ic3 Flashcards
thrombosis
process in which thrombus forms
thrombus
intravascular mass formed during life from constituents of blood (blood clot)
predisposing factors for thrombosis
1) injury to endothelium
2) alteration in blood coagulability
3) alteration in blood flow
venous thrombosis
stasis -> build up of activated clotting factors -> thrombus formation
deep vein thrombosis
common clinical states for thrombosis
1) atrial fibrillation: desynchronised, irregular, ineffective beating of atrium in form of cardiac arrhythmia (irregular heartbeat) -> pockets of stasis in atrium -> increased possibility of thrombus formation -> spread to other parts of body -> cerebral infarction -> stroke
2) prosthetic cardiac valves
3) major surgeries (post op/post-partum state)
4) prolonged bed rest/immobilisation (deep veins in legs/pelvis)
5) disseminated cancer (cancer cells produce procoagulant substances -> inappropriate thrombosis)
6) oral contraceptive (increased oestrogen)
clinical significance of thrombosis
thrombus in veins -> local vascular occlusion (venous congestion, swelling, pain in affected lower limb) -> embolisation -> vascular occlusion elsewhere
thrombus in arteries -> arterial occlusion -> decreased blood flow to affected organ (ischaemia), cerebral artery -> brain necrosis, coronary artery -> myocardial necrosis, renal artery -> renal necrosis
fate of thrombus
1) ideal: resolution/lysis: broken down naturally by body natural fibrinolysis mechanisms/aid of drugs
2) propagation: thrombus enlarge, partial occlusion become more complete occlusion -> > serious outcomes
3) organisation & recanalisation: new blood vessels form, restore some degree of blood vessel formation
4) embolism: thrombus dislodged, travel to other parts of circulation, occlude elsewhere
embolism
process where embolus is carried by blood to site distant from point of origin
embolism
process where embolus is carried by blood to site distant from point of origin
embolus: detached intravascular solid/liquid/gaseous material
type of emboli
1) solid (e.g. detached thrombus, tissue fragments, tumour clumps, foreign body)
2) liquid (e.g. fat lobules, amniotic fluid)
3) gaseous (e.g. air, nitrogen)
4) septic (infected blood clot, e.g. fungi, bacteria)
effects of embolism
1) vascular occlusion (necrosis of target organs, death)
2) septic emboli (infection)
3) tumour dissemination (cancer)
pulmonary (thrombo) embolism
comes from venous thrombosis (deep veins of legs/pelvis)
effects: sudden death (acute right heart failure), pulmonary necrosis
special types of embolism
1) fat (fat from bone marrow released during fracture)
2) air (DCI)
3) amniotic fluid
infarction
necrosis due to ischaemia (usually occlusion of artery, sometimes occlusion of venous drainage)
types of infarcts: white infarct (non-haemorrhagic), red infarct (haemorrhagic)
arterial occlusion -> renal infarct, venous occlusion -> testicular torsion
effects of ischaemia
1) remains viable/compensated by overlapping blood supply
2) infarction
3) healing by fibrosis
4) ischaemic atrophy
inflammation
first local response to injury
acute and chronic differentiated by duration, type of inflammatory cells
not all inflammation caused by infection, these type treated by anti-inflammatory/immunosuppressive meds/antibiotics
signs of inflammation
warmth (calor) (vasodilation)
redness (rubour) (vasodilation)
swelling (tumour) (oedema)
painful (dolor) (stimulation of nerve ending/medications that cause pain)
loss of function (functio laesa) (tissue damage/voluntary lack of use)
physiological response in acute inflammation
1) vascular response/changes
. increase blood flow (vasodilation)
. increase vascular permeability (loss of endothelial cell integrity, leakage of fluids/plasma proteins, transudate -> exudate)
. increase endothelial cell permeability (expression of adhesion molecules, production of chemokines)
2) cellular response: recruitment of leukocytes
. accumulation of leukocytes at injury site
benefits of vasodilation and oedema
1) improve supply of oxygen and nutrients
2) dilution of harmful chemicals/toxins
3) ‘deliver antigens’ to draining lymph nodes
4) facilitate emigration of leukocytes
5) bring in vital plasma proteins (fibrinogen, complement, antibodies, mannose-binding lectins), induce lysis, acts as opsonins (enhance phagocytosis)
leukocyte recruitment
1) adhesion to endothelial cells (produce chemokines to attract WBC)
2) diapedesis (transmigration of WBC, squeeze between gaps of blood vessel into tissue space)
3) chemotaxis (other WBC & cells produce chemicals that attract WBC)
primary effector cells during early phase of inflammation
macrophages, neutrophils
main functions of macrophages
1) phagocytosis of bacteria
2) production of inflammatory mediators
3) synthesis of molecules affecting antiviral defences
4) initiation of immune response
5) clean up (scavenging)
6) fever, acute phase reaction, cachexia
properties of chemical mediators of inflammation
1) cell derived (produced locally)/plasma
2) stored/easily generated
3) liable (short-lasting effects)
4) localised effects
5) bind to receptors of target cell
6) similar/opposing effects (control mechanism)
functions of chemical mediators of inflammation
1) vasodilation/vascular permeability
2) leukocyte recruitment & stimulation
3) systemic effects
inflammatory mediators
histamine, complement, arachidonic acid metabolites, TNF & IL-1
inflammatory mediators - histamine
stored preformed
sources: mast cells, platelets, basophils
short life in tissues (about 30s)
act via H1 receptors
cause vasodilation of arterioles
increase vascular permeability in venules
early trigger of inflammation
anti-inflammatory drugs (antihistamines) interfere with action of histamines
inflammatory mediator - complement
present in plasma & extracellular fluids
act via cascade system to form membrane attack complex (MAC)
actions: MAC (direct lysis of microbe/cell), complement fragments increase vascular permeability, chemotaxis, opsonin
activated via classical/alternative/lectin
inflammatory mediators - arachidonic acid metabolites
COX pathway (prostaglandins, thromboxane)
lipoxygenase pathway (leukotrienes, lipoxins)
functions:
1) induce vascular change
2) contribute to leukocyte recruitment (direct stimulation/ chemoattractant)
3) enhance platelet aggregation
4) some exert opposing effects (PGI2 vs TXA)
inflammatory mediators - TNF & IL-1
main cellular source of macrophage activation
chemokines
small proteins produced by endothelium, macrophages, leukocytes
immobilised on cell surface/extracellular matrix, provides chemotactic gradient (attract leukocytes)
bind to receptors expressed on leukocytes
regulate leukocyte migration & activation
other chemotactic agents: complement fragments, bacterial & mitochondrial products, leukotriene B4)
acute phase proteins
usually plasma proteins from liver
released within hours of injury
triggered by IL-1, IL-6, TNF
C-reactive protein (CRP) level as indicator of disease severity
normal < 0.5 mg/dl, inflammatory response -> increase by 100-1000x, host defense
forms of acute inflammation
1) suppurative/purulent inflammation
. pus (purulent exudate): neutrophils, cell debris, microbes, pyogenic bacteria
. abscess: abnormal cavity filled with pus (within solid tissue/pre-existing spaces)
2) serous inflammation
. characterised by copious amount of watery fluids with low cellular content
3) ulcer (usually when more chronic inflammation)
. near surface, damage to epithelial tissue (e.g. tissue necrosis)
. common in: mouth, stomach/intestine, genitourinary tract
function and consequences of inflammation
complex responses/reaction to injury, prevent spread, neutralise injurious agent, remove damaged cells/tissues, allow healing
may cause tissue damage/pathophysiological changes that cause further tissue damage
outcomes of acute inflammation
1) resolution (normal function)
2) extensive tissue damage -> fibrosis/scarring
3) chronic inflammation -> fibrosis/scarring
4) fibrosis/scarring
chronic inflammation
occurs when there is persistence of damaging stimulus so complete healing cannot occur
major contribution from adaptive immune response, long duration
causes of chronic inflammation
1) persistent infection by organisms difficult to eradicate (e.g. TB)
2) immune-mediated disease (especially autoimmune disease)
3) prolonged exposure to injurious agent: exogenous (external cause)/endogenous (internal cause)
4) lower host resistance
chronic inflammation characterised by
1) infiltration of mononuclear cells (macrophage, lymphocytes, plasma cells)
2) tissue destruction
3) attempts at healing
granulomatous inflammation
formation of granuloma (tiny white cluster of WBC & other tissues)
composed of epithelioid cells (transformed macrophages), multinucleated giant cells, lymphocytes (T cells)
pathogenesis process:
1) injury (bacterium/fungus/foreign particles)
2) inability to digest inciting agent
3) failure of acute inflammatory response
4) persistence of injurious agent
5) cell-mediated immune response / sequestration within macrophages
6) recruitment of macrophages with epithelioid & giant-cell formation
7) granuloma
importance of macrophages in inflammation termination
macrophage clean inflammatory site of cell debris, removal of dead neutrophils & secreted products (scavenging)
macrophage depletion, deficiency in molecules for macrophage infiltration = delayed healing
regeneration
replacement by cells of the same type
only in cells that can divide
> specialised cells = less likely to be replaced
underlying connective tissue must be intact
features of regeneration
1) migration: neighbouring cells move into wound area
2) contact inhibition: regeneration stops when wound covered
3) usually involves proliferation of neighbouring cells of the same type
why repair (wound healing) lead to scars
. replacement of tissue by different type
. formation of loose connective tissue (granuloma tissue), reepithelisation over hole, restore physical barrier to prevent entry of pathogens, provide support to damaged tissue to continue to function as best as it could
. occurs if tissue incapable of complete restitution/supporting structure tissue damaged
. persistent tissue damage -> fibrosis
growth of granulation tissue
granulation tissue rich in capillary buds & fibroblasts
grows from edge into damaged area
caused by sprouting of blood vessels
macrophage scavenge & secrete angiogenic growth factors & fibrogenic growth factors
angiogenesis
formation of new blood vessels
starts at 48-72 hours following homeostasis
sprout from pre-existing vessels
mobilisation of endothelial precursor cells from bone marrow
fibroblasts
migrate to cleaned, vascularised site
active proliferation
synthesise and deposit collagen (vitamin c responsible for collagen synthesis)
wound contraction
granulation tissue contracts
fibroblasts/myofibroblasts are contractile
draw edges of damaged area together
scar maturation and remodeling
increase amount of collagen
remodeling of granulation tissue composition (months-years)
. net result between synthesis & degradation of collagen & other extracellular matrix material
. modulated by metalloproteases
reabsorption of capillaries
deactivation of fibroblasts & decrease in numbers
scar tissue not as strong as normal
healing by
1) first intention: narrow wound with close approximated edge (e.g. surgical incision), small scar, strength 75% after 3 months, near normal after 1 year
2) second intention: broad wound, widely spread margins (e.g. deep skin burns, ulcers), larger volume of dead tissues to replace so longer to heal, big scar, functionally & aesthetically unsatisfactory
mediators for regeneration & wound healing (growth factors)
1) platelet-derived growth factor (PDGF)
2) transforming growth factor B (TGFB)
sources: macrophage, platelets, epidermal cells, fibroblasts, endothelial cells, lymphocytes
actions: fibroblast migration, fibroblast proliferation, angiogenesis, synthesis of connective tissue proteins
systemic factors that affect wound healing
1) age (younger heal better)
2) nutrition (protein & vit c deficiency inhibit collagen synthesis)
3) metabolic status (diabetes retards wound healing)
4) circulatory status (insufficient blood supply impair healing)
5) hormones (glucocorticoids anti-inflammatory effect, inhibit healin)
local factors that affect wound healing
1) infection
2) mechanical factors (movement delays healing)
3) foreign bodies (sutures impede healing, source of infection)
4) size, location, type of wound (richly vascularised area heals faster)
complications of wound healing
1) deficient scar formation: wound dehiscence (splitting open), ulceration (inadequate vascularisation), incision hernias (tear)
2) formation of contractures: following severe burns & chemical injuries, cause deformities (especially over joints)
3) excessive scar formation: hypertrophic scar (raised scar), keloid (overgrowth of scar tissue, overproduction of collagen, maturation arrest/block, dark skinned people more affected), excessive granulation tissue (protrudes above surrounding skin, prevent reepithelialisation
fibrosis
abnormal deposition of collagen that occurs in internal organs in chronic diseases
development of fibrosis
chronic inflammation -> activation of macrophage & lymphocytes ->
1) growth factors -> proliferation of fibroblasts, endothelial cells, specialised fibrogenic cells -> increase in collagen synthesis -> fibrosis
2) cytokines -> increase in collagen synthesis -> fibrosis
3) decrease in metalloproteinase activity -> decrease in collagen degradation -> fibrosis
diseases because of scarring
aortic valve stenosis
