23,24,25 Flashcards
What is atherosclerosis
Degeneration of arterial walls characterised by fibrosis, inflammation and lipid deposition which limits blood circulation and predisposes to thrombosis
How does endothelial injury occur?
Generation of oxygen free radicals e.g. smoking.
Also haemodynamic injury, chemicals, immune complex, deposition and irradiation
How does an atherosclerotic plaque form
Hyperlipidaemia
Lipid accumulates in the intimal
Monocytes migrate to the the intimal (due to lipid and endothelial injury)
Monocytes ingest lipids and form foam cells - makes a fatty streak
Monocytes secrete cheekiness to attract neutrophils/macrophages/smooth muscle
Smooth muscle proliferates and makes connective tissue
Atherosclerotic plaque formed consisting of extracellular material, fat and leukocytes of smooth muscle cells
What is the structure of an athersclerotic plaque
Fibrous Cap
Necrotic core where macrophages due
Fibrosis at the shoulder
What is the difference between a macrophage and monocyte
It is monocyte in the blood and a macrophage when it enters the tissue
What are the 3 consequences of atherosclerosis
Occlusion
Haemorrhages - vessel wall weakened can lead to an aneurysm
Erosion - thrombosis forms if cap is eroded
What is emobolus
A mass of material in the vascular system able to lodge in a vessel a block it
What is the most common type of embolus
A thrombosis
Features of a clot
Elastic
Enzymatic process
Takes shape of vessel
Stagnant blood
Features of a thrombosis
Forms during life
Platelet dependent
Firm
What is a thrombosis
Solidification of blood constituents formed in the vessel during life
Do platelets have a nucleus
No - they are just fragments of megakaryocytes
What do alpha granules in platelets secrete
Fibrinogen, fibrinonectin, PDGF
What do dense granules in platelets secrete
Chemotactic chemicals
What can cause arterial thrombosis
Plaque rupture - due to turbulent flow and intimal change
Hyperlipidaemia - change in blood constituents so more likely to clot
Platelets bind and fibrin is produced entrapping RBC’s as chemotactic chemicals are formed
What lines of Zahn
Show what atherosclerotic plaques look like
Describe blood flow around atherosclerotic plaques
Laminar flow on the way up
Turbulent flow on the way down - more likely to form clots here
Where are clots most likely to form with regards to an athersclerotic plaque
On the downside of the atherosclerotic plaque due to the turbulent flow
What is likely to cause venous thrombosis
Stagnation of blood e.g immobility
Change in constituents e.g. Factor V Leiden
Intimal changes e.g. valves
Effect of oestrogen on clotting
It is pro-thrombotic
What are thrombi in the heart known as
Mural thrombi
What increases the stickiness of the muscle wall
MI and myocarditis
Describe the sequelae of a thrombosis
Occlusion
Resolution
Incorporation of thrombus into the vessel wall
Recanalisation through the fibrotic thrombosis
Embolization of the thrombus detatches
Most common type of emboli
Pulmonary emboli
How to diagnose a pulmonary emboli
A CTPA
Congenital risk factors of thrombtic emboli
Protein S defeciency
Factor V Leiden
Acquired risk factors of thrombotic emboli
Paradoxical emboli e.g. hole in heart
Immobility, malignancy, smoking, oestrogen, obesity, pregnancy etc
What is saddle embolus
Sits where the pulmonary arteries bifurcate
Name the different types of emboli
Systemic Infective Tumour Air Amniotic Fluid Fat Foreign Body
Where do systemic emboli form
In the heart - following MI or AF
Or in arterial circulation
Types of systemic emboli
Atheroma - from eroded plaques
Platelet - often asymptomatic, arise from atherosclerotic plaques and responsible for causing TIA’s
What causes TIA’s
Platelet systemic emboli
What are infective emboli
Small emboli that break of from vegetations on infected heart valves
What can be the consequence of an infected emboli
Can form a microcytic aneurysm where it lodges
Who is infective endocarditis common in
young people with prosthetic heart valves and IV Drug Users
What happens in a tumour embolism
Small part of a tumour breaks off - often too small to be symptomatic but major route of tumour dissemination
Two types of gas embolism
Air
Nitrogen
How does an air embolism form
Due to obstetric or chest wall procedures
Only occurs if more than 100ml of air enters
How does a nitrogen embolism form
Occurs in divers/tunnel workers
Nitrogen dissolve in the blood under the pressure
When we surface the nitrogen bubble out of the blood
Nitrogen bubbles enter bones, joints lungs affecting all systems neurological/cardiac
How does an amniotic fluid embolism occur
High intrauterine pressure during labour forces some amniotic fluid into maternal veins (may contain foreignsbstance)
Emboli lodge in blood causing respiratory distress
What histological findings might you get in amniotic fluid embolism
May see shed skin cells in the lung
What usually causes a fat embolism
80% occur in patients with significant trauma
E.g. mainly bone fracture or severe burns (fat precipitates out at high temperature)
Fatal in 15%
Sudden onset respiratory distress
Why is it hard to detect fat emboli in a post mortem
as we don’t specifically stain for fat
What is a foreign body emboli
Emboli due to foreign material injected intravenously
E.g. IVDU’s
Leads to a granulomatous reaction!
What is hypoxia
state of reduced oxygen availability
general = anemia/altitude
can be tissue specific
what is ischaemia
pathological reduction on blood flow, can cause hypoxia
Problems with therapeutic reperfusion
Can get reperfusion injury
What is reperfusion in jury
the generation of oxygen free radicals produced during hypoxia and released in repercussion
Activates inflammatory cascade causing widespread damage
What is infarction
Ischaemic necrosis due to the occlusion of arterial supply
Causes of infatction
Thrombus/emoblus Vasopasms Atheroma spasm Steal - at the branching of the vessels if one is narrowed blood goes down the path of least resistance Venous occlusion Extrinsic compression Volvulus Vasculitis Hyperviscosity
Morphology of infarction
Red (hemorrhagic) - occurs if there is dual blood supply/venous infarction e.g. pulmonary embolus
White (anaemia) occurs with single blood supply
4 factors affecting the degree of ischaemic damage
Blood supply
Oxygen demands of tissue
Rate of occlusion
Blood oxygen content
What areas have dual blood supply
liver, lungs, hands
what areas have single blood supply
Kidney, testis, spleen
Watershed regions between anastamosis e.g. the splenic flexure
Portal vasculature e.g. part of exocrine pancreas
How does rate of occlusion affect ischaemic damage
If slow can generate collateral circulation
E.g. coronary arteries have small anastomosis between main branches through which blood can be redirected
Which tissue is most vulnerable to hypoxia
Brain - uses 20% of bodies oxygen
Neutrons die within 3 to 4 minutes
Cardiac myocytes can live for 20 to 30 minutes
Why does congestive heart failure make ischaemic damage more likely
Poor cardiac output and pulmonary ventilation
Decreases the oxygen content in the blood
What do we give to treat angina
GTN
What is TIA
Stroke reduced within 24 hours
When would we suspect ischaemic bowel disease
Pain after eating due to increased blood demand
What are the 2 types of cerebrovascular disaese
Ischaemic stoke
Haemorrhagic stroke
What is a hemorrhagic stroke
Intracerebral haemorrhage secondary due to hypertension
Get ruptured aneurysm e.g. berry aneurysm
common in patients with tissue disroders
What type of incident is common in people with connective tissue disorders
Intracerebral haemorrhage
What is gangrene
The infarction of entire portion of a limb or organ
When do you get gas gangrene
Necrosis with superimposed infection of a gas producing organism e.g. clostridium perfringens
What is shock
Significant reduction of systemic perfusion (HYPOTENSION) causing reduced oxygen delivery to the tissue
Cellular effects of shock
Membrane ion pump dysfunciton
Cellular swelling
Leakage of intracellular proteins into extracellular space
Anaerobic respiration - makes lactic acid - inappropriate pH regulation
Systemic effects of shock
Alteration in pH (Acidic)
Endothelial dysfunction - vascular leakage
Stimulation of inflammatory and anti-inflammatory cascades
End organ damage
Cardiac output =
Stroke volume x heart rate
What affects stroke volume
Skeletal pump
Respiratory pump
Blood volume
Mean arterial prssure =
cardiac output x total peripheral resistance
What affects total peripheral resistance
arterial radius
Name the 3 main types of shock
Hypovolaemic
Cardiogenic
Distributive
What happens in hypovolaemi stroke
Due to intravascular fluid loss
Decreased cardiac output - increased SVR (vasconstriction)
Causes of hypovolaemic stroke
Haemorrhagic - e.g. trauma, GI leed, fractures etc
Non-haemorrhagic - DnV, burns, third spacing
What is third spacing
Loss of fluid into body cavities - occurs commonly post op and in intestinal obstruction
Can cause hypovolaemic shock
What is cardiogenic shock
Cardiac pump failure
Decreased cardiac output and increased systemic vascular resistacnce
4 types of cardiogenic shock
Myopathy
Arrythmias
Mechanical
Extra-cardiac
What is myopathy cardiogenic shock
Occurs after MI, RV Infarction =, cardiomyopathies etc
Stunned myocardium
What is arrhythmia cardiogenic shock
Occurs with atrial and ventricular fibrillations, tachycardias and arrhythmias etc
What is mechanical cardiogenic shock
Problems with valves, septal defects etc
What is extra-cardiac cariogenic shock
Anything that impairs cardiac filling or ejection of blood from heart
E.g. massive PE, tension pneumothorax, restrictive pericarditis, cardiac tamponade
What is distributive shock
Decreased SVR due to severe vasodilation. Increase cardiac output by increasing heart rate
Types of distributibe shock
Septic
Anaphylactic
Neurogenic
Toxic shock
What is septic distributive shock
Sever overwhelming systemic infections
Increase cytokine mediators causing vasodilation
Procoagulation - causes DIC
What is anaphylactic distributive shock
Allergen causes IgE cross linking - mast cell degranulation - vasodilation
Contraction of bronchioles causing respiratory distress
Laryngeal oedema
Circulatory collapse - death
When does laryngeal oedema occur
In anaphylactic shock
What is neurogenic shock
Occurs in spinal injury/anaesthetic
Loss of sympathetic tone
vasodilation
What is toxic shock syndrome
S. aureus and S. pyogenes produce exotoxins
Exotoxins do not require processing by APC
Non-specific binding of MHCII to T cells receptors
Upton 20% of all T cells activated - widespread release of cytokine - decreases of SVR
What type of shock can tampons cause
Toxic shock syndrome (part of distributive shock)
How can shock types combine
One type can lead to the next e.g.
Septic shock - primary causing inflammatory and anti-inflammatory cascades - increaes vascular permeability
Hypovolaemic opponent - decreased oral intake and insensible losses through VnD
Cardiogenic shock - sepsis-related myocardium dysfunction
Mortality of septic shock
35-60% die within 1 hour
Cardiogenic shock mortality
60-90%
When do most inborn errors of metabolism present
In childrhood
What are most inborn errors of metabolism defects in
Defects in enzymes
What can occur if blockages occur in pathways in inborn errors of metabolism
Can get accumulation of one substance
This substance may then be converted into compounds not usually seen - potentially toxic
Role of cofactors in inborn errors of metabolism
Need to determine it is an enzyme defect not a cofactor deficiency
Problems making co factors cause the same effects as a defecient enzyme
If we replace the cofactor we can maximise what residual enzyme activity might be remaining
Mechanisms of disease in inborn errors of metabolism
Accumulation of toxins
Enzyme defeciency
Defecienct production of essential metabolite/structural component
When does ammonia accumulate
Defects in the urea cycle
What does the urea cycle aim to do
Remove ammonia produced from the breakdown of amino acids
What are the symptoms of ammonia accumulation
Lethargy, vomiting, tachypnoea, convulsions, coma, death
When does a childhood with defects in the urea cycle become recognised
Usually normal at birth as using the mothers metabolism
Usually presents over the next few days/weeks
When do porphyrins accumulate
Problems in harm synthesis
can only have mild problems as severe problems are incompatble with life
What are the 2 types of problems in porphyrias
Acute attacks - only in times of stress Photosensitivity porphyria (thought of as werewolfs)
What happens in acute porphyria attacks
Severe abdominal pain Chest/back pain Vomiting, constipation, diarrhoea Red/brown urine Insomnia/anxiety Hypertension Seizures/metnal changes Breathing problems/muscle problem
What happens in photosensitive porphyria attacks
Sensitivity to sun/artifical light Itching Sudden painful erythema and oedema Fragile skin Increased hair growth Red/brown urine
When can enzyme defeciency present
Present due to defects in fatty acid oxidation e.g. could be hypotonic
Often well until the patient becomes ill
Describe a type of deficient production of essential metabolties
Healthy female phenotype but the abnormal breast development and absent pubic hair - genetic male
Occurs due to defect in androgen receptor
Presentation of primary amenorrhoea, infertility and ambiguous genitalia
Usually needs surgical resection of residual gonads
How to diagnose Inborn errors of metabolism
Pre-symptomatic screening
Investigating symptomatic individuals e.g. basic urine screens for amino acids etc.
Problems of homocytinuria
Mental retardation Marfinoud habitus Ectopia lentis Osteoporosis Thromboembolism
What is the presence of hyperhomocystinanaemia
5%
Complication of mild hyperhomocystinaemia
Higher risk of stroke, peripheral vascular disease and coronary artery disease
What do classic organic acidaemias often defects in
Branched chain amino acid catabolism
What are the 3 inborn errors commonly picked up
Leucine, isoleucine, valine
What do we test for in the first trimester for Down’s syndrome
PAPA, hCG, nuchal translucency
What do we test for in the second trimester for Downs Syndrome
Maternal serum AFP, hCG, inhibin and estriol
Also test free foetal DNA
