Mechanisms Of Disease Flashcards
What is hypoxaemic hypoxia?
Arterial content of oxygen is low (high altitude, secondary to lung disease)
What are the 7 main causes of cell injury?
Hypoxia- oxygen deprivation
Toxins- glucose and salt in hypertonic solutions, high [CO2], poisons, asbestos, asbestos, alcohol, narcotic drugs, medicine, pollutants, insecticides, herbicides
Physical agents- direct trauma, extreme of temp, change in pressure, electrical currents
Immune mechanisms- immune system can damage cells: hypersensitivity reactions (host tissue damaged secondary to overlying vigorous immune reaction HIVES) and autoimmune reactions (immune system fails to distinguish self from no self GRAVES)
Microorganisms
Radiation
Dietary insufficiencies, deficiencies and excess
What is anaemic hypoxia?
Decreased ability of Hb to carry oxygen (anaemia, CO poisoning)
What is ischaemic hypoxia?
Interruption to blood supply (blockage of vessels, heart failure)
What is histiocytic hypoxia?
Inability to utilise oxygen, in cells dues to disabled ox phos enzymes (cyanide poisoning)
What reversible metabolic cell injury occurs as a result of hypoxia?
In mitochondria, there is less ox phos, less ATP=
- less sodium-potassium pump (dependent on ATP), influx of sodium followed by water influx of calcium, ONCOSIS
- increased anaerobic glycolysis, decreased pH (lactate build up), less glycogen, clumping of nuclear chromatin
- detachment of ribosomes from ER, less protein synthesis, increased lipid deposition
What reversible structural cell injury occurs as a result of hypoxia?
Swelling
Chromatin clumping
Autophagy with lysosomes (normal functioning)
Ribosomes dispersal
Bless (little bumps on the membrane surface where cytoskeleton has detached)
What irreversible metabolic cell injury occurs as a result of hypoxia?
Massive accumulation of cytosolic calcium (biologically very active)
Activates enzymes in the cytoplasm
- endonucleases (breakdown DNA)
- ATPase (breakdown ATP)
- Phospholipases (breakdown membrane)
- Proteases (breakdown membrane and cytoskeleton of proteins)
What irreversible structural cell injury occurs as a result of hypoxia?
Nuclear changes - pyknosis (shrinkage), karyorrhexis (fragmentation), karyolysis (dissolution)
Lysosomal rupturing (out flux of harmful enzymes)
Membrane defects (appearance of myelin figures- damaged membrane)
ER lysis due to phospholipases and professes
Amorphous densities in swollen mitochondria
What are the two main types of cell death?
Oncosis/ Necrosis
Apoptosis
What is Oncosis?
Spectrum of changes that occur in injured cells prior to death
Swelling of the cell
Contiguous groups of cells
What is necrosis?
(What we see)
Morphological changes that occur after a cell has been dead some time in a living organism, largely due to the progressive degradation of enzymes on a lethally injured cell
With oncosis
What are the two main types of necrosis and the two not so common types of necrosis?
Coagulative and liquefactive necrosis
Fat and caseous necrosis
What is coagulative necrosis?
More protein denaturation than release of protease enzymes
Cellular architecture is preserved - ghost outline
Solid consistency of dead tissue
Followed by acute inflammatory reaction
Tends to be due to ischaemia (=infarcts) and hypoxia
Heart, spleen and liver
What is liquefactive necrosis?
More protease enzyme release than protein denaturation
Tissue is lysed and disappears
Tends to be due to infection
Brain (even with no infection- in this case due to ischaemia = infarcts)
What is gangrene?
Necrosis visible to the naked eye
What type of gangrene forms as a result of coagulative necrosis?
Dry gangrene (umbilical cord)
What type of gangrene forms as a result of liquefactive necrosis?
Wet gangrene - usually due to infection
Where is gangrene most like to appear the body?
In ischaemic limbs - legs
It is dead and so cannot be salvaged
What is an infarct?
Area of necrosis due to ischaemia
(coagulative- heart, liver and spleen/ liquefactive- brain)
Can be white and red
What is white infarct and its causes?
Area of no blood
Obstruction of end artery (heart, kidney, spleen)
What is a red infarct and its causes?
Area full of blood
In organs with dual blood supplies, blockage of vein (exceeding arterial pressure), loose tissue ( haemorrhage from surrounding tissue), reperfusion (white–>red), collateral circulation (lots of anastomising blood vessels)
Bowel
What is an infarction?
Process of ischaemic necrosis
What is infarction caused by?
Thrombosis
Embolism
External compression of vein
Twisting of vessels
What is apoptosis?
Cell death with shrinkage
Induced by a regulated intracellular program where a cell activates enzymes that degrade its own DNA and proteins
Membrane integrity is maintained
Cells activate enzymes that deactivate its own DNA and proteins
Active process - requires energy
Single cells
When does apoptosis occur?
When cells which are no longer needed are removed to remain in a steady state
During hormone controlled involution
Cytotoxic T cell killing of virus infected or neoplastic cells
Embryogenesis
When cells are damages and there is DNA damage
What is caseous necrosis?
Amorphous (structureless) debris (no ghost outline) Particularly associated with TB Granulomatous inflammation (chronic)
What is fat necrosis?
Destruction of adipose tissue
Seen as a consequence of acute pancreatitis
- release of lipase from acinar cells- acts on fatty tissue of pancreas and on fat elsewhere in abdominal cavity
- fat necrosis causes release of free fatty acids which react with calcium to form chalky deposits (calcium soaps)- can be seen on X rays or with the naked eye at surgery/ autopsy
What are the two initiation and execution processes of apoptosis?
Intrinsic
Extrinsic
Describe intrinsic initiation and execution of apoptosis
Mitochondrial (apoptotic machinery within cell)
Various triggers- DNA damage, withdrawal of hormones or growth factors (p53 important)
Increased permeability of membrane
Release of cytochrome c from mitochondria
Cytochrome c interacts with APAF1 and caspase 9 to for, an apoptosome
Activates downstream caspases
Describe the extrinsic initiation and execution process of apoptosis
Rector mediated
Caused by external ligands (TRAIL and Fas)
Bind to death receptors (TRAIL R)
Activates caspases (independently of mitochondria)
Describe the degradation/ phagocytosis stage of apoptosis
Cell membrane breaks into membrane bound fragments by caspase action - APOPTOTIC BODIES
Apoptotic bodies express proteins on their surface that induces phagocytosis by neighbouring cell or phagocytes
Review free radicals and how they can cause cell damage
Free radicals are reactive oxygen species. They have a single unpaired electron in an outer orbit. This is an unstable configuration and because of this free radicals react with other molecules, often producing further free radicals. Free radicals are particularly produced in chemical and radiation injury, ischaemia-reperfusion injury, cellular aging, and at high oxygen concentrations. Free radicals attack lipids in cell membranes and cause lipid peroxidation. They can also damage proteins and nucleic acids. They are also known to be mutagenic. However they also have important roles in the body as they are produced by leucocytes and used for bacteria killing. They are also used in cell signalling.
Three free radicals are of particular biological significance in cells: OH• (hydroxyl) (the most dangerous), 02- (superoxide) and H202 (hydrogen peroxide). OH• can be formed in a number of ways:
Radiation can directly lyse water → OH•
The Fenton and Haber-Weiss reactions produce OH• (see below). Note that H202 and 02- are substrates for these reactions. This is one reason why it is important to rapidly remove 02- and H202 so that the more dangerous OH• cannot be generated.
The body has defence systems to prevent injury caused by free radicals. These are known as the anti-oxidant system. If there is an imbalance between free radical production and free radical scavenging and free radicals build up the cell or tissue is said to be in oxidative stress. This causes cell injury. The anti-oxidant system consists of:
Enzymes:
o Superoxide dismutase (SOD) catalyses the reaction O2- →H202.
H2O2 is significantly less toxic to cells.
o Catalases and peroxidases complete the process of free radical
removal: H202 → 02 + H20
Free radical scavengers that neutralise free radicals. Vitamins A, C and E and glutathione are free radical scavengers
In the extracellular matrix, storage proteins (e.g., transferrin and ceruloplasmin) sequester transition metals, e.g., iron and copper, which catalyse the formation of free radicals.
Review alcohol metabolism and how it can cause cell damage
Chronic excessive alcohol intake can result in psychological and physical dependence on alcohol. Ethanol (the type of alcohol that we drink) is metabolised by alcohol dehydrogenase, the cytochrome p450 enzyme CYP2E1 and catalase to acetaldehyde. This in turn is metabolised by aldehyde dehydrogenase to acetic acid. There are lower concentrations of alcohol dehydrogenase in women and this means that they can have a higher blood alcohol concentration then men who have drunk the same amount of alcohol. Approximately 50% of oriental people have reduced activity of aldehyde dehydrogenase resulting in a build-up of acetaldehyde when they drink alcohol. This results in symptoms such as facial flushing. Metabolic tolerance to alcohol can occur due to induction of CYP2E1. This increases the rate of metabolism of ethanol and will also increase the rate of metabolism of other drugs that are metabolised by this enzyme.
Excessive alcohol intake can affect many organs. Here we will consider its three major effects on the liver:
Fatty change – the toxicity of alcohol to the liver results in steatosis which can be so marked as to cause hepatomegaly. This happens acutely, is reversible and generally asymptomatic.
Acute alcoholic hepatitis – as alcohol and its metabolites are directly toxic, a binge of alcohol can result in acute hepatitis with focal hepatocyte necrosis, the formation of Mallory bodies and a neutrophilic infiltrate. It can give symptoms of fever, liver tenderness and jaundice. It is usually reversible.
Cirrhosis – this occurs in 10-15% of alcoholics. It results in a hard, shrunken liver and histologically appears as micronodules of regenerating hepatocytes surrounded by bands of collagen. It is irreversible and serious, sometimes fatal.
Review paracetamol metabolism and overdose and how it can cause cell damage
Paracetamol is detoxified in the liver by sulphonation and glucuronidation, Small amounts are metabolised by cytochrome p450 oxidation (CYP 2E1) to a highly toxic metabolite (N-acetyl-p-benzoquinone imine (NAPQI)). NAPQI is detoxified by interaction with glutathione. If a large dose of paracetamol is ingested, glutathione is depleted and NAPQI accumulates. It binds with sulphydryl groups on liver cell membranes, eventually causing hepatocyte necrosis and liver failure. With a large paracetamol overdose massive liver necrosis occurs 3-5 days after the overdose. This can be fatal.
Some people have lower reserves of glutathione and in them paracetamol overdose is more dangerous. Such people include:
Those who took alcohol with the paracetamol overdose.
Those who are alcohol dependent.
Malnourished people.
People on enzyme-inducing drugs, e.g., carbamazepine.
People who are HIV positive or who have AIDS.
People who have taken an overdose of paracetamol can be given an antidote called N-acetylcysteine (NAC). This increases availability of hepatic glutathione. To decide whether NAC is required, from 4 hours after the overdose the serum concentration of paracetamol is measured. The prothrombin time (or the INR) measured 24 hours after the overdose is a guide to the severity of the liver damage in these patients.
Review aspirin overdose and how it can cause cell damage
Aspirin (acetylsalicylic acid) is a drug which acetylates platelet cyclooxygenase and blocks platelets’ ability to make thromboxane A2, a substance which activates platelet aggregation. The major consequences of aspirin overdose are metabolic. Aspirin stimulates the respiratory centre which results in a respiratory alkalosis. Compensatory mechanisms result in a metabolic acidosis. A fall in serum pH indicates serious poisoning.
Aspirin in overdose also interferes with carbohydrate, fat and protein metabolism and oxidative phosphorylation. This results in an increase in lactate, pyruvate and ketone bodies all of which contribute to acidosis.
As platelet cyclooxygenase is inhibited there is decreased platelet aggregation and petechaie may be present. Aspirin in overdose can also cause acute erosive gastritis producing GI bleeding.
What is acute inflammation?
Acute inflammation is the response of living tissue to injury, initiated to limit the tissue damage.
What are the main causes of acute inflammation?
Causes of Acute Inflammation: - Microbial infections o E.g. Pyogenic Organisms - Hypersensitivity reactions (acute phase) - Physical agents - Chemicals - Tissue necrosis
What are the macroscopic features of acute inflammation?
Calor – Heat
Rubor – Erytherma (Redness)
Tumor – Oedema (Swelling)
Dolor – Pain and loss of function
What are the main microscopic features of acute inflammation?
- Vasodilation
Small adjacent blood vessels dilate with increased blood flow. - Gaps form in endothelium
Endothelial cells swell and retract; there is no longer a completed intact internal lining. - Exudation
Vessels become leaky. Water, salts and small plasma proteins leak through. (Exudate) - Margination and Emigration
Circulating neutrophils adhere to swollen endothelial cells. (Margination.)
Neutrophils then migrate through the vessel basement membrane. (Emigration). - Macrophages and Lymphocytes
Migrate in a similar way to Neutrophils.
What are some of the chemical mediators of acute inflammation?
Vasodilation- histamine, prostaglandins, C3a and C5-
Increase vascular permeability- histamine, prostaglandins, kinins
Emigration of leukocytes- leukotrienes, IL 8, C5a
Describe the initiation and the action of neutrophils
Stasis causes neutrophils to line up at the edge of the blood vessels along the endothelium = MARGINATION
Neutrophils then roll along the endothelium sticking to it intermittently = ROLLING
They can stick more avidly = ADHESION
Followed by EMIGRATION (diapedesis) of neutrophils through the blood vessel wall (due to relaxation of inter endothelial cell junctions, digestion of vascular basement membrane and movements by chemo taxis)
Chemo taxis- movement of neutrophils along concentration gradients of chemo attractants
Neutrophils phagocytose microorganisms, by making contact, recognising and internalising them. Phagosomes are then fused with lysosomes to destroy the contents.
An activated neutrophil may also release toxic metabolites and enzymes, causing damage to the host tissue.
What are some local complications of acute inflammation?
Swelling - Blockage of tubes, e.g. bile duct, intestine Exudate - Compression, e.g. cardiac tamponade (fluid builds up in pericardial sac exerting pressure on the heart) - Serositis Loss of fluid - E.g. burns Pain and loss of function - Especially if prolonged
What are some systemic complications of acute inflammation?
Acute Phase Response
Decreased appetite, raised heart rate, altered sleep patterns and changes in plasma concentration of Acute Phase Proteins, such as C-Reactive Protein (CRP), Fibrinogen and a1-antitrypsin.
The spread of micro-organisms and toxins can lead to Shock, a clinical syndrome of circulatory failure (See CVS Session 12)
Fever Endogenous pyrogens (substances that produce fever) IL-1, TNFa and prostaglandin are produced.
Leukocytosis
IL-1 and TNFa produce an accelerated release from marrow. Macrophages, T-Lymphocytes produce colony-stimulating factors.
What may happen after the development of acute inflammation? (Sequelae)
- Complete resolution
- Suppurations- pus and abscess formation
- Organisation- formation of granulation tissue- a bit of chronic inflammation and fibrous repair
- Progression of acute inflammation onto chronic inflammation
- Death
What is resolution?
Complete restoration of tissues to normal after an episode of acute inflammation
All mediators of acute inflammation have short half-lives and may be inactivated by degradation, dilution in exudate or inhibition.
Gradually all of the changes of acute inflammation reverse, and the vascular changes stop. Neutrophils no longer marginate, and the vessel permeability and calibre returns tot normal.
Therefore, the exudate drains via the lymphatics, fibrin is degraded by plasmin/other proteases and the neutrophils die.
Damaged tissue may then be able to regenerate, but if tissue architecture has been destroyed, complete resolution is not possible.
What are skin blisters? (As an example of acute inflammation)
Skin Blister
- Caused by heat, sunlight, chemicals
- Pain and profuse exudate
- Collection of fluid strips off overlying epithelium
- Inflammatory cells relatively few, therefore exudate is clear
- Resolution or scarring
What is an abscess? (As an example of acute inflammation)
Abscess
- Forms as a result of suppuration (pus formation) in acute inflammation
- Solid Tissues
- Inflammatory exudate forces tissue apart
- Liquefactive necrosis in centre
- May cause high pressure, therefore pain
- May cause tissue damage and squash adjacent structures
What is pericarditis? (As an example of acute inflammation)
Pericarditis
- Inflammation of serous cavity
- Pericardium becomes inflamed and increases pressure on the heart
Lobar pneumoniae ? (As an example of acute inflammation)
Lobar Pneumonia
· Causative microorganism: Streptococcus Pneumoniae (Pneumococcus)
· Clinical course: worsening fever, prostration, hypoxaemia, over a few days, dry cough, breathlessness, can resolve completely if treated
Bacterial meningitis? (As an example of acute inflammation)
· Bacterial Meningitis
· Fluid accumulates in space between pia and arachnoid mater
· Acute inflammation in meninges can cause vascular thrombosis and reduced cerebral perfusion
What is chronic inflammation?
Chronic response to injury with associated FIBROSIS
What are the main causes of chronic inflammation?
- May ‘take over’ from acute inflammation
o If damage is too severe to be resolved within a few days, take over from suppurative inflammation (pus forms abscess)- abscess has thick pyogenic membrane (granulation and fibrous tissue; rigid abscess cavity walls fail to come together after drainage- fibrous scar formation) - May arise de novo
o Some autoimmune conditions (organ specific (hashimotos), non organ specific (RA) or contact hypersensitivity)
o Some Chronic Infections (E.g. viral hepatitis)
o Endogenous materials (necrotic adipose tissue and bone)
o Exogenous materials ( silica, asbestos fibres)
o Resistance of infective agent to phagocytosis and intracellular killing ( TB, leprosy)
o Diseases with unknown causes (chronic IBS - ulcerative colitis)
o Primary granulomatous disease (Crohns disease and sarcoidosis) - May develop alongside acute inflammation
o In severe, persistent or repeated irritation
o Chronic low-level irritation
What are the main effects of chronic inflammation and what are some examples of diseases/conditions where these effects are apparent?
o Fibrosis- Gall bladder (chronic cholecystitis), chronic peptic ulcers, cirrhosis
o Impaired function- Chronic Inflammatory Bowel Disease
• Rarely, increased function, e.g. mucus secretion, thyrotoxicosis
o Atrophy- Gastric mucosa, adrenal glands
o Stimulation of immune response- Macrophage-Lymphocyte interactions
o Granulomatous inflammation/ GRANULOMA- tuberculosis
What is chronic cholecystitis? (As an example of chronic inflammation)
FIBROSIS caused by chronic inflammation Chronic inflammation of the gall bladder - damaged mucosa - blocked neck of gall duct - blocked cystic duct Gall stones cause repeated obstructions Thick fibrotic wall of gal, bladder Repeated attacks of acute inflammation leads to chronic inflammation
What is gastric ulceration? (As an example of chronic inflammation)
FIBROSIS caused by chronic inflammation
- acute gastritis (due to alcohol and drugs) = abdominal pain and reflux
- chronic gastritis (due to helicobacter pyolori)
Ulceration occurs because of the imbalance of acid production and mucosal defence
What is Inflammatory bowel disease? (As an example of chronic inflammation)
IMPAIRED FUNCTION caused by chronic inflammation
Idiopathic inflammatory disease affecting the large and small bowel
Patients present with diarrhoea, rectal bleeding and other symptoms
- Ulcerative colitis (superficial)
— colon, causes ulcers, diarrhoea, bleeding
- Crohn’s disease (transmural/ heterogenous/ not stereotyped)
— Small and large bowel, strictures = narrowing, fistulae = abnormal connection between two epithelium lined organs
What is cirrhosis? (As an example of chronic inflammation)
IMPAIRED FUNCTION AND FIBROSIS caused by chronic inflammation
Common causes: alcohol, infection with HPV/HCD, immunological, fatty liver disease (obesity and DM2), drugs and toxins
Normal liver cells are replaced with nodules of hepatocytes
Chronic information with fibrosis – formation of lots of bands of fibrous tissue
Disorganisation of architecture, and attempted regeneration
What is thyrotoxicosis? (As an example of chronic inflammation)
INCREASED FUNCTION caused by chronic inflammation
Graves’ disease – autoimmune, stimulates TSH receptors, causes hyperthyroidism
What is atrophic gastritis? (As an example of chronic inflammation)
ATROPHY caused by chronic inflammation
Tightly packed cells in gastric mucosa normally produce enzymes, acid and mucus
Auto antibodies destroy the parietal cells so that acid production stops
Causing atrophy
What is rheumatoid arthritis? (As an example of chronic inflammation)
STIMULATION OF IMMUNE RESPONSE caused by chronic inflammation
Autoimmune disease
Localised and systemic immune response
Localised chronic information needs to joint destruction (synovial inflammation)
Systemic immune response- can affect other organs (skin, subcutaneous tissue and lungs) and cause amyloidoses
What are the 7 main types of cells involved in chronic inflammation?
Macrophages Lymphocytes Eosinophils Plasma cells Fibroblasts Myofibroblasts Giant cells
How are macrophages involved in chronic inflammation?
- recruited due to adhesion molecules present on endothelial cells
- Important in acute and chronic inflammation
- derived from blood monocytes
- Various levels of activation
- Structure: lots of granular cytoplasm, large central nucleus
- Functions
o Phagocytosis and destruction of debris and bacteria; opsonisation
o Processing and presentation of antigen to the immune system
o Synthesis of cytokines, complement components, clotting factors and proteases
o Control of other cells via cytokine release
o Important in granuloma formation
o Important in angiogenesis
How are lymphocytes involved in chronic inflammation?
Lymphocytes
- Sometimes called ‘chronic inflammatory cells’
- normal component of many tissues
- Structure: large nuclei: little or no cytoplasm
- Functions
o Complex, mainly immunological
o B Lymphocytes (Plasma Cells) differentiate to produce antibodies
o T Lymphocytes involved in control (CD4+) and some cytotoxic (CD8+) functions
How are eosinophils involved in chronic inflammation?
- Structure: bilobed nucleus (Mickey Mouse head)
- Function:
o Allergic reactions
o Parasite infections
o Some tumours
How are fibroblasts/ myofibroblasts involved in chronic inflammation?
- Recruited my macrophages
- Structure: spindle shaped
- Function- make collagen-FIBROSIS; contract in repair/healing
How are giant cells involved in chronic inflammation?
Giant cells are multinucleate cells made by the fusion of macrophages, through the process of frustrated phagocytosis (where organisms cannot be dealt with by macrophages) There are several types recognised:
- Langhans - Tuberculosis (horseshoe arrangement of nuclei around periphery)
- Foreign Body Type (distorted mish mash)
- Touton - Fat Necrosis (smaller Langhans)
What do macrophages look like?
Lots of granular cytoplasm
Large central nucleus
What do you lymphocytes look like?
Large nucleus
Little/no cytoplasm
What do Plasma cells look like?
Clockface nucleus/lumpy bumpy chromatin
Abundant pink/blue cytoplasm filled with ER
Pale halo around nucleus= Golgi apparatus
What do Eosinophils look like?
Bilobed nucleus
Mickeys mouse head
What do fibroblasts/Myofibroblasts look like?
Spindle-shaped
What do Langhans giant cells look like?
Horseshoe arrangement of nuclei around periphery
What do Touton giant cells look like?
Like Langhans but smaller
What do foreign body giant cells look like?
Distorted mishmash
Give examples of how proportions of each cell type may vary in different conditions
Morphology of most chronic inflammatory reactions is non-specific but proportions of each cell type may vary in different conditions
Rheumatoid arthritis – mostly plasma cells
Chronic gastritis – mostly lymphocytes
Leishmaniasis (protozoan infection) - mostly macrophages
Giant cell type may be a help to diagnosis
What is granulomatous inflammation?
Chronic inflammation with granulomas
What is a granuloma?
Mass of macrophages (epitheloid histiocytes- modified and immobile) and lymphocytes
When do granulomas form?
Granulomas form when the immune system walls off something that it is unable to eliminate, for example bacteria, fungi and other foreign material. Granulomas arise with persistent, low-grade antigenic stimulation and hypersensitivity.
What are the main causes of granulomatous inflammation?
- Mildly irritant foreign material
- Infections
o Mycobacteria: Tuberculosis, leprosy
o Syphilis
o Some fungi - Unknown causes
o Sarcoid
o Wegener’s Granulomatosis
o Crohn’s disease
What is Tuberculosis? (an example of chronic inflammation)
GRANULOMA/ granulomatous chronic inflammation
Caused by mycobacteria, especially Mycobacterium tuberculosis which is difficult and slow to culture
Contains wall lipid mycosides
Produces no toxins or lytic enzymes
Causes disease by persistent and induction of cell mediated immunity
Lymphocytes, Macrophages, giant cells (Langhans), caseous necrosis
Miliary TB equals many bugs
Single organ TB equals few bugs
What are some outcomes of tuberculosis?
- Arrest, fibrosis, scarring
- Erosion into bronchus (bronchopneumonia- severe acute inflammation process in living, TB in GIT- coughed up and swallowed from lungs)
- Tuberculous empyema (collection of pus)
- Erosion into blood stream
What are some other examples of granulomatous infections?
Leprosy, syphilis,chronic fungal infections, cat scratch disease, xanthogranulomatous, pyelonephritis and Malakoplakia
What are some examples of granulomatous diseases of unknown cause?
Sarcoidosis
Crohn’s disease
Wegener’s granulomatosis
What is sarcoidosis? (an example of chronic inflammation of unknown cause)
Variable clinical manifestations/unknown cause
Young adult women
Non caseating granulomas, giant cells
Involves lymph nodes, lungs
What is Crohn’s disease?
Regional enteritis: patchy full thickness inflammation thoughout the bowel
What is regeneration?
The replacement of dead or damage cells by functional, differentiated cells
Where do differentiated cells needed in regeneration derive from?
Stem cells
What are stem cells?
Cells that have potentially limitless proliferation
Daughter cells can either remain as a stem cell to maintain the stem cell pool or differentiate into a specialised cell type
What are 3 examples of where stem cells are used?
Early life
Internal repair system to repair lost or damage cells and tissues
Therapeutic utility in degenerative disease
What does Unipotent mean?
Cell can only produce one type of differentiated cell
For example, epithelia
What does multipotent mean?
Cell can produce several different types of differentiated cell
For example, haematopoetic cells
What does totipotent mean?
Cell can produce any type of cell
For example, embryonic stem cells
How does the propensity to regenerate vary between cell types?
Labile cells- e.g. Epithelia or haematopoeitic cells
Normal state is active in cell division G1 to M to G1
Usually rapid proliferation (hallmark= mitotic figures)
Stable cells- e.g. Hepatocytes, osteoblasts, fibroblasts,
Resting state- G0
Speed of regeneration is variable
Permanent cells- e.g. Neurones, cardiac myocytes
Unable to divide- G0
Unable to regenerate
What factors are thought to control regeneration?
-Growth factors-
Promote proliferation in stem cell population
Extracellular signals transduced into the cell
Promote expression of genes controlling the cell cycle
Proteins EGF, PDGF, FGF
Hormones e.g. Oestrogen, testosterone, growth hormone
Autocrine, paracrine, and endocrine signals from many cell types: inflammatory, mesenchymal cells
-Contact between basement membranes and adjacent cells-
Signalling through adhesion molecules
Inhibits proliferation in intact tissue
Contact inhibition
Loss of contact promotes proliferation leading to a tumour
These mechanisms are deranged in cancer
What is fibrous repair?
The replacement of functional tissue by scar tissue
What are three key components of fibrous repair?
Cell migration
Angiogenesis
Extracellular matrix
How is cell migration involved in fibrous repair?
Migration of:
- Inflammatory cells: Phagocytosis of debris – neutrophils and macrophages; mediators – lymphocytes and macrophages
- Endothelial cells: Angiogenesis
- Fibroblast/Myofibroblasts: Extracellular matrix proteins E.g. collagen; Wound contraction
How is angiogenesis involved in fibrous repair?
Development of the blood supply is vital to wound healing – provides access to the wound for inflammatory cells and fibroblast; delivery of oxygen and other nutrients
Endothelial proliferation induced by pro angiogenic growth factors such as VEGF
Pre-existing blood vessels sprout new vessels
Mechanisms are exploited by malignant cells CANCER
What is the process of angiogenesis?
Endothelial proteolysis of basement membrane
Migration of endothelial cells by chemotaxis
Endothelial proliferation
Endothelial maturation and tubular remodelling
Recruitment of periendothelial cells
How is the extracellular matrix involved in cellular repair?
It facilitates cell migration and contains collagen important in fibrous repair
What are the functions of the extracellular matrix?
Supports and anchors cell Separates tissue compartments (e.g. Basement membrane) Sequesters growth factors Allows communication between cells Facilitates cell migration
What does the extracellular matrix in fibrous repair contain?
Collagen
Matrix glycoproteins
Proteoglycans
Elastin
What is collagen?
The most abundant protein in animals
Provide extracellular framework
Composed of triple helices of various polypeptide alpha chains
The fibrillar collagen for type IV to type VI e.g. BM
Remodelled by specific collagenases
What are matrix glycoproteins important for in fibrous repair and give some examples?
Organise and orientate cells, support cell migration
Fibronectin, laminin, and tenascin
What are proteoglycans important for in fibrous repair and give some examples?
Matrix organisation, cell support, regulate availability of growth factors
Heparan sulphate proteoglycan
What is elastin important for in fibrous repair?
Provides tissue elasticity
Describe collagen synthesis
Polypeptide Alpha chain synthesised in endoplasmic reticulum
Enzymatic modification steps including vitamin C dependent hydroxylation
Alpha chains align and cross-link to form procollagen triple helix
Soluble procollagen is secreted
After secretion procollagen is cleaved to give tropocollagen
Tropocollagen polymerises to form fibrils
Bundles of fibrils form fibres
Slow remodelling by specific collagenases
What are some defects of the synthesis of collagen?
-Vitamin C deficiency, scurvy
Inadequate hydroxylation of the chains implies defective helix formation
Lack strength, vulnerable to enzymatic degradation
Particularly affects collagen supporting blood vessels
Haemorrhage and skeletal changes in infants
-Ehlers Danlos syndrome
Defective conversion of procollagen to troprocollagen
-Osteogenesis imperfecta
Defective type 1 collagen
- Alport syndrome
Defective type 4 collagen
What is the mechanism of fibrous repair?
-Inflammatory cells infiltrate
Blood clot forms
Acute information around the edges- neutrophils infiltrate and digest the clot
Chronic inflammation: macrophages and lymphocytes migrate into the clot
-Clot replaced by granulation tissue
Angiogenesis – capillaries and lymphatics then sprout and infiltrate
Myo/fibroblasts migrate and differentiate
ECmatrix is produced by myo/fibroblasts, collagen is synthesised by fibroblasts, glycoproteins synthesised by Myofibroblasts
- Maturation
Comparatively long lasting
Cell population falls, collagen increases, matures and remodels
Myofibroblast contracts – reduces volume of defect
Vessels differentiate and are reduced
Left with a fibrous scar
How was the mechanism of fibrous repair discovered?
Discovered using rabbit ear chamber model
Plastic chambers surgically inserted into the ear of lop rabbit
Thin tissue bed develops between layers of chamber
Enables in-vivo microscopic visualisation of healing and repair
How is fibrous repair controlled?
Inflammatory cells are recruited by chemotaxis
Angiogenesis – platelets, extracellular matrix and others produce angiogenic cytokines in response to hypoxia (VEGF, bFGF)
Fibrosis- macrophages produce various profibrotic cytokines: e.g. IL1, TNF alpha, TGF beta; Fibroblast proliferation and ECM production
Describe the regeneration and repair of skin
Primary intention-
Incised wound
Apposed edges
Minimal clot and granulation tissue
Epidermis regenerates
Dermis undergoes fibrous repair
Sutures out at about 10 days: approx 10 % normal strength
Transition from granulation tissue to scar tissue
Maturation of scar continues up to 2 years
Minimal contraction and scaring, good strength
Risk of trapping infection – abscess
Secondary intention-
In part, ulcer, abscess, any LARGE wound
Quantitative differences
-Unopposed wound edges
-Large clot dries to form a scab/ ESCHAR
-Epidermis regenerates from the base up
-Repair process produces much more granulation tissue
Compare secondary with primary intention healing of skin
Produces more contraction to reduce volume of defect
Produces more a larger scar, not necessarily weaker
Takes longer
Describe the regeneration and repair of bone
Haematoma forms from ruptured vessels within the marrow cavity and periosteum
Organising haematoma provides a framework for ingress of macrophages, endothelial cells, fibroblasts and osteoblasts
Necrotic tissue is removed
Capillaries develop
Specialised mixture of cells is called a callus
Bone is laid down in an irregular woven pattern sometimes with islands of cartilage (soft callus to hard callus)
External callus provides splint like support
Woven bone gradually replaced by more organised lamellar bone
Lamellar bone is gradually remodelled to the direction of mechanical stress
Describe the regeneration and repair of the liver
Can regenerate to repair damage by proliferating hepatocytes (uni potent) – both acute and chronic liver damage
Resection of the liver can induce proliferation of remaining hepatocytes until lost mass is restored
Describe the regeneration and repair of the kidney
Regenerative capacity of mammalian kidney is limited compared to that of lower vertebrates
Proximal tubule and glomerulus is believed to regenerate after acute injury
Bone marrow stem cells are involved
Describe the regeneration repair of the heart
Cannot regenerate
Causes scarring and fibrosis
Cardiomyocytes are terminally differentiated and cannot divide
Describe the regeneration and repair of cartilage
Cannot regenerate
Describe the regeneration and repair of peripheral nerves
Wallerian degeneration
Neurofilaments break up, axons break up into short lengths
Myelin sheaths break down into lipid droplets around the axon
Myelin gets denatured chemically
Macro phages from endoneurium invade the degenerating myelin sheath and axis cylinder and phagocytose debris
Pre axon sprouts and innervates the post axon
Describe the regeneration and repair of the central nervous system
In demyelination, axon retraction, sprouting, cell death Neurotrophic factor delivery Cellular replacement Modulation of immune response Manipulation of intracellular signalling Axon guidance Removal of growth inhibition
What are some local factors which influence wound healing?
Type, size, location of wound
Apposition, lack of movement – skin wounds, bone fractures, severed nerves
Blood supply: arterial, venous
Infection – suppuration, gangrene, systemic
Foreign material: dirt, glass, sutures, necrotic tissue
Radiation damage
What are some systemic factors which influence wound healing?
Age
Drugs (steroids) and hormones
General dietary deficiencies (protein)
Specific dietary deficiencies (vitamin C, essential amino acids)
General state of health/chronic diseases (diabetes, rheumatoid arthritis)
General cardiovascular status
What are some complications of repair?
Insufficient fibrosis-
- wound dehiscence, hernia, ulceration
- obesity, elderly, malnutrition, steroids etc.
Excessive fibrosis-
-cosmetic scarring, keloid, cirrhosis, lung fibrosis
Excessive contraction-
- obstruction of tubes and channels = strictures
- limitation of joint movement = contractures
Infection-
-resistance of wounds to infection is proportional to their blood supply- leukocytes become deprived of oxygen so there is no oxygen burst
What is a stricture?
Obstruction of a tube and channel
What is a contracture?
Iimitation of the joint movement
What is chronic granulomatous disease?
Group of disorders – XLR or AR
Failure to produce high concentrations of toxic oxygen radicals during a respiratory burst that accompanies activation of phagocytes
Failure to produce functional NADPH oxidase enzyme
Typically presents in first three months of life as severe skin sepsis caused by Staphylococcus aureus or fungal infection
Results in regional lymphogenopathy , hepatosplenomegaly, hepatic abscesses and osteomyelitis
Affected organs show multiple abscesses and noncaseating giant cell granulomas
What is angio-oedema?
Inherited
Deficiency of inhibitor of first component of complement (C1 inhibitor) which also regulates bradykinin metabolism
Patients are non susceptible to infections but do experience recurrent attacks of cutaneous, intestinal or laryngeal oedema which can be fatal airway is occluded
Loss of regulation complement pathway
What is haemostasis?
Process of stopping a haemorrhage/excessive bleeding
How fast does haemostasis have to occur and why?
Has to occur within seconds to prevent blood loss
What are the three steps of haemostasis?
- Severed artery contracts not enough to stop the bleeding but enough to decrease the pressure downstream (contraction doesn’t occur in the veins but the pressure in them is much lower)
- Primary haemostatic plug of activated platelets forms at the mouth of the vessel sticking to the injured artery and connective tissue outside it. This is fragile but may control the bleeding. It forms in seconds to minutes.
- Secondary haemostatic plug forms as fibrin filaments stabilise to the platelet plug. This forms in approximately 30 minutes. It eventually becomes organised and is replaced by granulation tissue and a tiny scar.
What are two conditions where there is defective haemostasis?
Patients with low platelet count or non functional platelets- lack step 2
Haemophiliacs (have normal platelets but impaired clotting so they can’t produce fibrin- lack step 3
What four things does successful haemostasis depend on?
Blood vessel walls
Platelets
Coagulation
Fibrinolysis
What are some activators of platelets?
Collagen surfaces (within extravascular areas)
Thrombin (tells platelets that the clotting sequence is activated)
ADP (released by activated platelets and injured red blood cells and amplifies the platelet response)
Some prostaglandins
Adrenaline
How are platelets involved in haemostasis?
STEP 2
-Platelets adhere to the subendothelium specifically to von Willebrand factor which is concentrated on the subendothelial basement membrane. (vWF glues platelets to subendothelium)
-Platelets adhere with other platelets (aggregation). This is how the primary haemostatic (platelet) plug grows. (fibrinogen glues platelets to other platelets)
- Swelling
-The secretion of factors that help clotting for example fibrinogen, ADP (which activates more platelets), thromboxane A2 (a powerful platelet aggregator). This helps platelet plug to grow.
(Platelet release reaction: ATP –> ADP; ADP, thromboxane A2 cause platelet aggregation; 5HT, Platelet factor 3 is also released- important in coagulation)
Describe some features of the platelets release reaction
ATP is converted to ADP (energy is required)
ADP, thromboxane A2 causes platelet aggregation
5 HT, platelet factor 3 also released
Platelet factor 3 also important in coagulation
Platelets coalesce after aggregation
How is coagulation involved in haemostasis?
STEP 3
Basic purpose is to produce fibrin clot
Thrombin cleaves fibrinogen to fibrin (series of inactive components converted to active components)
Thrombin can’t circulate in an active state or blood would be a solid, therefore thrombin is activated by an array of circulating molecules numbered I to XIII (in order of discovery)
At several steps there are feedback loops that inhibit or accelerate the reactions
Blood can clot in the absence of platelets but not as well
1ml of blood contains enough fibrin to convert all the fibrinogen in the body into fibrin- so tight regulation is required (by thrombin inhibitors- antithrombin III, alpha 1 antitrypsin, alpha 2 macro globulin, protein C and S (inherited deficiencies in these May cause thrombosis)
What are the two pathways of coagulation and what are there differences?
Intrinsic pathway- involves factors contained in the blood; triggered by a negatively charged surface (e.g. Glass, subendothelium); no vessels need to be broken open.
Extrinsic pathway- needs a ‘tissue factor’ (thromboplastin) from outside the blood. Triggered by thromboplastin released from damaged cells when blood is spilled out of vessels.
What is retraction/contraction of a clot?
As platelets die they cling to the filaments of fibrin and pull by the actin- myosin system. Therefore the mechanism is basically the same as muscle contraction
What is the purpose of clot retraction?
Possibly to toughen the clot by squeezing out fluid. It also helps in pulling together the sides of small wounds.
What factors oppose clotting?
Dilution of clotting factors by blood flow Natural anticoagulants (oppose the formation of fibrin, don't destroy it after it has been formed – that is fibrinolysis) – antithrombin III, protein C and S. If you lack these in inherited deficiencies, you get repeated episodes of thrombosis. Alpha-1-anti trypsin, alpha-2-macroglobulin
How is fibrinolysis involved in haemostasis?
Breakdown of fibrin clot after bleeding has stopped
Fibrin has a built in short term absolescence
Macrophages recognise it and break it down and it is destroyed by free floating enzymes (plasmin). Also the split products of fibrin inhibit blood clotting.
How does plasmin breakdown a fibrin clot?
Plasmin is the enzyme responsible for fibrinolysis
It circulates as an inactive precursor (plasminogen produced by the liver) with its activator tissue plasminogen activator (tPA)
tPA, streptokinase (plasminogen activator obtained from streptococci) and urokinase (plasminogen activator found in urine)
Plasminogen –(tPA, sk, uk)–> Plasmin
Fibrin clot–(plasmin)–> fibrin fragments
How are plasminogen factors used therapeutically?
They dissolve fibrin and therefore thrombi and thromboemboli
Streptokinase and urokinase also attack fibrinogen and cause a general depletion of fibrinogen (preventing formation of fibrin clots)
Streptokinase is antigenic
tPA has a higher affinity for fibrin and is not antigenic
Recombinant tPA was obtained from a human melanoma- therapeutic use of a malignant tumour!
As tPA breaks down fibrin in thrombi and in a haemostatic clot it can cause bleeding
How is the blood vessel (vascular) wall involved in haemostasis?
It is not passive - the arterial media contracts and the subendothelium traps platelets
Only endothelium, WBCs, platelets and RBCs can be in contact with blood and not clot it- artificial blood vessels are hard to make
How does the endothelium perform a balancing act between opposing and favouring clotting?
Opposing (stops haemostasis) - the endothelium:
- opposes platelet aggregation- it secretes prostacyclin that inhibits platelet aggregation
- opposes thrombin
- favours fibrinolysis - it secretes tPA and urokinase
Favouring (promotes haemostasis)
- favours platelet aggregation- it produces von Willebrands factor (glue that sticks platelets to subendothelium)
- favours coagulation cascade
- opposes fibrinolysis
What are some antithrombotic substances that the endothelium secretes?
Plasminogen activators
Prostacyclin
Nitric oxide
Thrombomodulin
Define thrombosis
Formation of a solid mass of blood within the circulatory system
Inappropriate haemostasis
When does a thrombus form?
When normal haemostatic mechanisms are turned on inappropriately, thrombi form in the blood vessels or heart
Thrombus forms within heart or vessels, from constituents of the loos, during life
Why do thrombi form?
Virchow’s triad
Changes in the vascular wall (endothelial damage, atheroma, direct injury, inflammation)
Changes in blood flow (stagnation, turbulence)
Changes in blood components (hypercoagulabilty, smokers, post partum, post op)
Just two are needed for a thrombus to form
How does a change in vessel wall (in particular endothelial damage) affect the formation of a thrombus?
Endothelial damage
Occurs after trauma or surgery, in inflammation, on the surface of atherosclerotic plaques when they break open
Platelets adhere to exposed von Willebrand factor/factor VIII complex
In arteries the platelet thrombi generally don’t grow because swift currents wash away the platelets and the chemical mediators
How does a change in blood flow (in particular sluggish flow) affect the formation of a thrombus?
Sluggish flow
Gives platelets better chance to stick and clotting factors a chance to accumulate
Thrombosis is more frequent in veins as they have slower flow and valves produce eddies and pockets of stagnant blood
In pregnancy (and after surgery) two of Virchow’s triad are present and thrombi in the lower limbs are more common – stasis due to pressure on large veins of the pelvis and the blood is hypercoagulable
How do changes in blood components (in particular hypercoaguability) affect formation of a thrombus?
Smoking activates Hageman factor (factor VII)
Pregnancy and recent surgery result in increased levels of fibrinogen and factor VIII
These all cause hypercoaguability which increases the likelihood of formation of a thrombus
How is a thrombus formed in a post surgical patient?
Platelets in a vein are more concentrated along the endothelium because they are the smallest formed elements in the blood (rocks flow in the centre of a stream, sand is deposited along the banks)
Platelets post surgery aggregate more easily
Platelets catch in an eddy behind a valve, form an aggregate, settle on the wall, and other platelets stick to the collection
Fibrin grows out of the platelet layer (it is not clear how) and traps red blood cells. So a white layer of platelets is covered by a red layer of fibrin and red blood cells. The surface of the red layer is thrombogenic as platelets stick to the fibrin. A second white layer of platelets then forms and the process continues.
Laminations are visible to the naked eye as lines of zahn
What is a parietal thrombus?
Thrombus which restricts the lumen of the vessel
What is an occlusive thrombus?
Thrombus which fills and obstructs a lumen
What is the most important mechanism for limiting the spread of thrombus?
Blood flow
What does an arterial thrombi look like?
Pale, granular, lines of zahn (white- platelets/ red- red blood cells), lower cell content
What does a venous thrombi look like?
Soft
Gelatinous
Dee red
Higher cell content
What are the outcomes of thrombosis?
Resolution and lysis- complete dissolution of thrombus, fibrinolytic system active, blood flow reestablished, most likely when thrombi are small
Propagation- progressive spread of thrombus, distally in arteries and proximally in veins
Organisation- reparative process, in growth of fibroblasts, macrophages and capillaries (similar to granulation tissue), lumen remains obstructed, fibrous scar forms on wall of vessel
Recanalisation- blood flow reestablished but usually incompletely, one or more channels formed through organising thrombus
Embolism- parts of thrombus break off and travel through look stream, lodging at a distant site
Partial calcification
Occlusion of the vessel
What is the difference between a thrombus and post mortem clot?
Thrombi are typically laminated with lines of zahn and are opposed to the intimal surface; can cause death
Post mortem clots are rubbery and shiny and are never laminated (as this requires blood flow). They are also not attached to the intima; cannot cause death as person is already dead!
What is a thrombus on a cardiac valve called and what are some key features?
Vegetation
They can be 2-3 cm long and easily embolism
Usually occur on valves of the elf heart as they are exposed to a greater pressure and therefore micro trauma
Subendothelial tissue that is exposed is thrombogenic- they can become infected
What are the most dangerous sources of emboli?
Thrombi in the large veins of the lower limbs – femoral/iliac/popliteal veins
Is pain always present when a thrombus forms?
Pain is not always present when a thrombus forms (although it often is in thrombi in superficial veins (thrombophlebitis – even though there are aseptic))
How does aspirin prevent thrombus formation?
Aspirin is antithrombogenic
It irreversibly acetylates in platelets an enzyme of prostaglandin metabolism so that platelets can’t produce thromboxane A2 – a platelet activator
The formation of a haemostatic plug is inhibited and the bleeding time is prolonged
What is disseminated intravascular coagulation?
In this condition blood clots throughout the circulation
It never occurs as a disease in itself but is a complication of a primary event that triggers generalised blood clotting for example sepsis (especially gram negative sepsis as such bacteria produce an endotoxin which activates clotting, Severe trauma (especially to the brain as it contains large amounts of thromboplastin), complications of childbirth (amniotic fluid embolism, retained dead foetus), shock, tumour, snakebite
It is a combination of clotting and nonclotting resulting in thromboembolism and haemorrhage. It has also been called haemorrhagic micro thrombosis and consumption coagulopathy. Clotting factors and platelets are used up by the widespread clotting resulting in susceptibility to haemorrhage – a therapeutic nightmare
There are signs of:
Microvascular thrombosis – neurological impairment, gangrene of the skin, renal failure, respiratory distress, Gastro intestinal ulceration
Haemorrhage – intracerebral bleeding, petechiae, haematuria, epistaxis, gastrointestinal bleeding
An activator of clotting gets into the blood. Microthrombi (but not large thrombi) form. The fibrinolytic system is activated and they fibrin degradation products (FDPs) are released.
Red blood cells can be traumatised by fibrin in the microthrombi = microangiopathic haemolytic anaemia
Define embolus
An embolus is a solid, liquid or gas that is carried by the blood and is large enough to become impacted in a vascular lumen
What is an embolism?
Impaction open embolus
Why can’t an embolism form in a vein?
It can’t occur in veins as bloodflow is from smaller to larger vessels
Where do most emboli arise from?
From thrombus in Thromboembolism
Besides arising from a thrombus, what else can an emboli arise from?
Body fat Bone marrow (usually after trauma) Atheromatous plaque Tumour Parasites Bubbles of air or other gases Debris injected intravenously Bits of brain or liver after trauma
Where do emboli from peripheral veins or the right heart end up in?
Lungs
Where do emboli from the left heart or aorta end up in?
Anywhere in the systemic circulation especially the lower limbs
Describe pulmonary saddle emboli
Large emboli become lodged in both pulmonary arteries= saddle emboli. They are usually fatal.
Where do majority of pulmonary emboli arise?
Approximately 80% arise in thrombi in the deep veins of the thigh and the popliteal vein
What are the three severities of pulmonary emboli?
Massive PE >60% reduction in blood flow
Major PE medium sized vessels blocked, patients short of breath, +/- cough, blood stained sputum
Minor PE small peripheral pulmonary artery blocked, asymptomatic, shortness of breath, recurrent minor PEs lead to pulmonary hypertension
What are some predisposing factors of deep vein thrombosis?
Immobility Bed rest Post operative Pregnancy Postpartum Oral contraceptives Severe burns Cardiac failure Disseminated cancer
How can DVT be prevented?
High risk patients must be identified and offered prophylaxis Heparin subcutaneously Leg compression during surgery Mobility after surgery Thrombolytic drugs
How can DVT be treated?
Surgery – embolectomy
Intravenous heparin- anticoagulant, co factor for antithrombin III
Oral warfarin- interferes with synthesis of vit K dependent clotting factors; slow effect
Thrombolytic drugs – streptokinase, tPA
How can pulmonary embolism be prevented?
By putting an umbrella shaped filter in the inferior vena cava
Why are thrombi often seen in the left heart?
Infarcts commonly affect the left ventricle causing thrombosis in the ventricular cavity. As heart is beating these often embolise.
Vegetations are commoner on valves on the left side of the heart.
Atrial fibrillation results in decreased atrial contraction, dilatation of the left atrium, stagnation of blood in the atrium and hence thrombi.
