Lecture 12 – Thrombosis Relevant Terms • Haemorrhage – escape of blood from ruptured blood vessel • Thrombus – a blood clot formed within the vascular system of the body and impeding flow • Thrombosis – process of forming a blood clot • Thrombocytothaemia – high platelet counts in the blood • Thrombocytosis – disorder where the body produces too many platelets (increased chance of clotting) • Thrombocytopaenia – deficiency of platelets in the blood (not able to clot easily) Haemostasis 1) Vascular spasm • Damage to smooth muscle • Immediate vasoconstriction 2) Form platelet plug • Injury to vessel wall exposes underlying collagen • Platelets become sticky; swell; stick to area • Release chemotactic substances o Thromboxane A2 3) Coagulation • Liquid blood forms gel • Formation of prothrombin activator • 2 pathways which eventually reach a common pathway • Extrinsic o Chemicals from outside the blood vessels leak into blood o Short, rapid, few steps o Begins within seconds • Intrinsic o Responsible for clotting blood within the damaged blood vessel o More complex o Takes longer to begin • Common pathway o Starts when PTA is activated o PTA turns inactive prothrombin into active thrombin o Thrombin turns inactive fibrinogen into fibrin • Clot retraction o Final step o Platelets pull on fibrin to contract o Pulls vessel walls closer together – permits healing Fibrinolysis • When the clot is no longer beneficial • Dissolved by plasmin • Inactive plasminogen (in plasma) is turned on when needed

Thrombosis • Formation of a blood clot (thrombus) inside an unbroken vessel • Obstructs flow of blood through circulatory system Aetiology of Thrombosis 1) Injury to vascular endothelium 2) Alteration in blood flow (turbulence, stasis) 3) Hypercoagulability of blood Virchow’s Triad • Formula of formation of thrombosis

1) Vascular damage • Underlying connective tissue exposed • Clotting mechanisms activated 2) Alteration in blood flow • Turbulent blood flow o Caused by atherosclerosis o Cells and heavier elements of blood come into contact with endothelial cells o Increases risk of endothelial injury • Stasis of blood flow o Platelets have greater chance of making contact with vessel wall o Activated clotting factors will accumulate and anti clotting factors may not be present in adequate amounts

3) Hypercoagulability • Concentrations of clotting factors are higher than anti-clotting factors o Inherited disorders (anti thrombin deficiency, plasmin deficiency) o Cancer patients o Atrial fibrillation What happens to thrombus? • Can dissolve o Fibrinolytic mechanisms break down clot • Grows and occludes o Can cause ischaemia or infarction • Becomes embolus o Can block blood flow through vessels Venous thrombosis • Deep vein thrombosis o Sluggish blood flow o Local oedema, ischaemia & infarction of tissue o Can break off and travel • Arterial thrombosis o Found over damaged areas caused by ATH or aneurism o Blockage to arterial blood flow ! Infarction Commonly used drugs • Anti-platelet o Decrease platelet aggregation and inhibit thrombus formation o Aspirin (inhibits COX, blocking formation of thromboxane A2) • Anti-coagulant o Prevent coagulation o Heparin (blocks formation of thrombin) o Warfarin (antagonist to Vitamin K) • Fibrinolytic o Dissolve blood clots by activating plasminogen o Happens naturally through endogenous tissue plasminogen activator (tPA) o Or streptokinase which does the same thing(SK) (drug)

Lecture 13 – Coronary Artery Disease AKA: ischaemic heart disease or coronary heart disease Major cause of CAD • Atherosclerosis Myocardial Requirements • Adequate blood flow o For O2 and nutrients o From coronary arteries • Balance between oxygen supply and demand o Oxygen demand increases if HR speeds up or force of contraction becomes stronger Coronary Artery Disease • Narrowing/blockage of coronary arteries o By atherosclerosis • Inadequate blood flow to myocardium o Less oxygen and nutrients o Damage and death of cells • Usually alright at rest, but problems arise when activity is increased o Because of narrowing/obstruction, the heart cannot supply body with the oxygen and nutrients it needs Risk factors for CAD • Ageing o Overall increase in TPR • Smoking o Chemicals in cigarettes are vasoconstrictors o Increases LDL levels (hyperlipidaemia) o CO replaces O2 in blood • Family history • Hypertension o Constant shearing force causes damage and plaque forms • Obesity o Causes hypertension • Diabetes o Glucose attches to amino acids and attaches to vessel walls and causes damage • Lack of exercise • Hyperlipidaemia

Pathogenesis of CAD • Severe and chronic atherosclerosis that causes narrowing of the lumen of one or more coronary arteries o Critical stenosis o 75% or greater narrowing in lumen o Narrowing # increased TPR # increased BP etc.… Angina • Chest pain caused by insufficient blood flow and oxygen to heart muscle (from exertion) o Imbalance between heart’s oxygen demand and supply • Blood flow is restored, pain recedes and heart is not permanently damaged Forms of Angina • Stable angina o Chest pain associated with exertion o Some obstruction • Unstable angina o Chest pain with less exertion o Fore frequent, more intense and lasts for longer o More obstruction • Variant angina o Pain at rest, particularly during sleep o Blood vessels are responding to plaque by spasming Pathogenesis of Angina • Atherosclerosis develops in coronary artery • Plaques form and protrude into lumen • Partial obstruction to blood flow • Increased cardiac demand (exercise) • Less oxygen available to myocardium • Anaerobic respiration in cardiac tissue instead of aerobic • Increased adenosine in ECF • Chest pain and possible referred pain Consequences of Ischaemia • Heart attack (MI) o Part of the heart muscle is destroyed, causing serious and in some cases fatal heart damage • Irregular heart rhythm (arrhythmia) o Electrical impulses in heart may malfunction, causing you heart to beat too fast, too slow or irregularly • Heart failure o Damage to heart muscle reduces its ability to effectively pump blood o Because effectiveness is decreased, blood pools and gets backed up either in lungs or in trunk (depends if damage is to L or R of heart)

ECG Changes in Myocardial Ischaemia • Abnormalities in ST segment • Transmural ischaemia effects all layers of heart muscle and is usually a total occlusion

Myocardial Infarction • Reduced blood flow through coronary arteries due to COMPLETE obstruction • Myocardial cells die from lack of oxygen • Collagen scar forms when tissue starts to die Pathogenesis of MI • Disruption of atherosclerotic plaque (rupture) • Clotting cascade (thrombus) • Coronary artery occlusion • Myocardial cell death • Scar tissue formation Clinical Manifestations • Severe crushing chest pain • Angina pectoris before MI in some people • Shortness of breath due to pulmonary shock and oedema • Cardiogenic shock o Occurs when 40% of your ventricle has died o CO drops significantly and tissues do not get enough oxygen • Dysrhythmia Diagnosis of MI • ECG o To detect ischaemia or acute coronary injury o STEMI (S-T Segment Elevation MI) or NSTEMI o STEMI is worse because it involves total occlusion (transmural) • Cardiac markers o Dead cardiac tissues release creatine kinase and troponin o Leak out of injured myocardial cells into blood

o Levels rise over time Treatment • Glyceryl trinitrate (GTN) o Vasodilator • Coronary stenting o Pushes back plaque and restores blood flow • Coronary artery bypass graft o Healthy blood vessel is connected (grafted) to coronary artery slightly past the site of blockage

Lecture 14 – Stroke Stroke • Abnormality of cerebral perfusion • Blocked or broken cerebral blood vessels • 50,000 Australians have a stroke every year • 80% of strokes occur in people over 60 • Stroke is a leading cause of morbidity and mortality Risk factors • Advancing age • Hypertension • Diabetes mellitus • Hyperlipidaemia • Smoking • Family history • Alcohol consumption • Heart disease Physiology – blood supply of the brain • Nerve cells depend on uninterrupted supply of oxygen • Brain consumes 20% of cardiac output and 20% of O2 consumed by body • 750mL of blood pumped to brain every minute • Cerebral blood flow normally stable over a wide range of blood pressures • Circulatory interruption o 5-8 seconds # unconsciousness o 20-25 seconds # no electrical activity o 4-6 minutes # irreversible brain damage • Two main arterial systems that supply the brain o Left and right carotid arteries ! Anterior cerebral artery (ACA) ! Middle cerebral artery (MCA) o Left and right vertebral arteries ! Posterior cerebral artery (PCA)

Categories of Stroke 1) Generalised reduction in blood flow to brain • Anything that interferes with cardiac output could potentially cause you to have a stroke 2) Infarcts (blockages) 3) Haemorrhages (broken vessel) Infarcts (Ischaemic Strokes) • Aetiology o Vascular obstruction due to ! Cerebral ATH ! Thrombosis of an atherosclerotic segment ! Embolus • Pathogenesis o Related to development of ATH, thrombosis and embolus o Related to energy failure at the cellular level o Less blood flow to the brain # less O2 # less ATP # sodium potassium pumps lose function # sodium cant leave # water moves in # neurons swell # brain swells # increases intracranial pressure # symptoms worsen o Macrophages engulf dead tissue after infarction (liquefactive necrosis) leaves hole in brain filled with fluid Clinical Manifestations • Manifestations are related to location of occlusion • E.g. occlusion in middle cerebral artery could lead to o Contralateral hemiplegia (paralysis) o Contralateral sensory loss o Aphasia (language disorder) o Altered consciousness o Neglect syndrome Transient Ischaemic Attacks (TIA) • Predictors/warning signs for stroke (the angina of stroke) • Neurological dysfunction from minutes to hours • Symptoms include weakness, slurred speech, dysphagia, unsteadiness • Symptoms resolve completely without evidence of neurological dysfunction Stroke due to haemorrhage • Many types of haemorrhages can occur in the brain • Primary brain haemorrhage within brain tissue o Aetiology: hypertension (can cause small cerebral BVs to burst) o Pathogenesis: related to development of hypertension, ATH and/or aneurysms ! Weakened vessel wall ruptured

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o Clinical Manifestations ! Abrupt onset ! Haemorrhage distorts brain tissue ! Severe headache, vomiting, rapid loss of consciousness ! Deep coma, irregular respirations, dilated non-responsive pupils. Spasticity Primary haemorrhage within subarachnoid space o Aetiology: rupture of Berry aneurysm (weakening of a BV wall), ATH o Pathogenesis: related to the development of an aneurysm

Stroke Sequelae • Depends on location and size of affected area (Brodmann areas) • Seizures, pneumonia, fever • Contralateral loss of motor function • Contralateral loss of sensory function • Language deficits • Cognitive deficits • Autonomic deficits o Problems with urination, defecation, erection Stroke Management • FAST • Control blood pressure, glucose levels seizures, body temperature • Ischaemic stroke o Fibrinolytic therapy within 90 minutes • Haemorrhagic stoke o Surgical approach