test or ELISpot (detects IFN-gamma secreting T cells when mixed with TB antigens.
what are examples of type 4 hypersensitivity
-contact dermatitis e.g nickel -TB (APC will take mycobacterium antigen and present it to CD4 cells = differentiate into Th1 cells which will secrete TNF and IFN causing monocytes to migrate to the area of infection = granuloma -chronic granuloma
What is MDR-TB
This is TB that is resistant to multiple drugs -higher in former soviet union people and people with HIV -requires extensive chemotherapy up to 2 years with 2nd line anti-TB drugs. -more costly than 1st line drugs and have more severe adverse reactions.
what are some examples of chronic inflam
infection atherosclerosis RA Psoriasis (skin reproduced every 3-4 days causing a build up of the epidermis and keratin = thickening, increased blood flow which reddens the skin
what is pulmonary TB
-air borne -infection with mycobacterium TB -primary infection often in childhood but not all people will become sick with the disease if they have a good immune system -only need to inhale a small number -the immune system walls of the bacteria with a granuloma -the bacteria can lie dormant for years and are protected by a thick waxy coat -when someone is immunoincompetent that chances of becoming sick are greater
what is type 2 hypersensitivity
Antibody-mediated = IgG produced against own cells -antigens expressed on target cells will be targeted by the antibody = destruction of cell by compliment activation (MAC and opsonisation by C3b) and phagocytosis by macrophages-have a receptor for C3b and Fc receptor for antibody. NK cells also have a receptor for IgG so NK can induce apoptosis of the target cell coated in antibody
what is prevention BCG
Bacille calmette Guerin. -A live attentuated version of TB -works on the same principle as smallpox vaccination -BCG is the only vaccine currently available against TB -greatest effectiveness in children -given to infants in high-risk groups -for lower risk groups the benefit ratio is too low. -adjunct in cancer therapy, local inflam helps reduce tumor load
what is an example of prolonged acute
Osteomyelitis = infection of the bone and marrow - can becomes chronic if you fail to eliminate the pathogen.
what is miliary TB
The bacteria enter the pulmonary circulation and then systemic circulation via hematogenous dissemination= affect other organs such as the liver and spleen. This is the fatal version and can develop from primary and secondary progressive TB. Miliary lesions may expand = almost total consolidation of large regions or whole lobes of the lung.
What is pots disease
TB of the vertebra
what is CRP
it is an acute phase protein released from the liver during inflammation. It activated complement by binding to the surface of dying and dead cells and some bacteria
what are the outcomes of type 1 hypersensitivity
A skin reaction to the allergen peaks at 30 mins and then subsides -wheal (leakiness of BVs) -flare (vasodilation). Systemic manifestation = anaphylaxis shock can be life threatening- over release of chemicals causes body to in to shock = systemic vasodilation, decreased BP and HR, narrowing of airways. Adrenalin = induce vasoconstriction to increase BP, increase HR, bronchodilation
what is systemic miliary TB
bacteria get into pulmonary venous return to the heart = bacteria spreads around body and almost every organ can be infected. The lesion resemble those in the lungs. With adequate treatment this process can be stopped, but healing by fibrosis often distorts the pulmonary architecture. -dissemination can occur via airways, lymphatic system, vascular system.
Section 6
(50 cards)
How does the immune system recognise self and produce a reaction
-certain HLA types present unique antigens -molecular mimcry = a foreign antigen shares sequence similarity with self-antigens -following infection -disruption of tissue barrier allowing microbes to enter Autoimmunity arises from the inheritance of susceptibility genes causing failure of self-tolerance (self-reactive lymphocytes) in association with environmental triggers (infection, tissue damage, inflammation) that alters the display of self-antigens and promotes self-reactive lymphocytes entry into tissue = will become activated due to recognising own tissue being presented = tissue injury (autoimmune disease)
What is RA
-dont know the cause Genetic susceptibility (MHC-II)- CD4 T cell reacts to an antigen (unknown) causing cytokine release----> 1. B cell activation = RF, other autoantibodies->immune complex formation and deposition->joint injury 2. macrophage activation = release cytokines-> IL-1 ->fibroblasts, chondrocytes, synovial cells proliferate and cause release of collagenase, stromelysin, elastase and other enzymes (macrophages also cause release of these enzymes). 3. Endothelial activation -> expression of adhesion molecules -> accumulation of inflammatory cells -> PGE2 ->release of collagenase, stromelysin, elastase and other enzymes. All of these 3 processes leads to pannus formation, destruction of bone and cartilage, fibrosis, ankylosis
What is the mechanism of CD4 T cell depletion in HIV
HIV causes chronic T cell activation---> 1. viral replication in infected CD4 T cells = death of infected cells 2. Activation of uninfected CD4 T cells = apoptosis 3. Expression of HIV peptides on infected CD4 T cells = killing of infected cells by cytotoxic t cells specific to HIV (main way CD4 cells get destroyed)
Primary vs secondary immunodeficiency
Primary -most are rare -most are genetically determined -most are diagnosed early in life Secondary -much more common -seen in people with malnutrition, infection, cancer, renal disease -can be transient or permanent
In what people do you see secondary immunodeficiency
-autoimmune disease -neoplasms -accompanies measles, chicken pox, mumps, severe trauma leprosy, hodgkins disease -malnourishment -HIV-AIDs -People with an infection can have a predominance of 1 type of immune response - a if you have strong Th1 response = cant make a strong Th2 response e.g people with measles will have a strong Th1 response, making them susceptible to infections that require a Th2 response- can make lots of antibody to deal with bacterial infection so often die from this secondary infection. -People with neoplasms can have a predominance of 1 type of WBC e.g B cells in myeloma. Can have absence of WBCs due to chemotherapy e.g neutropenia
What is SCID
Severe immunodeficiency disorder. -it is a stem cells disorder resulting in no B or T cell. 2 most common forms: -ADA deficiency (enzyme important to remove purines as they are toxic to lymphocytes -common y chain mutation in cytokine signalling resulting in no growth factors for lymphocyte cell survival -very susceptible to infection -have to live in a controlled environment (bubble boy) -bone marrow transplant to try regenerate lymphcytes
what areas of the body does OA affect
-cervical spine -lumbar spine -hips -knees -1st metatarsophalangeal joint -distal and proximal IPJ in women
what is anti-citrullinated peptide antibodys (ACPA)
auotantibody against peptides that are citrullinated. Caused by smoking
Progression of HIV to AIDs
Acute phase = increase in virulence (HIV RNA copies) due to dissemination of the virus and a decrease in CD4 T cells, development of an immune response to HIV, often an acute viral syndrome. Chronic phase (9 weeks to years) = a period of clinical latency where viral replication continues and there is gradual decrease in CD4 cells. Crisis phase = virulence is very high and CD4 cells are low- AIDs. This is when people get opportunistic diseases due to immunodeficiency leading to death. People are really susceptible to infections controlled by CD4 T cells - 1/3 will die from TB
what is Digeorge syndrome
-have no thymus gland= cant develop T cells so susceptible to infection -cant produce a cell mediated response or induce switching of antibody -can get a partial Digeorge syndrome when people have a small thymus so only make a small amount of T cells.
summary slide of hypersensitivity
look at lecture
what is Sjogren syndrome
-is the destruction exocrine glands -commonly lacrimal and salivary = dry eyes and mouth -common in older women -infiltration of CD4 T cells and B cells -autoantigen is unknown -75% will have RF -50-80% have ANAs
What are the clinical features of RA
-female -pain in hand joints -morning stiffness -swelling of wrists, MCP, PIP joints -Aunt has RA -sister with type 1 diabetes -smokes 20 cig/day
what is hashimotos thyroiditis
-local -thyroid epithelial cells are destroyed by CD8 and CD4 T cells, autoantibodies and ADCC (antibody depended cell cytotoxicity) -results in hypothyroidsm
What are the 5 pathological changes in OA
1. Fibrilation of cartilage: cartilage degeneration due to a decrease in proteoglycans and cleaved collagen (will cause narrowing of joint space on x-ray) 2. Eburnation: the underlying bone is polished by the grinding action of bone on bone without cartilage 3. Sclerosis: The underlying bone becomes more dense. It is unclear if this happens before or as a result of cartilage loss of corresponding changes in weight distribution. 4. Subchondral cysts: after the loss of cartilage, small fractures occur through the eburnated bone and joint synovial fluid is forced under pressure into the subarticular area in a one way direction. The fluid causes a host response and becomes surrounded by a fibrous capsule 5. Osteophytes: mushroom shaped bony outgrowth that develops at the margins of the articulating bone- they are called Heberden nodes in the distal IPJ of women
How can you be resistant to HIV infections
Chemokine receptor mutation. Can get donor CD4 cells and put the mutated chemokine receptor on them and then re-inject them into HIV infected patients = CD4 cells are resistant to HIV infection
What other diseases is RA associated with
-type 1 diabetes -SLE -Graves disease (hyperthyroidism) -Hashimoto thyroiditis (hypothyroidism)
What is Bare lymphocyte syndrome
-caused by MHC-II deficiency = cant activate CD4 cells -susceptible to fungal and viral infections -also have reduced IgG, IgA etc
What is crohns disease
-An inflammatory bowel disease -skip lesions along GI tract due to chronic inflammation -HLA-DR1 association -NOD2 involvement (inflammasome) -CD4 T cell activation and granuloma formation -may be specific gut bacteria involved but not sure -can happen anywhere from mouth to anus
what is X-linked Agammaglobulinemia/Brutons disease
-one of the more common forms of primary immunodeficiency -failure of pre B cells to develop into B cells. -antibody cant be produced -also a significant reduction in B cell numbers in the blood
what are regulatory T cells
-They control T cell proliferation by production of IL-10 and TGF-beta. -can be inducible -regulatory effect is often dependent on cell-cell contact
T lymphocyte immunodeficiency
-reduced number of circulating CD3 T lymphocytes (help activate CD8 cells) -variation inf proportion of circulating CD4 and CD8 lymphocytes (AIDs) -low response to polyclonal activators (substance that activates B cells or T cells or both) -changes in T lymphocyte areas in primary lymphoid tissue
what is MS
-local -demyelinating disorder -occur at any age -more frequent in females -due to CD4 t cells specific for antigens of the myelin sheath. -Th1 cells activate macrophages which induces demyelination -relapsing, remitting disease
B lymphocyte immunodeficiency
-reduced levels of circulating antibody -variation in the proportion of classes of antibody -reduced numbers of circulating B cells -reduced cellularity in B cells areas of lymph node -poor response to polyclonal activators -poor antibody response to vaccination with inactivated vaccines- all vaccination induce IgG resposne
What is local autoimmunity and examples
its affects one organ -type 1 diabetes -hashimotos -chrons disease -MS
what is rheumatoid factor
An autoantibody against IgG
what is type 1 diabetes
-B islets of pancreas are attacked by CD8 T cells due to recognising a Beta cell specific peptide= pancreas cant make insulin. -role for CD4 cells also -may be associated with infection (coxosackie virus) but antigen unknown -onset in childhood -HLA DR3/DR4 association for 95% of caucasians with type 1 Process: Genetic predisposition and then an event- maybe infection, triggers and immune reaction causing progressive loss of insulin due to B-cell destruction.
Is there treatment for OA
no way to prevent it physio management for pain and education about activity
What do the different complement deficiencies cause
Makes you susceptible to infection from capsulated bacteria. Wont be able to clear bacterai so easily. C1,2,4 = pyogenic infections, immune complex disease C3 = severe pyogenic infections, immune complex disease properdin (only know positive regulator of complement ativation) = neisserial infections C5-9 = neisserial infections, immune complex disease, often healthy
what is Hyper IgM syndrome
-normal or elevated levels of IgM with a reduction in IgG and IgA = cant switch to high affinity antibody. -caused by a variety of deficiencies: CD40L, CD40, activation induced cytidine deaminase deficiency (AID), uracil DNA glycolase deficiency (UNG)
Features of autoimmune disease
- presence of autoantibodies -lymphocyte, macrophage and plasma cell infiltration in to lesions -presence of more than 1 autoimmune disease is common -more common in females (e.g lupus has a 10:1 ratio female:male) -occurs in families-genetic -HLA associations- if you have the HLA it doesnt always mean you will have the autoimmune disease -lesion is classified by hypersensitivity type II, III, IV -breakdown of tolerance
What is the cause and pathogenesis of OA
-wear and tear disease -strong association with age -mechanical stress - affects weight bearing joint (hip, knee) -genetic factors are unclear Altered chondrocyte homeostasis with a decrease in proteoglycan concentration and cleavage of collagen type II fibers = degradation of cartilage.
what is SLE
systemic lupus erythematosus = lupus -caused by autoantibodies which form immune complexes and then get lodged (type III) -autoantibodies directed at nuclear antigens (ANA) -manifests as nephritis (inflammation of kidneys), skin lesions, arthritis. -remitting, relapsing disease (gets worse each time due to production of more and more antibodies) -common (1 in 2500) -can manifest at any age but normally 20-30s. Inherited susceptibility genes = MHC-II, complement, other Environmental triggers = .something causing cellular apoptosis such as UV radiation. This causes nuclear antigens and other self antigens to be exposed = activates helper T cells and B cells specific for self antigens (genetic) --> IgG autoantibody produced --> immune complex and autoantibody mediated tissue injury
what are local complications of RA
-joint instability due to inflammation involving the adjacent joint capsule and tendons -joint space occupied by pannus-cartilage and cortical bone eroded -fibrous ankylosis of the bone ends which can ossify- bony ankylosis = immovable joint
Type 1/immediate vs type 4/delayed
time: type 1 = 30 min type 4= 48-72 hrs appearance of central area: type 1 = blister (wheal and flare) type 4 = red induration appearance of peripheral area type 1= red (flare type 4= red palpation of central area type 1= soft type 4= hard Main cell type involved type 1= mast cell (IgE) type 4= Th cell
How do you diagnose lupus
some peope may have the antibody suggesting an autoimmune disease but doesnt mean they have so they must have 4 things on a criteria of 11. e.g oral ulcers, arthritis, renal disorder, photosensitivity
what are possible deficiencies of the innate response
-defective production of polymorphs (neutrophils, basophils, eosinophils) -defective response to chemotactic stimuli (lazy lymphocyte syndrome) -defective leucocyte adhesion -defective lysosomes in polymorphs (pyogenic infection) - no production of reactive oxygen intermediates (needed to kill off bacteria once phagocytosed)
What is AIDs
acquired immune deficiency syndrome -infection by HIV RNA retrovirus (gp120 envelope glycoprotien binds to CD4) -cofactor required (chemokine receptor): macrophage trophic HIV uses CCR5 lymphotrophic HIV uses CXCR4 -once in the host cell, reverse transcriptase turns it RNA into DNA which is then integrated into host DNA -low levels of CD4 on macrophages and DC -high levels of CD4 on Th cells. Process of entering cell: -gp120 binds CD4 -conformational change -gp120 binds chemokine receptor -membrane penetration and fusion.
What are the 4 most common primary immunodeficiencies
more than half are antibody disorders > phagocyte disorders > T cell disorders >complement
how can we target HIV
-attack reverse transcriptase -stop protease -stop integration of viral DNA into host DNA
What is the pathogenesis of RA
Susceptibility genes (HLA, other) --> failure of tolerance AND environmental factors (infection, smoking) --> enzymatic modification (e.g citrullination) self protein. ----> T and B cell responses to self antigens (including antigens in joint tissues)--> Th17 and Th1 produce cytokines (e.g TNF) and plasma cells produce antibodies (form immune complexes with RF and gets deposited in joints)--> activates macrophages--> secrete more cytokines--> proliferation of fibroblasts, chondrocytes and synovial cells but at the same time they produce enzymes that degrade the cartilage and bone (collagenase, stromelysin, elastase, PGE2) --> pannus formation, destruction of bone and cartilage, fibrosis, ankylosis
what is systemic autoimmunity and examples
It effects many organs -SLE -Sjogrens syndrome -Scleroderma -RA
what is seroconversion
the time when HIV antibodies develop, usually takes place within a few weeks of infection
what is systemic sclerosis/scleroderma
-Abnormal accumulation of fibrous tissue in skin and multiple organs -cause unknown but involves CD4 T cells are involved -more common in older women -likely trigger is the combination of an immune response and vascular damage = something triggers activation of effector T cells causing cytokine release = injury to BVs and narrowing = ischemia. Growth factors are also release by immune cells and this along with ischemia causes fibroblasts to secrete more ECM = fibrosis
what are the joint changes during RA
- inflammation and proliferation of the synovium which extends into the joint space -pannus = proliferated synovial cells, inflammatory cells, plasma cells, lymmphoctyes, granulation tissue, fibrous tissue -releases proteases damage and erode the cartilage -underlying bone is exposed and damaged = bony surfaces become pitted and irregular
what are the normal joint key components
1. cartilage -a shock absorber -enable weight distribution across entire surface, protects underlying bone -proteoglycans (esp aggrecan) and type II collagen prevent wear by protecting the bone ends from grating together -Aggrecan is the major proteoglycan in the articular cartilage that gives it load-bearing properties 2. Synovium -line the non-articulating aspects of the joint -secretes synovial fluid which lubricates the joint 3. supporting ligaments and joint capsule -prevents instability
what is RA
-Systemic autoimmune disease -inflammatory polyarthritis -symmetric involvement of the small joints of the hands and feet -80% have rheumatoid factor. anti-citrullinated peptide antibodies or both
what is ankylosis and does it happen in OA
It is fixation of a joint due to fusion of the articulating surfaces. Not in OA
what is the lifetime risk of women getting RA
3.64
where is AIDs incidence high
Africa and America
Section 7
(50 cards)
Enzymopathies- G6PD deficiency
G6PD = glucose-6-phosphate dehydrogenase -produces NADPH to protect against oxidative damage G6PD deficiency: -early death of RBCs in spleen -provides resistance to malaria because parasites need NADPH for energy Pharmaceutical and dietary impilcations (oxidative crisis): Avoid--> -primaquine (antimalirial drug) -dapsone (anti-inflammatory drug) -fava beans -Oxidant drugs can saturate the pathway too. NADPH is required to convert oxidised glutathione to glutathione = without NADPH = oxidant radicals = RBC membrane damage and Hb damage (Heinz bodies). The proteins in Hb get cross linked (precipitated) and get stuck in the spleen
What happens during chronic osteomyelitis
-Abscess forms in the bone (localised collection of pus) = increasing pressure within the bone shaft compresses the blood supply, leading to large areas of dead medullary bone -pus is forced through the bone cortex to locate under the periosteum = lifting of periosteum = loss of blood supply to the cortical bone = becomes necrotic and entrapped (sequestrum) because the periosteum lays down new bone (involcrum) on the surface, trapping the dead bone underneathe.
What are the causes of anaemia
1. Reduced RBC or Hb production: -deficiencies of iron, folate, vitamin B12 -globin gene defects -bone marrow disease 2. Increased RBC destruction (haemolysis) -inherited or acquired 3. Blood loss -acute trauma, surgery
What is the RBC lifecycle
EPO is released from the kidney in response to low oxygen --> RBCs get produced in haematopoietic bone marrow--> circulate though the body (travel 150-300km over 120 days) --> must pass though sinusoids of mononuclear phagocyte sytem (MPS) in the spleen--> some will get trapped and phagocytosed --> RBC gets broken down into globin --> AAs (get recycled) and Haem--> bilirubin and iron
What are the 3 types of anaemia classified by RBC size and colour
1. Microcytic hypochromic anaemia (most common) = low MCV (mean cell volume) and MHC (mean cell Hb), small, pale (underfilled) red cells. 2. Macrocytic anaemia= high MCV and large RBCs 3. Normocyctic normochromic anaemia = normal MCV and MCH, RBCs are normal but there just isn't enough.
What is B-thalassaemia major and what can it result in
It happens when there is reduced B-globin synthesis and relative excess of a-globin chain. The excess alpha chains bind together forming an insoluble a-globin aggregate. This means the erythroblasts are abnormal: -most will die in the bone marrow = ineffective erythropoiesis -few abnormal red cells will leave (hypochromic red cells) but will be destroyed at the monocyte phagocytic system in the spleen -----> this leads to anaemia --> tissue anoxia--> EPO increase ---> marrow expansion ---> RBCs made in places other than marrow --> skeletal deformities. It also causes systemic iron overload
How is intact endothelium anti-thrombotic
1. Anti-platelet effects: Prostacyclin, NO, ADPase released from endothelium prevents platelet aggregation 2. Anticoagulant effects: -anti-thrombins inactivate thrombin and other factors, enhanced by heparin-like-molecule on endothelium -thrombomodulin is a cofactor for thrombin and together its activates protein C and S which inhibits coagulation. -tissue factor pathway inhibitor produced by endothelium (inactivates tissue factor-VIIIa to inhibit the extrinsic pathway) 3. Fibrinolysis -t-PA (tissue type plasminogen activator) breaks down fibrin
What happens to platelets on contact with collagen and vWF from ECM
Form the primary platelet plyg by -Adhesion -activation -change shape -secretion (release reaction) -aggregation using pseudopodia and receptors
What is haemostasis
Process of stopping bleeding at site of vascular injury and maintain blood in a fluid state in normal vessels
Causes of macrocytic anaemia
Megaloblastic anaemia = related to defective DNA synthesis causing cells to swell -vit B12 and folate are needed for DNA synthesis--> deficient--> delayed and abnormal nuclear maturation and cell division --> defective cells undergo apopotosis in the marrow and the few surviving cells have fewer divisions and are big. Non-megaloblastic anaemia = less common and not related to defective DNA synthesis -due to liver disease, alcohol and cytotoxic drugs
Features of normal RBCs
-biconcave disc (important so they can change shape to fit through BVs) -7um diameter -central pallor (1/3, is white because the light shines through as there isnt as much Hb in the middle) -contain Hb which carries O2 to tissue and CO2 back tot eh lungs
What is the iron cycle
Iron can be very toxic and can react with lots of things. Absorption of iron is really tightly controlled Food iron = 10-20 mg/d --> 1 mg/d absorbed in duodenum --> transferrin transports iron in the blood to the tissue (daily loss of 1 mg/d in urine, faeces, nails, hair, skin) and to bone marrow--> 2/3 of body iron us used to form RBCs--> RBCs can then be lost by haemorrhage (menstrual- 0.5-1 mg/d) or digested by macrophages--> iron go back to being transported by transferrin
What are the inherited causes of haemolytic anaemia
-cell membrane or cytoskeleton abnormalities e.g hereditary spherocytosis (lack of central pallor and shaped like spheres due to defect in protein under phospolipid bilayer) -disorders of Hb -enzymopathies -extravascular haemolysis predominates (spleen and liver)- RBCs die outside BVs e.g splenomegaly, jaundice, gallstones
What is Thalassaemias
-most common single gene disorder in humans -variable severity depending on the number of genes affected. -An alpha (genes) or beta (2 genes) globin gene is defective, lost or abnormally regulated = -> imbalanced production of globin chains (not enough of 1 and too much of the other) -> defective Hb production -> Red cells and precursors are damaged by accumulation of the globin chain that is produced in relative excess
What is Hb S
Sickle cells anaemia homozygotes -point mutation in b-globin -forms crystal-like structures when deoxygenated -RBCs become rigid and elongated -reduced survival of RBCs and may block capillaries. -Sickle crisis = infarcts in spleen, brain etc -Severe risk if hypoxic or febrile heterozygotes -sickling only if severely hypoxic - resistant to malaria
Platelet features
-disc shaped -granular -anucleate cell fragments -shed from magakaryocytes in bone marrow -have pseudopodia that stick out when activated -complex membrane system with a large surface area -a-granules: fibrinogen, FV, vWF, PF4, PDGF -dense granules: ATP, ADP, serotonin, Ca, adrenaline
How to platelets aggregate
involves ADP, fibrinogen and vWF. The aggregation receptor (GpIIb/IIIa complex on platelet) binds to fibrinogen-ADP induces a conformational change. TXA2 amplifies the aggregation and activates more platelets and constricts vessels
Causes of normocytic normochromic anaemia
-Acute blood loss followed by haemodilution (plasma volume redistributes to maintain BP and this dilutes the blood) -bone marrow disease and malignancy (cancer) -chronic renal failure -haemolysis
what are the normal ranges for Hb
Male = 130-170 g/L female = 120-160 g/L
What are the 3 main ingredients for haemostasis
1. Endothelium- vasoconstriction 2. Platelets- activation of platelet plug 3. Coagulation- fibrin formation
What are the types of immune hemolytic anaemia
Cold: -IgM active at <30 degrees -acute (secondary): infections e.g EBV, mycoplasma -chronic (primary): idiopathic, B cell cancers Warm: -usually IgG active at 37 -primary: idiopathic -secondary: immune disorders, drugs
What is the most common blood disease
Anaemia
Anaemia in bone marrow disease and malignancy
Marrow replacement: -metastatic cancer -marrow infiltration and failure -severely reduced red cell production due to cancerous cells taking up all the space and nutrients May be mildly microcytic: -anaemia of chronic disease -bleeding leading to iron deficiency especially in bowel, gastric, uterine and urinary tract cancers
What are systemic complications of RA
People will have the hallmarks of chronic disease: -anaemia of chronic disorders (interleukins causes the liver to produce hepcidin = reduction in the formation of an iron carrying protein which compromises the ability of Hb to carry oxygen) -fatigue -loss of appetite -high CRP and acute phase proteins (produced by the liver in response to chronic inflammation) -intermittent fever -weight loss Subcutaneous rheumatoid nodules may develop along extensor surfaces of the skin and may involve viscera (antibody reaction)
What is the sequestrum in osteomyelitis
It is the dead bone either due to pressure within the marrow cavity or due to the loss of blood supply to the cortical bone from the lifting up of the periosteum
Immune haemolytic anaemia
Antibodies may arise spontaneously or be induced by exogenous agents e.g drugs, viruses, transfused RBCs -they opsonise RBCs -macrophages engulf RBCs or remove some of the membrane = spherocytes and reduced lifespan -classified based on type of antibody and any predisposing conditions
What are the normal types of adult Hb
HbA = a2B2 = >95% HbA2 = a2sigma2 = <3.5% HbF = a2y2 = <1% HbA is most commonly affected
What is anaemia
-Reduced Hb concentration. -Normal Hb varies with ages, gender and pregnancy
what is the coagulation cascade
it an enzyme cascade where proenzymes are sequentially activated to enzymes on the surface of activated platelets. End result is fibrin formation which stabilises the platelet plug and RBCs and WBCs get trapped.
What normally happens at the site of vascular injury
1. Transient vasoconstriction -neurohormonal reflex: endothelin released from endothelial cells -temporarily slow the bleeding and helps platelets and factors come in to contact with each other. 2. Primary Haemostasis -the exposed sub-endothelial ECM is highly thrombogenic -platelets adhere to each other and the collagen by vWF and become activated = release granules (ADP, TXA2) that recruits more platelets to form a platelet plug -fibrinogen helps platelets stick together. 3. Secondary Haemostasis -tissue factor is released from endothelial cells = activates coagulation cascade -Thrombin is generated which recruits and activates more platelets and coverts fibrinogen to fibrin. -fibrin polymersies to act like a net to stabilise that platelet plug and also traps other cells (neutrophils, RBCs) 4. Thrombus and antithrombotic events -counter-regulatory system to limit the plug to the site of injury. -release of t-PA (fibrinolysis) and thrombomodulin (blocks coagulation cascade) prevents thrombus formation in other areas
What do hands look like for people with RA, hand deformities
-common to have radial deviation at the wrist and ulna deviation at the fingers -swollen, tender, warm due to aggressive inflammation -Boutonniere deformity = flexed PIP and hyperextended DIP -Swan neck deformity = PIP hyperextended and DIP flexed
Anaemia of renal failure
The kidneys normally secrete EPO in repsponse to low O2 levels so renal failure----> Decreased EPO -reduced RBC production -Hb falls to 50-80 g/L -treat with subcutaneous EPO Red cell survival -70-90 days -some waste products normally cleared by kidney can shorten red cell survival
Causes of iron deficiency
Disrupted parts of the iron cycle. -inadequate intake or absorption of iron -increased demand of tissue iron (exercise, pregnancy) -chronic blood loss
How does endothelial injury promote thrombosis
Injury = trauma, cytokines, infectious agents, haemodynamic forces, plasma mediators. -Injury exposes ECM collagen = activates platelets and adhere via vWF -Tissue factor then activate coagulation cascade in secondary hemostasis -Anti-fibrinolytic effects = plasminogen activator inhibitors
What are the acquired causes of haemolytic anaemia
-physical damage: prosthetic valves, burns, microangiopathy (disease of small vessels) -infections: bacterial toxins, malaria, RBC parasitised -immune: complement, antibodies -Intravascular haemolysis predominates: Haemoglobinaemia, haemoglobinuria, haemosiderinuria
What do we want a balance between for blood
Want a balance between prothrombotic (clotting, thrombus) and anti-thrombotic (bleeding, haemorrhage)
What is the platelet release reaction
1. Platelet receptors are activated by collagen, vWF, ADP, TXA2, thrombin, serotonin (causes vasoconstriction), adrenalin 2. Dense granules (ADP activates platelets and serotonin activates platelets and constricts vessels) and a-granules (vWF, fibrinogen, FV, PF4) are secrected 3. More platelets are activated by thromboxane A2 (COX pathway) 4. Fibrinogen or vWF bind and platelets aggregate Activated platelets secrete more TXA2 and vWF which activates more platelets
What is the aim of treatment for RA
-control pain -early treatment to prevent joint destruction and deformity -active monitoring of disease progress -prevention of disease complications -improving QoL Treatment: -pain relief -physio -immunosuppression - steroids, disease modifying anti-rheumatic drugs (DMARDs) e.g TNF antagonists, methotrexate
Thrombus vs clot
Thrombus is a solid mass of coagulated blood formed within the cardiovascular system. A clot is the same things but forms outside the cardiovascular system.
What are the disorders of Hb
-Thalassaemias: globin defect, some degree of haemolysis -Haemoglobinopathies: abnormal globin peptide, >1000 Hb variants identified, many are clinically silent e.g haemoglobin S: point mutation in b-globin, significant clinical problems
what does it mean if you have anaemia
It is a symptom of another problem
What treatment is used for osteomyelitis
-broad spectrum antibiotics are given until specific culture and sensitivity is done -if antibiotic treatment is delayed- inadequate or inappropriate infection may continue = important to relieve the pressure surgically and debride the dead tissue and pus -debridement done if there is no clinical improvement in 24-48 hours.
what is a G6PD deficiency haemolytic crisis
An acute episode of haemolysis with severe anaemia -cells are sphered and retracted due to precipitated Hb = blister cells -splenic macrophages pluck out precipitate Hb = bite cells On a reticulocte stain: Heinz bodies -oxidised, denatured adn aggregated Hb attached to the inside of RBC membrane
Explain microcytic hypochromic anaemia
-low MCV and MCH 1. Iron deficiency -unable to make the normal amount of haem for Hb = increased central pallor -small red cells, reduced amount of Hb, look like bicycle rims. 2. Thalassaemias -reduced production of a globin protein needed for Hb -small red cells, reduced amount of Hb 3. Chronic disease
Haemolytic anaemia
Reduced RBC survival in circulation due to: -abnormal RBC (inherited) -excessive destruction of normal RBC (acquired) The marrow responds by increasing RBC production -reticulocytes are young RBCs and are in the blood for 1-2 days -reticulocytosis = raised reticulocyte count Blood film will show polychromatic cells indicated raised reticulocyte count. Reticulocyte stain = RNA and organelles of young RBCs will be blue.
What can be an outcome of osteomyelitis
The pus may ooze into the soft tissue and form an abscess which may erupt on to the skin surface forming a sinus. The sequestrum may be extruded through the sinus
What are the clinical features of anaemia
Symptoms: -often none because its a chronic process and the body can compensate -weakness, fatigue, lassitude (mental and physical tiredness) -short of breath -heart racing, palpitations If vascular disease presents: angina, claudication Signs: -pallor of mucus membranes -if severe: tachycardia, heart failure Some are specific to the type of anaemia: -neuropathy -glossitis (inflammation of the tounge) -bone deformities -impaired immunity, bruising -kollonychia (spoon shaped nails) -jaundice -unusual food craving
What is osteomyelitis
Inflammation of the bone marrow. Usually caused by bacteria = its an infection. -staphylococcal aureus 80-90% -others = E.coli, group B strep, Salmonella, M tuberculosis These organisms gain entry to the bone by: -haematogenous dissemination from some other focus or bacteraemia (bacteria on blood) -spread of infection from and adjacent site to the bone -trauma -surgical- Iatrogenic
what is vWF
von Willebrand factor is a glycoprotein released from endothelial cells at the site of injury and binds to subendothelial collagen and glycoprotein receptors on platelets Causes activation and adhesion of platelets
Anaemia of chronic disease
-Tends to be microcytic/low normocytic -looks like iron deficiency but iron stores are normal or high its just that the iron isn't being used. - happens in severe chronic infection, inflammation or malignancy. (happens in RA) -during inflammation, macrophages will secrete IL-6 which causes hepatocytes to release hepcidin = stops macrophages iron release and intestinal iron absorption. -it may be protective to prevent bacterial infections getting worse
Section 8
(50 cards)
How do we investigate coagulation
-platelet count- 150-400 x10^9 -platelet function- platelet function analysis, aggregometry, bleeding time -coagulation studies- APTT, PT/INR, factor assays
What are the clinical consequences of superficial venous thrombosis
-varicose veins = occlusion causes local congestion, pain and swelling of the veins, can also get varicose ulcers -oedma and impaired drainage predispose to infection from light trauma -rarely embolise
Risk factors, main sites and morphology of arterial thrombosis
Risk factors: -turbulence and endothelial injury Main sites: -coronary, cerebral, femoral arteries, ventricles -usually superimposed on endothelial injury e.g heart post MI, atherosclerotic plaque Morphology: -grow back from point of attachment -friable mesh of fibrin, platelets, RBC, WBC
What is the intrinsic pathways of the coagulation cascade
Has a role in inflammation and infections. Hageman factor (XII) can be activated by endotoxin and once activated (XIIa) cleaves prekallikrein to kallikrein and activates factor XI. XIa then activates factor IX Leads to the common pathway resulting in fibrin formation Involves factors 12, 11, 9, 8
What is thrombophilia
Hypercoagulability due to abnormalities of coagulation the predispose to thrombosis- mostly venous thrombosis Inherited = factor V leiden, prothrombin mutations, increased levels of coagulation factors are common ones Acquired = HIT, APS, DIC
What is cor pulmonale
Multiple emboli over time --> pulmonary hypertension and right ventricular failure
What is Factor V Leidin
-An inherited thrombophilia -single nucleotide mutation - mutated factor V resists cleavage and inactivation by protein C (normally protein C binds to factor V and cleaves it into 2 inactive fragments) -associated with venous thrombosis -2-15% of caucasians: 60& have recurrent DVT, homozygotes 50x increased risk of VT and heterzygotes 5x increased risk of VT
What are the clinical consequences of DVT
1. Local pain, swelling, warmth, purple/blue skin discolouration -occlusion often offset by collateral channels -50% are asymptomatic and only identified after embolisation 2. pulmonary embolism (80-90%) -shortness of breath, chest pain, cough, bloody sputum 3. post thrombotic syndrome (20-50%) -pain, oedema, heaviness, itching, skin hardening and discolouration 4. Venous ulceration (5-10%) -severe post thrombotic syndrome
What is haemophilia A and B
Inherited disorder Families of genetic disorders with many different causative mutations: -haemophilia A = factor VIII -haemophilia B = factor IX Both effect intrinsic pathway and thus the common pathway of making fibrin Increased risk of bleeding into joints and muscles: -variable severity -occasionally other sites affected Treat with IV clotting factor: -regularly for prophylaxis for severely affected patients -before surgery or dental treatment -if trauma or spontaneous bleeding occurs
When are you at lower risk of acquired thrombophilia
-pregnancy -oral contraceptive -smoking -age -obesity
what is DIC
Acquired thrombophilia = disseminated intravascular coagulation. Diffuse small thrombi formation throughout the microvasculature Why? Sepsis, malignancy, major trauma leads to widespread thrombin activation and at the same time anticoagulant and fibrinolytic pathways are also activated --> bleeding catastrophe = infarction due to micro-thrombi and haemorrhage due to platelet and factor consumption and fibrinolysis. Example = gangrene due to DIC in meningococcal sepsis
Acquired: warfarin
Give warfarin orally- vit K antagonist so inhibits carboxylation of clotting factors 2, 7, 9, 10 = inactivated -used to reduce clotting after thrombosis and to reduce risk of thrombosis -Has a narrow therapeutic window so needs to be carefully monitored -Is also affected by other drugs, diet, metabolic rate If the action of warfarin is too high = bleeding
Adequate vs Inadequate CV function and PE morphology
Adequate CV function = Small PE -Bronchial arterial supply sustains the lung tissue and the embolus is restored over time. Inadequate CV function = Larger PE -the tissue downstream from the occlusion is infarcted = Wedge shaped hemorrhagic infarcts: -apex points towards hilus and occluded vessels -ishemic necrosis and leaky BVs causing haemorrhage -RBC lyse in 48hrs and the infarct becomes pale and forms a scar
What is the common pathway
Factor Xa converts prothrombin (II) thrombin (IIa). Thrombin then converts fibrinogen (I) to fibrin (Ia) which forms a stable meshwork. Involves factors X, V, prothrombin (II) and thrombin, fibrinogen (I) and fibrin
What blood flow causes venous thrombosis
stasis
What is APS
Acquired thrombophilia = Antiphospholipid antibody syndrome -antibodies bind to plasma proteins associated with phospholipids = prothrombin, protein C and S --> antibodies interfere with phosopholipids and inhibit coagulation tests (in vitro) --> antibodies cause endothelial injury , activate platelets + complement + clotting factors causing a hypercoaguable state (in vivo) -Associated with arterial and venous thrombosis
Why does a mural thrombus form post MI
-damage to endocardial and endothelial cells -subendothelial ECM and collagen exposed---> prothrombotic
What are the causes of thrombocytopenia
1. Reduced platelet production -bone marrow failure and infiltration (e.g leukemia, metastatic cancer, drugs) -liver disease 2. Reduced thrombopoietin 3. Reduced survival of platelets -viral infections -immune complexes -autoimmune (auto-antibodies for platelets) or drug-induced -consumptive (DIC = disseminated intravascular coagulation) 4. Sequestration in hypersplenism 5. Dilutional
Acquired Vit K deficiency
-Vit K is a biological redox reagent = it adds y-carboxy group to glutamic acid to activate factors 2, 7, 9, 10. All newborn infants have it due to limited transfer across placenta = given vit K injection or orally after birth Intestinal malabsorption of Vit K = lack bile salts, small intestine disorders such as coeliac disease.
What is inherited von Willebrand disease (vWD)
It means there is a problem with sticking the platelets to the collagen to stop bleeding. -there is a family of disorders affecting vWF: autosomal dominant, common (1:500), deficient of defective vWF, can lead to reduced levels of factor VIII because it circulates in the blood bound to vWF It reduces platelet function: -increased bleeding from mucous membranes -prolonged bleeding time -bruising tendency -menorrhagia
Pathogenesis of thrombi at different sites (arterial vs venous thrombus)
Endothelial injury = associated with arterial abnormal blood flow = tuburlence is arterial and stasis is venous Hypercoagulability = coagulation for venous, platelets for arterial
Risk factors, main sites, morphology of venous thrombosis
Risk factors: -stasis and hypercoagulability Main sites: -usually at sites of stasis e.g behind valve pockets (can force valves closed) -90% in leg veins (iliac, femoral, popliteal) Morphology: -grown in the direction of blood flow -forms along cast of the lumen -red gelatinous mass, rich in RBCs trapped in fibrin Often referred to as red thrombus or stasis thrombus
What is economy class syndrome
-VTE following air travel -Involves usual risk factors (virchows triad) and the low air pressure and humidity in the cabin may contribute Prophylaxis = hydration, leg exercise, compression stockings, low molecular weight heparin fro high risk groups
What are lines of Zhan
These are lamination formed during a venous thrombus due to RBCs being trapped in fibrin and platelets = appear as lines microscopically
What happens with BV wall abnormalities
Common and dont usually cause serious problems. In skin and mucous membranes: -petechiae = < 3mm -Purpura = 2-5 mm -Ecchymoses (bruise) = > 1 cm Sometimes can have more serious bleeding: -menorrhagia -nose bleeds -GI bleeding -haematuria Various causes: -infection (DIC) -drug reactions (immune complexes) -nutritional deficiency (Vit C)
What are the main causes of endothelial injury
-trauma -ischemia -hypertension -turbulent blood flow -toxins -metabolic abnormalities Injury is more important for arterial thrombosis
What are therapeutic applications to prevent blood clotting
-Block TXA2 production with aspirin, COX inhibitor (NSAID) -Block platelet receptor binding so platelets cant aggregate by monoclonal antibodies, clopidogrel -Interfere with the coagulation cascade and thrombin activity using warfarin, heparin, clexane, dabigatran -Cleave plasminogen to plasmin by streptokinase, urokinase, rt-PA Clinical implications: -reduced risk of thrombosis -enhanced fibrinolysis -prolonged bleeding time -increased bleeding time
What is the extrinsic pathway
Tissue injury causes tissue factor (thromboplastin) to be released from endothelial cells, monocytes, macrophages and nijured tissue cells. Tissue factor activates factor VII. Leads to the common pathway Involves factor 7 and tissue factor
Acquired severe liver disease
Coagulation factors are mostly made in the liver Severe acute or chronic liver disease causes: -reduced production of vit K dependant factors (2, 7, 9, 10) -reduced production of fibrinogen -thrombocytopenia due to reduced production and survival
Why do we get bleeding disorders
Due to a problem with: -endothelium or BVs (fragile) -Platelets (deficient or defective) -coagulation factors (deficient or defective)
what is APTT
activated partial thromboplastin time. Targets intrinsic pathway of coagulation
When are you at higher risk of acquired thrombophilia
-prolonged immobilisation -MI -atrial fibrilation -prosthetic valves -surgery -fracture -malignancy
What is a pulmonary embolsim
95% arise from DVT in leg breaking off and travelling to the lungs and get lodged in pulmonary arteries Major contributing cause of death in 10% of acute adult hospital deaths Usually in predisposed patients = underlying disorder, immobilised, hyper-coaguable
What is aplastic marrow
It when haemopoetic tissue in the bone marrow is damaged and replaced with fat.
what are the clinical consequences of arterial thrombosis
-occlusion and infarction e.g MI, stroke -embolisation and downstream infarction e.g stroke, limb gangrene, renal and bowel infarcts
Abnormal or deficient clotting factors
Bleeding -large post-trauma ecchymoses and haematomas and get can bleeding into joints and muscles (haemarthrosis) -prolonged bleeding post trauma or surgery- can be oozing blood for days post dental extraction. Inherited : usually single factor deficiency e.g vWF, haemophilia Acquired: usually multiple factors e.g liver disease, warfarin, DIC
Why do you get the colour changes of a bruise
Red-blue = Hb Green-yellow = bilirubin yellow-brown = haemosiderin
What does the presentation and outcome of PE depend on
-extend that pulmonary arterial blood flow is obstructed -size of the occluded BV -number of emboli -overall status of CV system -release of vasoactive factors from platelets -note that atheletes can have increased risk if had trauma, fracture, injury
What is Virchows Triad
Shows the 3 things involved in pathogenesis of a thrombosis -endothelial injury -abnormal blood flow -hypercoagulability
How can obesity cause acquired thrombophilia
Risk of VTE increases with BMI and have higher risk of recurrence in obese people Why? 1. Physical effects of body fat limits venous return 2. an environment that is -proinflammatory = increased FFAs, cytokines, oxidative stress, endothelial dysfunction -prothrombotic = increased fibrinogen, factor 7 and 8, vWF, leptin -hypofibrinolytic = increased plasminogen activator inhibitor (PAI-1)
What are the clinical consequences of PE
-respiratory compromise -hemodynamic compromise -risk of recurrence
What blood flow causes arterial thrombus
turbulence
What is an embolism
An obstruction in a BV due to material that gets stuck whilst traveling in the blood stream -thrombus (thromboembolism) -air -fat -amniotic fluid
What is HIT
Acquired thrombophilia = heparin-induced thrombocytopenia -antibodies (IgG) bind to complexes of heparin and platelet factor 4 on the surface of platelets= immune complex: -triggers activation and aggregation of platelets = thrombin activation = thrombosis -macrophages remove the platelets = thrombocytopenia Associated with venous and arterial thrombosis
What is the fate of venous thrombosis
-resolution -embolisation to the lungs -organised and incoporated into the vessel wall
Abnormal blood flow
Normal flow = laminar = cells are in the middle and are separated from the endothelium by a slower layer of plasma Disruption in blood flow = turbulence and stasis = -platelets come into contact with endothelium causing adhesion and activation -prevents washout of activated clotting factors and the inflow of clotting inhibitors -turbulence can also cause endothelial injury or dysfunction
What is thrombocytopenia
Low platelet count Can be mild (50-150 x10^9 / L), moderate (20-50) or severe (< 20). Bleeding: -mucosal (epistaxis (nose), menorrhagia (heavy period), GI tract, gingiva and palate) -surgical wounds -increasing bruising tendency in skin -intracerebral -rare but potentially fatal
What are the inherited and acquired platelet function defects
Inherited defects of adhesion, aggregation or secretion. -mostly midly -effects enzymes, receptors, storage granules Acquired causes: -uermia (renal disease) -drugs and food related: -aspirin and other NSAIDs -Anti-platelet receptor drugs -herbal remedies -garlic, chocholate
what is PT and INR
PT = prothrombin time = time it takes for blood clot INR = international normalised ration = ratio of patients clotting time to the normal mean clotting time. Targets extrinsic pathway
What is fibrinolysis
Triggered by the activation of the coagulation cascade or by plasminogen activators e.g t-PA (tissue plasminogen activator) Plasminogen is cleaved to plasmin which breaks down fibrin and interferes with its polymerisation. There will be fibrin degradation products such as FDP, FSP, D-dimers which can be measured in the blood
Section 9
(50 cards)
Why do you need to fast for 12 hours after eating before doing a lipid test
You would have expect to have excess chylomicrons in circulation following a high-fat meal- fasting for 12 hours means that the excess chylomicrons from food will be gone. If you still have a high TG measurement after a 12 hour fast = may have a lipoprotein disorder
Do the lipids themselves cause atherosclerosis
No, its the particles that contain the lipids
Cholesterol
Its a key component of: -bile acid -sex and adrenal hormones - Vit D When we look at lipoproteins = talking about cholesterol with free fatty acid attached. Most of the cholesterol in the blood will be in the form of cholesterol esters.
LDL
Density = low IDL catabolism Apoproteins = B-100 Lipids = TG (5%), high cholesterol (60%) Key in transporting cholesterol around the body
Pathogenesis of atherosclerosis
1. Damage to endothelium (excess lipoproteins, HTN, diabetes smoking etc) = platelet adhesion/activation resulting in thrombus and allows LDL to enter into intima = LDL gets oxidised 2. Oxidised LDL gets engulfed by macrophages = foam cells = release cytokines to recruit more monocytes into the initima = more macrophages = more foam cells 3. Foam cells die = lipid layer stay in arterial intima = necrotic lipid core 4. cytokines also causes more LDL to be oxidised and recruits smooth muscle cells (PDGF from also recruits and causes proliferation) into the intima from the media--> proliferation of smooth muscle cells = occludes the lumen. The smooth muscle cells can also take up oxidised LDL = lipid rich smooth muscle cells adding to lipid core 5. Smooth muscle cells form a fibrous cap on the atherosclerotic plaque As long as the fibrous cap is intact the plaque is stable. The bigger the plaque gets the more unstable it becomes = caps weakens and can rupture = exposure of lipid core to platelets = thrombus formation = occlude artery and can lead to embolism and thus greater risk of mortality
Mechanical treatment of thrombosis
Thromboectomy or embolectomy -reserved for arterial thrombosis, massive DVT or patients who fail anticoagulant or fibrinolytic therapy. -catheter -surgically remove thrombis/embolism -last resort because always a risk that it will create more damage
What is type III lipid disorder
Increased IDL and chylomicron remnants = increased cholesterol and TG
What is a saddle embolus
It is a large embolus that can get stuck in the major branches of the pulmonary trunk --> sudden death: -RV cant pump blood to the lungs -Acute right sided heart failure
What are D-dimers
-These are fibrin degradation products (FDP) produced by fibrinolysis -Elevations are non-specific because it can occur in DVT, PE and other conditions such as malignancy, infection and age. -it has high negative predictive value in the diagnosis of thrombosis because if its negative you can exclude a thrombus but if its positive its doesn't necessarily mean they have a thrombus
Phospholipid
-glycerol -2 fatty acids -phosphate group Major constituent of cell membranes and lipoproteins Has a hydrophobic and hydrophilic part
What is type I lipid disorder
Chylomicrons increased = increased TG
Chylomicrons
Density = lowest Intestine Apoproteins = C-II, C-111, E Lipid = high TG (85%), cholesterol (10%) Key in transporting TG around the body
What is type IV lipid disorder
Increased VLDL = Increased TG
IDL
Density = intermediate VLDL catabolism Apoproteins = B-100, E Lipids = TG (25%), cholesterol (35%)
What are the normal lipid levels
We no longer use reference ranges because even if your in the range you may still have high lipid level and therefore at risk of atherosclerosis-> use optimal levels instead. total cholesterol = <5.2 mmol/L LDL cholesterol = <2.59 TAG = <1.7
Why are lipid level important
Because as cholesterol increases, CHD mortality rate increases exponentially 54% of people admitted to hospital with a heart attack have high cholesterol and many people are unaware of this--> blood tests are used to measure lipid levels.
How to we investigate DVT/PE
-clinical examination, history -chest X-ray, ECG -Ultrasound scan with compression (normally with compression the vein will close and the artery will stay open due to high pressure but if have a thrombus it will appear open) -Coagulation testing for fibrin degradation products (D-dimers) -CT venography
Endogenous lipoprotein metabolism pathway
Endogenous = lipid made in the body and then transported The liver produces VLDL (high TG)--> delivers TG to muscle and adipose involving ApoC-II and LPL--> becomes IDL after delivering TG--> either be taken up by liver (Apo-E mediated) or more TG can be removed to become LDL--> LDL stays in cirulation and transports cholesterol around the body and back to the liver (ApoB-100 mediated). LDL is the key cause for atherosclerosis because is can be taken up by scavenger receptor
What is type IIa lipid disorder
Increased LDL = increased cholesterol
What are the major lipis
-cholesterol -phospolipid -fatty acids -triacylglycerol
TAG
Most of lipids in the blood stream are in this form Energy rich molecule Glycerol and 3 fatty acids
What is the major risk factor for CHD
Dyslipidemia (abnormal amount of lipids)
What will determine if lipoproteins cause atherosclerosis
-can it gain access to arterial wall -the amount that can be deposited -if it can leave once deposited (HDL can, LDL wont) -capacity to produce more atherogenic lipoproteins -capacity to remove lipid from the arterial wall
What are the 3 names for lipid disorders
Hypercholesterolemia = increase in cholesterol only Hypertriacylglycerols = increase in TG only Hyperlipidaemias = Increases in both
Prophylaxis for DVT/PE
-post op ambulation -physio -compression stockings -drugs for high risk patients e.g low molecular weight heparin
What lipids increase atherosclerotic risk
Elevated cholesterol and TG (high VLDL and LDL) and lower HDL
What are the types of lipoproteins
Chylomicrons (largest and least dense) VLDL IDL LDL HDL (smallest and most dense)
Where does the TG content come from for the endogenous pathway
-Most from CARB metabolism not fat -Excess dietary carbs are converted to FFA and then to TG which is stored in adipose tissue -FFA from other lipoproteins delivered to the liver and from adipocytes
How are lipids transported in the blood stream
The poor water solubility of lipids (hydrophobic properties) creates a problem for their transport in the blood stream. --> free fatty acid is bound to serum albumin --> TAG, phospholipid and cholesterol are packaged in lipoprotein particles.
What are the key cells involved in atherosclerosis and there roles
1. Endothelial cells -regulate permeability to lipoproteins -secrete collagen leading to fibrosis -stimulates proliferation and migration of smooth muscle cells 2. Platelets -stimulate proliferation and migration of smooth muscle cells by PDGF 3. Smooth muscle cells -take up LDL and other lipids to become foam cells -synthesis collagen and proteoglycans 4. Macrophages -oxidise LDL -take up lipids = foam cells -secrete cytokines = recuits more monocytes, SMC proliferation and more oxidation of LDL 5. Lymphocytes -TNF may affect lipoprotien metabolism -stimulate proliferation and migration of SMCs 6. Neutrophils -secrete proteases leading to continued local damage and inflammation
Exogenous lipoprotein metabolism pathway
Exogenous = lipid from diet Dietary lipid --> small intestine --> chylomicrons made and have certain apolipoproteins --> chylomicron enters cirulations --> ApoC-II interacts with LPL (lipoprotein lipase) which lines the capillaries --> hydrolysis of TG to free fatty acid --> moves into the muscle for energy (beta oxidation) or adipose for storage (lipogenesis)--> chylomicron remnant (lost apoproteints) which has less TG travels to the liver and is removed from cirulation (ApoE is key for removal as it binds to a receptor on the liver)
What are apoproteins
A key component of lipoprotein particles. -key for metabolism of lipoproteins -some will stay on the same lipoprotein throughout metabolism (apoB) and some will switch between lipoproteins -Switching is key for turning on some parts of lipoprotein metabolism and switching off others.
What are foam cells
-Macrophages that have engulfed oxidised LDL = forms fatty streaks in the arterial intima -Can be seen in children
Fatty acids
-key energy source for aerobic metabolism in muscle -key for energy storage in adipose tissue -carboxylic acid with a aliphatic chain -can be saturated or unsaturated (mono or poly) -Saturated - increased risk of CVD -Mono unsaturated- reduces risk of CVD
What are the pharmacological treatments for thrombosis
1. Anticoagulant drugs:(prophylaxis) Prevents extension of the existing thrombus and formation of new ones. -Heparin, low molecular weight heparin (short term-IV or SC) -Warfarin, thrombin inhibitors (long term, oral) -Warfarin therapy is monitored by PT and INR 2. Fibrinolytic therapy (arterial) -for acute phase of thrombosis only e.g withing 24 hrs of MI -streptokinase, urokinase, rt-PA (tissue plasminogen activator) 3. Anti-platelet drugs (arterial) -useful for reducing arterial thrombotic risk -aspirin, clopidogrel
Atherosclerotic timeline
First decade = foam cells and fatty streaks, growth mainly by lipid accumulation from third decade = intermediate lesion and atheroma, growth mainly by lipid accumulation form fourth decade = fibrous plaque and rupture, smooth muscle and collagen, thrombosis
What are the sources of cholesterol
25% is diet 75% is produced from the liver
How do we get lipids
Either absorbed from food or synthesised in the liver
What is type IIb lipid disorder
increased LDL and VLDL = increased cholesterol and TG
What are the main atherogenic lipoproteins
-VLDL and LDL -LDL is the main 1 because it can become oxidised -Increased production or decreased clearance of VLDL, LDL -If you have impaired catabolism of VLDL it can lead to small dense LDL which can be more rapidly oxidised = more atherogenic -Reduced HDL will increase the risk as HDL is preventative -The ratio of HDL to LDL is important = want increased HDL and decreased LDL
Why are lipids required
TAG and cholesterol contribute most to disease but all lipids have functions in peripheral tissue: -source of energy -part of the cell membrane -help absorb fat soluble vitamins -hormone synthesis
VLDL
Density = very low Liver Apoproteins = B-100, C-II, C-III, E Lipids = high TG (55%), cholesterol (20%) Key in transporting cholesterol around body
Do chylomicrons increase risk of atherosclerosis
arent thought to but still a health concern if elevated
What apoprotein stays on the lipoprotein
Apo-B
What are the key apoproteins relating to lipid disorders
-ApoB-100 -ApoC-II -Apo-E
What is type V lipid disorder
Increased chylomicrons and VLDL = increased TG and cholesterol
Do all lipid disorders increase your risk of developing atherosclerosis
No not all will
What is the leading cause of death
Coronary heart disease -atherosclerosis comes under this
What is a lipoprotein particle made of
Spherical structure with a hydrophobic center. - hydrophobic core of TAG and cholesterol esters -free cholesterol and phospholipids are on the outside -by converting cholesterol to cholesterol esters lipoprotien particles can be made easier -Apoproteins
HDL
Density = highest Liver, intestine Apoproteins = A-I, E, C-II, C-III Lipids = TG (5%), cholesterol (20%)
Section 10
(50 cards)
What is a transmural infarction
Ischemic necrosis involves full or nearly full thickness of the ventricular wall in the distribution of a single coronary artery. Usually associated with chronic coronary atherosclerosis, acute plaque change and superimposed obstructive thrombosis
What is the problem with gangrene
If the foot is affected you cant just amputate the foot because it would heal due to poor nutrition so you wouldn't get a viable closure = need to amputate higher up below the knee
Stable angina
-Most common -chronic stenosing coronary atherosclerosis reaches a critical level = heart is vulnerable during increased demand because it cant increase oxygen supply. -typically relieved by rest or a vasodilator
Epidemiology of atherosclerosis
-present in western and other developed countries -responsible for at least 1/2 of all deaths in developed countries -evidence that incidence of complications is declining- rate of death from MI is declining
Features of pulmonary
Between RV and pulmonary trunk Semilunar with 3 cusps
Features of tricuspid valve
Right AV valve between RA-RV 3 leaflets chorade tendinae attached to papillary muscle
Pathogenesis of angina
Increased oxygen demand by the heart cant be compensated by the stenosed coronary artery = sudden, recurrent chest pain -transient myocardial ischemia lasting from 15 seconds to 15 min but doesn't cause myocyte necrosis
What is atherosclerosis
It is an inflammatory disease of the CDV system affecting arteries --> leads to narrowing of arteries or complete blockages Main components = endothelial dysfunction, lipid deposition, inflammatory reaction. Remodelling of the vessel wall
What are the clinical problems of athersclerosis
1. Cardiac -angina pectoris -MI -sudden death 2. Cerebral -TIA -Stroke 3. Lower limb -intermittent claudication -gangrene 4. Aorta -aneurysm rupture (relatively common-can operate and resect it) 5. Intestine -transient ischemia and infarction 6. Other -renal infarction -retinopathy
How do you get coronary artery occlusion
The atherosclerotic plaque narrows the lumen and it can rupture = -> heal = severe fixed coronary obstruction (chronic IHD) -> Mural thrombus-acute (embolise) -> Occlusive thrombus-acute
Areas of perfusion of the heart
Left anterior descending artery = supplies most of the apex of the heart and anterior wall of the LV and the ant 2/3 of the ventricular septum. Left circumflex branch = supplies lateral wall of LV Right coronary artery = supplies RV, post 3rd of ventricular septum and post-basal wall of LV
What macroscopic changes will you see in MI
up to 12 hours = none to occasional mottling 12-24 hrs = dark mottling 3-7 days = central yellow tan with hyperaemic border 2-8 weeks= grey, white scar
What can happen if you have right or left heart failure
Right: -> congestion of peripheral tissues = ->oedema ->GI tract congestion -> anorexia, GI distress, weight loss ->liver congestion -> signs related to impaired liver function Left: -> decreased cardiac output-> activity intolerance and signs of decreased tissue perfusion -> pulmonary congestion = ->impaired gas exchange -> cyanosis and signs of hypoxia -> pulmonary edema -> cough with frothy sputum, orthopnea (distress when lying down), nocturnal dyspnea (breathlessness at night)
What are the causes of coronary ischemia
Partial obstruction -usually stable plaque -coronary vasospasm (rare) Complete obstruction -usually and unstable plaque
Interventricular septal rupture
• Occurs in 0.2% of patients with AMI • Higher 30-day mortality (74%) compared to those patients who do not develop this complication (7%)
What is LPL deficiency
-Rare -Recessive -Mutation of LPL -Cant remove TG from chylomicrons -> elevated chylomicrons -> cholesterol is normal to high -> TG is very high -> No atherogenicity -> relative frequency = <1
Unstable angina
-The pain occurs with progressively increasing frequency and tends to be more prolonged -associated with disruption of the atherosclerotic plaque, with superimposed thrombus and embolisation. -predictor of MI
What are the early complications of MI
-pericarditis -sudden death -cardiogenic shock -myocardial rupture: 3-7 days post MI--> septal wall rupture (cardiac tamponade) --> papillary muscle (acute valve dysfunction)
What arteries develop atherosclerosis
Large or elastic arteries: -aorta and large branches (iliac, common carotid, subclavian) Medium sized or muscular arteries: -coronary -cerebral -vertebrobasilar -renal -femoral -popliteal
What changes in an ECG might be seen in MI
1. elevation of ST 2. Inversion of T wave 3. Increased amplitude of Q wave
HDL metabolism
-HDL has key antioxidant properties = can reduce the amount of oxidised LDL -It can also enter arterial intima and take cholesterol away -HDL metabolism is complicated -Metabolism starts as a lipid pore particle and gains lipid -Small HDL particles are more rapidly removed -Reduced HDL = less particles to remove cholesterol from foam cells
What are secondary causes of combined hyperlipidemia
-Frequent in post menopausal women 1. hypothyroidism= decrease VLDL and LDL clearance 2. Cushing's syndrome = increase in VLDL production and conversion to LDL 3. Nephrotic Syndrome = increased VLDL and conversion to LDL
What drugs can stop the body from making more cholesterol
Statins
What are secondary causes of hypertriglyceridemia
Diabetes = increased VLDL production and decreased clearance Lipodystrophy = increased VLDL production Alcohol = increased VLDL production
Lipoproteins containing what apoprotein are athero protective
ApoAI -HDL -removes lipid from foam cells
What are clinical manifestations of IHD
1. Angina pectoris 2. MI 3. Chronic IHD 4. Sudden cardiac death
Prinzmental angina
-uncommon pattern -occurs at rest -due to arterial spasm -no related to physical activity, HR or BP -responds to vasodilators
How to detect MI in lab
Based on measurement of intracellular macromolecules leaked from damaged myocytes into circulation -Creatine kinase -Lactate dehydrogenase -Troponin (1 and T)
Lipoproteins containing what apoprotien are pro atherogenic
ApoB -LDL -VLDL
Hypertriglyceridemia
->elevated VLDL -> normal to high cholesterol -> high TG -> atherogenecity -> relative frequency = 45
Complications of MI
look at flow chart on lecture 19
What is Tangiers disease
A rare lipid disorder causing very low HDL. -large orange tonsils -mutation in ABCA-1 particles = cant remove the cholesterol from cells onto HDL = HDL particles are rapidly removed
Increased IDL
-IDL is normally metabolised fast so you dont normally see it -Mutation of ApoE particularly E2 -> high IDL and chylomicron remnants -> high cholesterol -> high TG ->high atherogenicity -> relative frequency = <1 Mainly found in homozygotes carrying ApoE2 variant- however only <5% develop hyperlipidemia = other genetic and environmental factors involved
What is a subendocardial infarct
Necrosis is limited to the inner 1/3 or at most one half of the ventricular wall. (regional subendocardial MI) May extend laterally beyond the perfusion territory of a single coronary arter (circumferential subendocardial infarct) In a majority of cases there is diffuse stenosing coronary atherosclerosis
Early MI
-20 min of ischemia leads to necrosis -Necrosis begins in subendocardial zone = area most distal from the vessel -Zone of necrosis extends over next 3-6 hrs can can be minimised therapeutically by thrombolysis
What is an aneurysm
-A localised abnormal dilation of a BV -not all are caused by athersclerosis Aortic anuerysm: -atherosclerotic aneurysms develop in the aorta below the renal arteries -the thinned media weakens the wall -often a mural thrombus on wall -the aneurysm can rupture
What are the possible causes of lipid disorders
-monogenetic -polygenetic -secondary -genetic and environmental
What are the 3 types of angina
1. Stable = happens upon exertion 2. Prinzmental = due to vasospasm 3. Unstable = can happen at any time, including at rest_
Features of mitral valve
Left AV valve between LA-LV 2 leaflets chordae tendinae attached to papillary muscle
What microscopic changes will you see in MI
• Early coagulation necrosis and oedema; haemorrhage (4-12 hours) • Pyknosis of nucleic, hypereosinophilia, early neutrophilic infiltrate (12-24 hours) • Coagulation necrosis, interstitial infiltrate of neutrophils (1-3 days) • Dense collagenous scar (> 2 months)
What are the later complications of MI
• Infarct extension • Mural thrombus • Ventricular aneurysm • Myocardial rupture - Ventricular free wall - Septal - Papillary muscle
How does type 1 diabetes cause hypertriglyceridemia
Insulin is key for inhibiting HSL (hormone sensitive lipase) and activating LPL.(lipoprotien lipase) Diabetics= no insulin = break down too much FFA from adipose tissue because cant inhibit HSL = go to the liver and be converted to TAG and then VLDL. Also wont be able to take up as much VLDL because LPL is inhibited --> increased VLDL production and decrease clearance = net VLDL increase
What are risk factors for athersclerosis
The causes haven't been determined with certainty but there are predisposing risk factors: Unmodifiable: -age -male (due to protective effects of natural estrogens from pre-menopausal women) - family history of premature CHD Modifiable: 1. Hyperlipidemia =strongest risk factor for athersclerosis in people <45 -both primary and secondary hyperlipidemia increase the risk -can be treated by diet, meds (statins) 2. Smoking -free radicals destroy endothelium 3. Hypertension -mechanical stress on endothelium -major risk factor in all age groups 4. Diabetes Mellitus -elevates blood lipid levels
What is IHD
Ishemic heart disease is a generic name for a group of closely related syndromes that result from myocaridal ischemia. In over 90% of cases its due to a reduction in coronary blood flow. Other conditions arise as a result of increased demand e.g hypertrophy, shock, increased HR
Cardiogenic shock
• Most severe clinical expression of LV failure • Occurs in up to 7% of patients with AMI • Low output state characterized by elevated ventricular filling pressures, low cardiac output, systemic hypotension, and evidence of vital organ hypoperfusion
Features of aortic
Between LV and aorta Semilunar valve with 3 cusps
What is familia hypercholesterolemia
It is a mutation in the LDL receptor -> high LDL -> high cholesterol -> normal TG -> high atherogenicity -> relative frequency = 10 -> 1/500 people in NZ -> family history of CVD -> both heterzygotes and homozygotes will have increases cholesterol levels by homozygotes more so -> orange tint of plasma because LDL transports fat soluble vitamins
What are the effects of ischemia on myoctyes
• Onset of ATP depletion = sec • Loss of contractility = < 2 sec • ATP reduced -to 50% of normal = 10 min -to 10% of normal = 40 min • Irreversible injury = 20-40 min Microvascular injury = >1 hr
What can be a complication of a plaque
Ulceration and calcification -abdominal aorta -coronary arteries (MI) -iliopopliteal arteries (can cause gangrene and amputation) -vertebrobasilar arteries (stroke) -carotid arteries (stroke)
What are the infectious inflammatory causes of athersclerosis
Research has suggested a link between atheroslerosis and chronic inflammation due to micro-organisms- particularly peridontal disease -chlamydophilia pneumonia -H. pylori - Cytomegalovirus
Section 11
(21 cards)