Clotting part 2/ Atherosclerosis / Lipids Flashcards
What endogenous factor typically supresses coagulation?
Endothelium produces:
Prostacyclin (PGI2)- inhibit platelet aggregation
Nitric Oxide - platelet aggregation inhibition as well as inhibition adhesion of platelets to vascular wall
In plasma, natural anticoagulants (i.e. antithrombin 3 produced by liver)
How does atherosclerosis relate to the clotting cascade?
Plaque rupture releasing contents can initiate coagulation
What is thrombosis?
Occlusion of blood vessel (venous or arterial) by intravascular blood clot or platelet clump
How many platelets are found in blood?
150,000-350,000 per microlitre
What is the role of fibrin?
Helps stabilize the platelet clot to prevent it embolising.
What receptors between platelets and collagen allow for platelet binding and adhesion?
Initial binding - Integrin alpha 2 beta 1 on platelets binds to collagen.
Initial binding allows GP6 receptors on platelet to bind collagen, initiating intracellular signalling
GP1b-9-5 receptor on platelet binds to von Willebrand factors on collagen (this is needed in high shear situations)
What does aspirin target to reduce clotting?
Arachidonic acid pathway, interfering with thromboxane A2 production
What are filopodia and why are they important in relation to coagulation?
They are cytoplasmic projections formed of actin and myosin, found on platelets following activation, which enhance binding and increase area of surface contact
What initiates the intrinsic clotting pathway?
Contact with underlying surface of blood vessel
What is the importance of the platelet production of thrombin?
Thrombin in turn turns soluble fibrinogen into gel-like fibrin which provides strength to blood clot.
It can also activate more platelets
What initiates the extrinsic pathway?
Tissue factor forms complex with factor 7 leading to activation of factor 10
What are some blood clotting disorders?
Von Willebrand Disease (most common)- deficiency of VW factor (it binds and stabilises factor VIII and binds platelets to collagen)
Haemophilia A- Deficiency of factor 8
Haemophilia B- Deficiency of factor 9
Haemophilia C-Deficiency of factor 11 (uncommon, but more common in Ashkenazi Jews), Rosenthal Syndrome
Are any clotting disorders sex specific?
Haemophilia A and B are single X chromosome, therefore only in males
What is tissue plasminogen activator?
Activates plasminogen bound to fibrin into plasmin so it can break down fibrin polymer into soluble degradation products
Can be given to arterial thrombosis stroke victims early in stroke.
What is venous thrombosis?
An intravascular blood clot forms in deep veins, particularly legs.
Fragment may bud off (embolus) and block vessels, commonly pulmonary artery
What is arterial thrombosis?
Platelet aggregate (white), usually at site of ruptured atherosclerotic plaque, then encapsulated by clot (red) Common in coronary arteries (causing MI), or cerebral artery (causing thrombotic stroke) Treatment: dissolve with fibrinolytics, and long term anti-platelet drugs
Where is Von Willebrand Factor found?
Produced by endothelial cells
It is a glycoprotein involved in binding factor 8 when in circulation in order to increase its half life (it dissociates to allow for activation and clotting)
Also binds collagen beneath endothelial surface when damage to vessels occurs, and helps with platelet adhesion via binding (particularly when high shear stress is present)
How do neighbouring platelets bind to eachother?
Fibrinogen and VW Factor acts as a bridge
What is heparin (don’t need to describe its action, just what it is)?
Anticoagulant
Sulphated glycosaminoglycan of variable chain lengths
Polyanionic
Not orally active (need to inject)
What are anticoagulants in vitro?
Heparin
Calcium chelators
Explain the process of platelet aggregation, beginning with platelet adhesion/activation and including role of ADP/TxA2/Thrombin?
Inactivated platelets bind subendothelial domains (i.e. Collagen or VWF) using Integrin alpha-2-beta-1 (also GP6, and GP1b-9-5 to VWF), causing activation of platelet (filopodia extend), and then release alpha and dense granules (ADP).
Released ADP, Thromboxane A2, and activated thrombin bind their respective membrane receptors on platelets, and initiate signalling pathways that convert integrin alpha-2b-beta-3 (aka GP2B3A) from low affinity resting state to high affinity active state (cytoplasmic intramembranous tail opens, conformational change in globular head domain occurs resulting in extended state)
They can now bind extracellular soluble ligands (fibrinogen and VW factor) which act as a bridge, binding to other platelets’ integrin Alpha2b-Beta3 (GP2b-3a) receptors, allowing for aggregation of platelets.
Mechanism of action of heparin?
Binds to and enhances action of endogenous anticoagulant, antithrombin 3
Low doses blocks action of 10a on prothrombin (preventing conversion to active thrombin), whereas large doses will block action of thrombin on fibrinogen.
Immediate
Low MW heparins inhibits factor 10a predominantly
How are unfractionated heparin and low MW heparin different?
Chain of LMWH is shorter
Not long enough to bind both antithrombin and clotting factors, so can inhibit factor 10a, but not the others (as need to bind both anti-thrombin and thrombin together to inhibit this clotting factor 5)
LMWH has high bioavailability, lower incidence of heparin induced-thrombocytopaenia
Don’t need to monitor PTT
Ideal agent during pregnancy
However, it has longer half life and you can’t get full reversal
How are unfractionated heparin and low MW heparin different?
Chain of LMWH is shorter, thus LMWH will inactivate only clotting factor X (10), whereas unfractionated will inactivate both factor 10 and thrombin (and will do so much quicker than LMWH).
LMWH has high bioavailability, lower incidence of heparin induced-thrombocytopaenia
Don’t need to monitor PTT
Ideal agent during pregnancy
However, it has longer half life and you can’t get full reversal
What are side effects of heparin?
Allergic reactions
Haemorrhage
Heparin induced thrombocytopaenia
What is warfarin and how does it work?
Structural analogue of vitamin K
blocks synthesis of coagulation factors (2,7,9,10) in liver via antagonizing vit k
This means delayed onset of action
What is warfarin and how does it work?
Structural analogue of vitamin K
Blocks carboxylation of coagulation factors (2,7,9,10) in liver via antagonizing vit k (warfarin inhibits vitamin k reductase which is needed to reduce (activate) vitamin K- no reduction results in no conversion from inactive to active clotting factors by gamma-glutamyl carboxylase).
This means delayed onset of action
When is warfarin used?
Venous thrombosis
Preventing pulmonary embolism, embolism in patients with atrial fibrillation
Prophylaxis of thrombosis after insertion of prosthetic heart valves
When is warfarin used?
Venous thrombosis
Preventing pulmonary embolism, embolism in patients with atrial fibrillation
Prophylaxis of thrombosis after insertion of prosthetic heart valves
What are important characteristics in regards to warfarin?
Orally active, but delayed onset
99% bound to plasma albumin (but it can be displaced by aspirin (and other NSAIDs) which can increase haemorrhage risk)
Can cross placenta
What are some newly introduced oral anticoagulants?
Dabigatran Exilate- direct thrombin 2a inhibitor Rivaroxaban- direct factor 10a inhibitor Active immediately Shorter half -life No antidotes
What activates platelets?
Collagen exposure
Thrombin
Thromboxane A2, ADP, and 5-Hydroxytryptomine synthesized by adjacent platelets
What are ways in which the vessel wall prevents platelet aggregation?
Endothelial cells release:
NO raises cGMP in platelets
PGI2 raises cAMP in platelets
both have anti-platelet activity
How does aspirin work as an anti-thrombotic agent?
Irreversibly inhibits cyclooxygenase via acetylation of terminal serine
How does dipyridamole work to inhibit platelet activation?
Inhibits cyclic nucleotide phosphodiesterases which results in increase cAMP and cGMP
Essentially works as copy cat for NO and prostacyclin
How does epoprostenol work?
Its a stabilized prostacyclin with a short half life
Used during haemodialysis to inhibit platelet activation
Given intravenously
How does Clopidogrel work?
Blocks platelet ADP receptors, preventing GP2b-3a receptors exposure (which is needed for linking platelets to each other)
Used to prevent re-infarction (by 20%)
Used in combo with aspirin
How does Abciximab work?
Blocks GP2b-3a receptors exposed by any pathway (preventing platelets from adhering to each other)
Used during surgical exploration
What does tissue plasminogen activator do?
Produced by vascular endothelium
Activates plasminogen bound to fibrin, meaning its selective to clots
What is streptokinase?
Non-selective thrombolytic enzyme
Used in STEMIs
Activates plasminogen systemically, causing conformational changes
What are examples of scenarios which may require the use of fibrinolytics?
Treatment of a ST segment elevation myocardial infarction (STEMI),
Acute stroke
Pulmonary embolism
Acute deep venous thrombosis
Why are anti-coagulants used to prevent venous thrombosis and antiplatelets arterial thrombosis?
Because arterial circulation is fast moving, and thrombi are rich in platelets, therefore anti-platelets are used.
Venous circulation is much slower and thrombi is largely composed of fibrin, hence the use of anticoagulants
What is the difference between anticoagulants and anti-platelets?
Anticoagulants slow down clotting, thereby reducing fibrin formation and preventing clots from forming and growing.
Antiplatelet agents prevent platelets from clumping and also prevent clots from forming and growing.
What are fibrinlytics?
Preventing growth of blood clots
What can arterial thrombosis lead to?
Acute myocardial infarction (MI)
Ischemic stroke
Limb gangrene.
What can venous thrombosis lead to?
Typically Deep vein thrombosis (DVT), can lead to post-thrombotic syndrome, and pulmonary embolism (PE), which can be fatal or can result in chronic thromboembolic pulmonary hypertension.
What regions of the body can cause chest pain?
Cardiac
Respiratory
Gastro Intestinal
Musculoskeletal
What are cardiovascular causes of chest pain?
Cardiac-Ischemia Aortic Dissection Pulmonary Embolism Aortic Stenosis Pericarditis Myocarditis Takotsubo cardiomyopathy (broken heart syndrome)
How is cardiac ischemia tested via blood?
Troponin positive:
Type 1 (physical blockage, Spontaneous Coronary Artery Dissection)
Type 2 (artery may be okay, but something like coronary spasm may have occurred)
Troponin Negative:
Angina- stable vs unstable
Coronary spasm- microvascular/endothelial
Describe the nomenclature and main histology of atherosclerosis progression.
Initial Lesion- macrophage infiltration, isolated foam cells
Fatty Streak- intracellular lipid accumulation
Intermediate Lesion- intracellular lipid accumulation, small extracellular lipid pools
Atheroma- intracellular lipid accumulation, core of extracellular lipid
Fibroatheroma- single of multiple lipid cores, fibrotic/calcified layers (cap)
Complicated Lesion- Surface defect, hematoma-haemorrhage, thrombosis
How may coronary artery disease present?
Many are asymptomatic
Angina
MI
Unstable angina
What are typical cardiac chest pains?
Central site
Radiation- moving down left arm, or maybe up neck to jaw
Character- tends to be heavy, tight
Severity- very severe (can be variable)
Duration- very long or very short
Associated symptoms- breathlessness, pallor, sweating, nausea and vomiting
Precipitating- usually brought on by exercise
Why do people get pain during cardiac events?
Imbalance between oxygen requirements (HR, contractility, wall tension (impacted by systolic pressure and volume))
and
Oxygen supply (coronary flow (HR, and autoregulation which is impacted by atherosclerosis))
What are basic tests done in patients with chest pain?
History Observations (pale and sweaty) Laboratory tests (troponin, myoglobin) ECG X-ray
What is done to investigate for ischemia?
Exercise tolerance testing Stress echo Myocardial perfusion scan CT coronary angiogram Stress perfusion cMRI Invasive testing: coronary angiogram (catheter through radial or sometimes femoral artery to visualize inside- gold standard)
What is a classic ECG finding in ischemia??
ST depression
Caused by impact in repolarization- the heart is deprived of oxygen and not able to repolarize as quickly
How do anti-anginal drugs work?
Reduce cardiac workload -slow HR -reduced force of contraction -reduce pre/after load Improve blood supply -coronary vasodilation
What drugs are typically used to treat angina and what areas do they impact?
Nitrates- venodilation, reduce pre-load
Beta blockers- impacts HR and contractility
Calcium antagonist- vasodilation
Can also use: K Channel activators, If blockers (function of sinus node, may be used if intolerant to beta blockers)
What drugs will impact vasodilation?
Calcium antagonists
Nitrates
What are acute coronary syndromes?
Unstable angina- unstable plaque without myocardial necrosis
Non-ST elevation MI- Plaque rupture
ST elevation MI- Complete vessel occlusion
How would you treat a type 1 NSTEMI?
Dual antiplatelet Low Molecular Weight Heparin Statin ACE-1 Beta blocker
How does a STEMI and NSTEMI differ in terms of ECG readings?
NSTEMI will have ST depression
STEMI has ST elevation as occlusion is complete
How do you treat a type 1 STEMI?
Primary percutaneous coronary intervention (placing a stent)
Systemic thrombolysis
Interventional cardiac centre (if accessible)
What are physiological complications of an acute MI in terms of the heart muscle, and what can these complications cause?
Inferior wall and septum impacted: repolarization impacted- seen as ventricular dysrhythmia (ventricular fibrillation)
Large amounts of infarct muscle: fluid build up within heart and heart failure
What are lipids, and what are primary examples?
Molecules with hydrocarbons, and non soluble in polar solvents (i.e. water, methanol)
Cholesterol
Triglycerides
Phospholipids
What role does cholesterol have within the body?
Cell membrane component
Synthesis of bile acid (needed for absorption of fat-soluble vitamins A, D, E, K)
Precursor for endogenous Vit D production
Precursor for steroid hormones
What are the role of triglycerides?
Used as energy source in tissues
Used for energy storage in adipose
What is the general structure of lipoprotein?
Spherical
hydrophobic core- Triglycerides and cholesterol esters
Surface of polar components (phospholipids, free cholesterol, proteins (apolipoproteins))
Moving from least to most, what are the density of lipoproteins?
Chylomicron Very Low Density Lipoproteins Intermediate DL Low Density L High Density L
What role do apolipoproteins have?
Protein component of lipoproteins
Critical role in lipid metabolism
Guide the formation of lipoproteins
-acting as ligands for lipoprotein receptors
-serve as activator/inhibitor of enzymes involved in metabolism of lipoproteins
What does lipoprotein lipase do?
Releases free fatty acids and monoglycerides from circulating chylomicrons and VLDL into tissues
What occurs in the exogenous cycle of lipoprotein metabolism?
Food is ingested and broken down, lipids are absorbed by gut as chylomicrons
Chylomicrons enter lymphatics and then move to bloodstream via thoracic duct
In the circulation, chylomicrons decrease in size as triglycerides are removed by the enzyme lipoprotein lipase which is present in capillaries of adipose and muscle
Remaining Chylomicron Remnant circulates, and can be taken up by LDL receptors in the liver
What occurs in the endogenous cycle of lipoprotein metabolism?
Liver produces VLDL which circulates
VLDL are broken down into IDL and LDL by lipoprotein lipase
LDL and IDL circulate and can either be taken up by LDL receptors in liver, or LDL receptors on extrahepatic cells
What happens when there is too much LDL or LDL is oxidized (i.e. in smoker)
LDL is taken up more readily by macrophages and scavenger cells which results in laying down of fatty plaques in arteries.
How is mature HDL formed within the body and what does it do?
Mediates the movement of cholesterol throughout the body back to the liver.
Cholesterol is within artery wall
Pre-beta-HDL is circulating
ABCA1 and ABCG1 mediate efflux of cholesterol from foam cells to Pre-b-HDL
HDL is formed and re-enters circulation
Cholesterol is passed to Scavenger Receptors Class B Type 1 (SR-B1) in liver
What are ApoI and ApoE?
The apoproteins involved in the HDL pathway
When assessing cardiovascular risk, what individuals are known to be at high risk of CVD due to pre-existing conditions?
Those already diagnosed w CVD
Chronic Kidney Disease (Stage 3+)
Diabetics over 40 year OR with over 20 years of disease
Familial Hypercholesterolaemia
How is alcohol and smoking consumption related to CVD?
Alcohol impacts liver function and this impacts triglyceride metabolism (results in increased levels)
Smoking results in increased oxidization of LDL which mean it is taken up more readily by macrophages resulting in formation of foam cells and atherosclerotic plaques
How much energy per unit is in fat, carbs, and protein?
Fat: 9kcal/g
Carbs/Proteins: 4 kcal/g
What is the structure of a fatty acid?
Carboxylic acid with a hydrocarbon chain
How many fatty acids are found on Triglycerides, phospholipids, and cholesterol?
Tri: 3
Phospho: 2
Chol: 1
What are the main types of polyunsaturated fats?
omega-3
omega-6
What are the structural configurations for unsaturated fatty acids?
Cis: hydrogen atoms attached to the carbon double bond on same side (bent)
Trans: hydrogen atoms attached to carbon double bonds on different sides (linear- don’t normally occur in nature)
What apoproteins are involved used with chylomicrons, VLDL, and LDL?
Chylomicrons: B48
VLDL: B100
LDL: B100
What happens in terms of LDL Receptors when cholesterol levels fall?
They are upregulated to enhance uptake of LDL by liver cells, so LDL can be degraded to form more cholesterol for release into circulation
Where is cholesterol absorbed in the GI?
Duodenum and proximal jejunum
What are the typical desired levels for total cholesterol, HDL, and LDL in primary prevention?
Total: < 5mmol/L HDL: >1 men, >1.2 women LDL: < 3 Fasting Triglycerides: 1.7 Non-Fasting: <2.3
What are the typical desired levels for total cholesterol, HDL, and LDL in secondary prevention?
Total: < 3 mmol/L HDL: >1 men, >1.2 women LDL: < 1.8 Fasting Triglycerides: 1.7 Non-Fasting: <2.3
How do un/saturated fats impact LDL formation?
Saturated- By decreasing LDL turnover as they decrease LDLR activity.
Unsaturated- Increase hepatic LDLR number and LDL turnover, reducing LDL levels
What is the mechanism of action for statins?
They prevent the action of HMG-CoA reductase which converts HMG-CoA into Mevalonate which can then be converted into cholesterol.
This inhibits cholesterol production, resulting in lower blood cholesterol, and an increase in LDLR production in an effort to break down more LDL to produce more cholesterol to increase blood concentrations
What is angina pectoris?
Chest pain due to myocardial ischaemia
Build-up of metabolites (ADP, CO2, lactate, K ions) activate sensory nerve
What is stable angina?
Attacks are predictable (i.e. exercise, stress)
Likely due to narrowing of a coronary artery (can use statins)
What is unstable angina?
Attacks are unpredictable
Coronary artery occlusion due to platelet adhesion to ruptured atherosclerotic plaque (use anti-platelet drugs)
Typically on waiting list for a procedure in order to prevent MI
What is variant angina?
Attacks are unpredictable
Least common
Coronary artery occlusion by vasospasm- so not plaque induced
Would give a drug that causes vasodilation
What is coronary steal?
You dilate areas of coronary circulation that don’t need to be dilated, or in areas where vessels cant be dilated any further, which cause dilation of already well perfused areas, stealing blood from areas that needed more perfusion
What drugs are associated with coronary steal?
Dipyridamole, SNO, and adenosine, L-Type calcium blockers
How do B1 adrenoreceptor blockers work?
Competitive reversible antagonist of adrenaline and noradrenaline at cardiac beta1 adreno receptors
Reduce heart rates and used to treat angina
What does ivabradine do?
Blocks funny current- sodium current contributing to SA depolarization
Decreases heart rate but not force, reduces myocardial o2 demand
This can be good in patients with heart failure where you don’t want to impact force
What are strategies for treating angina?
Dilation of arteries (reduce after-load) Venous dilation (reduce venous return and therefore pre-load)
What is the Bainbridge reflex?
Sympathetic reflex initiated by increased blood in the atria.
It causes stimulation of SA node
This stimulates baroreceptor in atria causing increased SNS stimulation
Causes increased HR, therefore want to reduce this in someone who is anginal
What are nitrovasodilators and an example?
Typically used as vasodilator of veins (typically) for angina (reducing preload)
Glyceryl Trinitrate- sprayed under tongue, not orally active due to first-pass metabolism
Isosorbide mono/dinitrate- taken orally, slower onset and prolonged duration
What makes a plaque more unstable?
Small fibrous cap
Few smooth muscle cells
High concentration lipid core
How does nitric oxide work?
Activate soluble guanylate cyclase (found in cytoplasm), nitric oxide can bind onto it causing conversion of GTP to cGMP which will bring about vasodilation (and muscle relaxation)
Where do L and T class Ca channel antagonist act?
L: In smooth muscle, cardiac muscle and pacemakers
T: Cardiac pacemakers and smooth muscle
In terms of tissue selectivity, what calcium channel blockers would you prescribe for smooth muscle vs cardiac?
Smooth: nifedipine>diltiazem > verapamil
Cardiac: verapamil > diltiazem> nifedipine
Verapamil is more selective to cardiac muscle
What is nicorandil?
Opens K channels allowing reductions in reaching action potential
Has cardiac-protective effect
Nitrate like drug, but no tolerance
