Atherosclerosis & thrombosis (Block 3) Flashcards
Atheroma
a focal disease of the intima-endothelial layer of large and medium-sized arteries
(Means that in specific areas the endothelial cells that line the arteries start to form fatty deposits)
Unalterable risk factor for atheromatous disease
Family history of ischaemic heart disease
Modifiable risk factors for atheromatous disease
Raised or reduced LDL (low-density lipoprotein) hypertension
obesity
physical inactivity
smoking
diabetes mellitus
etc.
Stages to atherogenesis
1) Endothelial dysfunction
2) Endothelium injury leads to monocyte attachment
3) Attached monocytes and ECs generate free radicals, oxidising LDL bound to ECs
4) Oxidised LDL is taken up by macrophages, which become foam cells. These migrate sub-endothelially to form fatty streaks (precursors of atheroma)
5) SMC hyperplasia and matrix deposition; leads to a dense fibrous cap overlying a lipid-rich core
6) Rupture leading to thrombus formation
Endothelial dysfunction
altered PGI2 and NO biosynthesis
Endothelium injury cause example
From disturbed flow at vessel junctions
Major dietary lipids
Triacylglycerols (TAGs; more than 90%)
Cholesterol esters
Phospholipids
Free fatty acids
Digestion of lipids in the mouth
Enzymes are aqueous; little effect of lipids
Digestion of lipids in the stomach
Causes a large physical change - churned into droplets called “chyme”
20% of TAGs hydrolysed in stomach by gastric lipase
Lipoprotein transport
Lipids and cholesterol are transported in the blood as lipoproteins **
4 main classes of lipoprotein
Chylomicrons (exogenous transport)
HDL (endogenous)
LDL (endogenous)
VDL (endogenous)
Transport of exogenous lipids
Chylomicrons (100-1000nm dia) transport dietary lipids from the gut via lymph and plasma to capillary beds
• The core triglycerides are then hydrolyzed to free fatty acids (FFA) by lipoprotein(LP)-lipase
• Chylomicron remnants (30-50nm) transport cholesterol esters to the liver where they are endocytosed
• Released cholesterol is either stored, oxidised to bile acids (secreted in bile), or transported with triglycerides by the endogenous transport pathway
Transport of endogenous lipids
Cholesterol and triglycerides transport from the liver to the tissues by VLDL
• Triglycerides are taken up by the tissues, leaving LDL containing cholesterol esters
• Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoprotein
• Cholesterol can return to plasma from tissues in HDL particles (7-20nm dia.)
LDL and thrombosis
• Lipoprotein(A) in LDL contains lipids and Apo(A). Apo(A) inhibits plasmin formation, thereby inhibiting fibrinolysis and promoting thrombosis
• LDL also activates platelets, hence further driving thrombosis
Elevated LDL and reduced HDL cholesterol levels lead to what?
Increased risk of cardiovascular disease
Dyslipidaemias
Dyslipidemia refers to abnormal levels of lipids in the bloodstream. There are primary and secondary forms
Primary dyslipidaemias
Genetic
Classified into 6 phenotypes
Primary dyslipidaemia example - type IIa hyper-lipoproteinaemia
Caused by LDL receptor defects, leading to elevated LDL levels, dysfunction thrombosis, and increases risk of ischaemic heart disease
Secondary dyslipidaemias
Caused by environment/lifestyle
Risk factors for diabetes and renal, thyroid, and liver diseases
Lipid lowering drugs
Used in addition to control of modifiable risk factors
Main classes of clinically used lipid lowering drugs
Statins
Vibrates
Bile acid-binding resins
Ezetimibe
Statins examples
Simvastin, Lovostatin, prevastatin
Statins
Competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis (catalyzing the conversion of HMG-CoA to mevalonic acid)
Lower cholesterol synthesis increases LDL receptor synthesis and leads to increased LDL clearance
Main effect is to reduce plasma LDL-cholesterol concentrations
Other actions of statins include
• Improved endothelial function (endothelial NOS)
• Reduced vascular inflammation
• Reduced platelet aggregration (NOS)
• Increased neovascularization under hypoxia
• Increased circulating endothelial cell progenitors
• Plaque stabilization
• Reduced atherosclerosis and plaque stabilization
• Increased fibrinolysis
• Possible increased bone mineral density
Clinical use of statins
Reduce the risk of myocardial infarction and stoke in patients with symptomatic atherosclerotic disease
Prevention of arterial disease in patients who are at high risk
Atorvastatin
Has long lasting effects and is used to lower serum cholesterol levels in patients with LDL-R mutations
Side effects of statins
Muscle pain in some patients (rhabdomyolysis) -> can be quite severe in some patients but is often very mild
Fibrates
Agonists of the nuclear receptor PPAR-alpha, activation of which stimulates lipoprotein lipase production.
Fibrates reduce SMC inflammation by inhibiting transcription factor NF-?B levels (this reduces fibrinogen)
Bile acid binding resins
Anion exchange resins
Sequester bile acids in the intestine and prevent their réabsorption and recirculation
This results in decreased absorption of exogenous cholesterol and increased metabolism of endogenous cholesterol into bile acids in the liver
LDL receptor expression on liver is increased, causing further removal of LDL from blood
Common side effects of bile acid binding resins
Nausea, bloating, and diarrhoea
Drugs that inhibit cholesterol reabsorption
• Ezetimibe is one of a group of azetidione cholesterol absorption inhibitors.
• Used as an adjunct to dietery changes and statins in hypercholesterolaemia.
• Inhibit absortion of cholesterol in duodenum and small intestine by blocking transport protein (NPC1L1).
• Administered by mouth
Haemostasis
The arrest of blood loss from damaged blood vessels
Main elements of haemostasis
Platelet adhesion and activation
Blood coagulation (fibrin formation)
Thrombosis
Abnormal formation of a haemostatic plug within a blood vessel, in the abscene of bleeding
A blood clot
3 main factors predispose to thrombosis
Damage to endothelium
Poor or turbulent blood flow
Hyper-coagulability
Blood cots vs thrombus
A clot form in static blood in vitro; they are amorphous and consist of a diffuse fibrin meshwork with random distribution of red and white blood cells
A thrombus forms in vivo; they are organised aggregates of white and red blood cells, bound with fibrin. They are fixed to the blood cell wall, but may break off ad travel as an embolus to lodge in small blood vessels
First step in the formation of arterial thrombosis
Platelet activation
Platelet activation is induced by
Collagen (exposed when endothelial cell lining blood vessels are damaged)
Thrombin (produced when they lood coagulation cascade is activated)
Activated platelets (produce substances that cause further aggregation)
What substances produced by activated platelets lead to the further activation of other platelets?
Thromboxane A2
5-HT
Platelet activating factor (PAF)
Coagulation cascade key facts
First step is conversion by thrombin of soluble fibrinogen to insoluble strands of fibrin
• This is mediated by an enzyme (coagulation) cascade involving serine proteases (clotting factors)
• Vitamin K is required for formation of clotting factors
• The main clotting inhibitor is antithrombin III (neutralises all serine proteases in cascade)
• Heparin is a major cofactor for antithrombin III activity
• Clot lysis mediated by action of plasmin (activated via plasminogen)
Drugs affecting haemostasis and thrombosis
Anticoagulants
Anti platelet drugs
Fribronlytic drugs
Anticoagulants
Anticoagulants prevent formation of thrombi (clots), but will not break down existing clots. Used in treatment of venous thrombosis and embolism (e.g. DVT)
Anticoagulants - 2 examples
Heparin
Warfarin
Anticoagulants - Heparin
Naturally occurring acidic mucopolysaccharide, administered by i.v. injection
• Reduces blood clotting by inactivating thrombin (via antithrombin III)
Anticoagulants - warfarin
Given orally, interferes with the synthesis of vitamin K which is a natural coagulation factor
• Potential for dangerous drug interactions; e.g. aspirin can increase its effect causing bleeding
Anti platelet drugs
Act of arterial thrombosis
Examples of antiplatelet drus
Aspirin
Clopidogrel
Epoprostenol
Endothelial cells
EDRF
Heparin sulphate
Antiplatelet drugs - aspirin
Low doses reduce platelet aggregation by preventing thromboxane A2 formation
Antiplatelets - clopidogrel
irreversibly blocks the effects of ADP on platelets
Antiplatelet drugs - Epoprostenol (synthetic PGI2)
given as an intravenous infusion. It promotes vasodilation and inhibits platelet aggregation
Thombolytic drugs
A thrombus can be ‘dissolved’ using fibrinolytic drugs that activate plasminogen into plasmin, which degrades fibrin
Thrombolytic drugs - examples
Streptokinase
Tissue plasminogen activator (tPA, alteplase)
Thrombolytic drugs - Streptokinase
Large protein molecule obtained from Streptococci cultures. Activates plasminogen
Thrombolytic drugs - tissue plasmingoen activator (tPA, altepase)
present in endothelial cells. Made recombinantly for drug use
