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ATHEROSCLEROSIS AND THROMBOSIS AND RELATED BASIC CARDIOVASCULAR PATHOLOGY Dr Angela Barbour, Discipline of Pathology (c) The University of Adelaide 2009. ISCHAEMIA AND INFARCTION Ischaemia: reduction in blood supply leading to impaired aerobic respiration. Ischaemia may be acute or chronic. Severe acute ischaemia of sufficient duration (varies depending on tissue) leads to infarction. Chronic ischaemia may lead to cell and tissue atrophy. Infarct: an area of necrosis within a tissue or organ that has resulted from acute ischaemia. The ischaemia may have been caused by abrupt occlusion of either its arterial supply or its venous drainage. Most are caused by arterial occlusion, either from thrombus forming over an atherosclerotic plaque or embolism.

The tissue changes of infarction take from 6-12 hours to be seen both macroscopically and microscopically Following infarction, tissues undergo coagulative necrosis. Microscopically the architecture and cellular outlines of the

dead tissue are retained initially but the tissue appears more eosinophilic than healthy tissue and nuclei undergo karyolysis.

Tissue necrosis incites an acute inflammatory response, then, except in the brain, healing occurs by organization (via granulation tissue formation) and fibrosis.

Infarcts macroscopically may be either pale (anaemic) or haemorrhagic (red). Pale infarcts contain little blood whereas haemorrhagic infarcts are full of blood.

Pale infarcts arise due to obstruction of a single end artery (e.g. coronary arteries, branches of renal, carotid and splenic arteries)

Red or haemorrhagic infarcts mainly occur as a result of any of: Venous occlusion (e.g. strangulated bowel or volvulus). Severe venous congestion then haemorrhage occur and the

rise in local venous pressure ultimately impairs arterial inflow. In tissues with a double blood supply (e.g. lungs, liver) though such tissues uncommonly undergo infarction Reperfusion of an infarcted area following lysis of the occluding thrombus or thromboembolus (e.g. some cerebral infarcts)

Whether or not an infarct results from arterial occlusion, or if it does, the size of the infarct, depend on The size of the artery occluded T he duration of occlusion and the vulnerability of the cells to ischaemia. e.g. neurons in the brain sustain irreversible

injury following 3-5 minutes of complete ischaemia whereas glial cells are less susceptible. Cardiac myocytes start to die following 20-40 minutes of complete ischaemia

The presence of a dual circulation. Organs with a dual circulation e.g. lung uncommonly undergo infarction Previous development of a collateral circulation. If an artery becomes narrowed slowly over time (by atherosclerosis)

the territory it supplies becomes chronically ischaemic. Small vessels at the edge of this territory supplied by adjacent arteries may dilate and grow into the periphery of the ischaemie area. If the narrowed artery then suddenly becomes completely occluded, the area of infarction will be less than if the artery had been normal then suddenly become blocked e.g. myocardial infarction

The general state of the circulation. When the circulation is already impaired e.g. in cardiac failure, the effects of ischaemia may be exacerbated

The oxygen content of blood N.B. Ischaemia is one cause of hypoxia (reduced amount of oxygen reaching the tissues). Other causes of hypoxia include anaemia (resulting in reduced oxygen carrying capacity of the blood), various pulmonary diseases leading to reduced oxygenation of the blood and generalised impairment of blood flow e.g. in cardiac failure. THROMBOSIS The formation of a clotted mass of blood within the cardiovascular system during life. The mass itself is called a thrombus. Occurs by a complex process involving the interaction of blood vessel walls, platelets and the plasma coagulants of the

blood clotting system. In contrast, the formation of a blood clot occurs in a wider variety of situations e.g. when a blood vessel ruptures, in a test

tube, post mortem. It is essential that blood remains fluid within the cardiovascular system yet is able to clot when necessary to prevent

excessive bleeding following injury to a vessel wall. Thrombosis is prevented in normal vessels by normal laminar blood flow, factors released by healthy endothelium that prevent platelet adhesion and activation and various factors that inhibit elements of the coagulation cascade and lyse fibrin once it is formed.

The formation, propagation and spontaneous dissolution of thrombi represent a balance between factors that promote thrombogenesis and those that promote thrombolysis.

Thrombogenesis is promoted by (Virchows Triad) 1) Injury to endothelium e.g.

Ulceration or fissuring of atheromatous plaque Endocardial damage in myocardial infarction Immunologic or infective inflammation of endothelium or endocardium e.g. infective endocarditis, vasculitis

2) Alterations in normal blood flow promoting platelet contact with endothelium Turbulence e.g. around abnormal cardiac valves, in aneurysms Stasis e.g. in deep veins in the leg due to poor mobility (leading to loss of the leg muscle pump)

3) Hypercoagulable states e.g. Post-operative and post-traumatic states and with severe burns Certain genetic abnormalities including mutations in the gene for coagulation factor V Certain malignancies (notably adenocarcinoma of the pancreas), probably via the release of procoagulant substances Myocardial infarction High oestrogens: peri-partum, oral contraceptives Antiphospholipid antibody syndrome

Characteristics of thrombi Arterial thrombi: most caused by atherosclerosis (-> endothelial injury) or aneurysms (-> turbulence +/- endothelial injury) Cardiac thrombi may occur in the left atrium (with atrial fibrillation), in the left ventricle following infarction and in left

ventricular aneurysms, and in endocarditis of any sort In an aneurysm are often laminated (lines of Zahn) due to progressive deposition of the thrombus Venous thrombi

Slowing of blood flow and hypercoagulability are especially important in the pathogenesis Most commonly occur in the deep leg and pelvic veins (deep venous thrombosis) Often deeper red in colour than arterial thrombi

Disseminated thrombi may form in small vessels (disseminated intravascular coagulation: DIC) in certain conditions e.g. septic shock, severe trauma and burns, acute pancreatitis.

Fate of the thrombus Embolisation Dissolution via fibrinolysis Organisation (replaced by scar) Persistence e.g. thrombi in aortic aneurysms Infection (rare) Complications of thrombosis Obstruction to blood flow - arterial, venous Can become dislodged or fragment to become emboli EMBOLISM An embolus is an intravascular solid, liquid or gaseous mass carried in the blood stream to some site remote from its origin or point of entrance into the blood stream. Examples Athero (piece of atherosclerotic plaque) or thrombo-emboli (most common) lodge in vessels downstream and may cause

ischaemia or infarction Septic emboli Gaseous nitrogen bubbles in decompression sickness/the bends Tumour emboli > spread of cancer Bone marrow or fat emboli after fracture -> fat embolism syndrome Amniotic fluid emboli Air emboli Potential complications of thrombo and atheroembolism Transient ischaemia e.g. in brain causing transient ischaemic attack Infarction e.g. cerebral or renal infarction ATHEROSCLEROSIS Extremely common disease in developed countries Underlying cause of ischaemic heart disease and many strokes Prolonged slow patchy focal accumulation of lipids and fibrous material in the intima of large and medium sized arteries Resulting in narrowing of the lumen and often impairment of the circulation, particularly when complicated by thrombosis. Appearances Macroscopically early lesions (frequently present by adolescence) appear as flat yellow streaks in the intima (fatty streaks). These do not necessarily progress. However, as plaques progress they become larger yellow elevations that protrude into the lumen and often coalesce. They may ultimately calcify and may ulcerate and show surface thrombus. Microscopically there are

Cells, incl. smooth muscle cells (that have migrated from the media and produce extracellular matrix), 'foam' cells, macrophages and lymphocytes

Collagenous extracellular matrix

Area of extracellular lipid containing cholesterol crystals Often patchy calcification Small blood vessels

Pathogenesis The main factors influencing the patchy anatomical distribution of atheroma are local stresses on the intima. Why it develops is not known but various hypotheses exist, the main one being the reaction to injury hypothesis that proposes that atherosclerosis results from a low grade chronic inflammatory response to chronic stresses, including biochemical, mechanical and toxic, to the endothelium: monocytes accumulate at sites of endothelial dysfunction, the endothelium becomes more permeable to these cells and blood lipids. Macrophages in the plaque phagocytose lipids (-> foam cells) and they and other cells release factors that stimulate chronic inflammation, smooth muscle cell migration and fibrosis. Risk factors Main: smoking, systemic hypertension, dyslipidaemia, diabetes mellitus, increasing age, gender: men > women (but after menopause, the rate in women increases) Others: including genetic factors (e.g. influencing lipid metabolism), obesity, lack of exercise, stress, elevated homocysteine levels, chronic renal failure (partly related to hypertension and dyslipidaemia) General complications of atherosclerosis Narrowing of vessel lumen may cause ischaemia: acute at times of increased oxygen demand, or chronic Acute plaque event (fissuring, ulceration, intra-plaque haemorrhage) -> acute thrombus formation which may be occlusive

or non-occlusive. Intraplaque haemorrhage may itself cause further narrowing of the lumen Occlusive thrombosis may -> infarction Secondary atrophy of the media (due to pressure effects of plaque or encroachment of the plaque into the media) may ->

aneurysmal dilatation -> thrombus formation and/or -> rupture Embolism of plaque or thrombus The relative incidence of these different general complications varies depending on the site. Main sites Coronary arteries -> angina, myocardial infarction, sudden death, cardiac failure Abdominal aorta -> aneurysms (most common site of atherosclerotic aneurysm), emboli to legs, kidneys Carotid and vertebrobasilar arteries -> cerebral infarction, transient ischaemic attacks Femoral and popliteal arteries -> claudication, skin ulcers, gangrene (i.e. peripheral vascular disease) Renal arteries -> renal artery stenosis -> hypertension Mesenteric arteries -> bowel ischaemia, infarction ANEURYSMS An aneurysm is an abnormal focal dilatation of a vessel or part of the heart (generally left ventricular wall) True aneurysm (most common): when the wall of the aneurysm is formed by the vessel (or left ventricular) wall False (pseudo) aneurysm: a breach in the vessel wall leading to an extravascular haematoma that communicates with the

lumen True aneurysms arise due to weakening of the media. There are 2 main architectural types of aneurysm: fusiform (dilation of the full circumference of the wall) and saccular

(focal dilation of one area of wall) Causes include:

Atherosclerosis. The most common site for atherosclerotic aneurysms is the abdominal aorta Infection in an artery wall (mycotic aneurysm) Inflammation: vasculitis Genetic connective tissue diseases e.g. Marfans syndrome -> cystic medionecrosis and fusiform aneurysm of the

ascending aorta Congenital weakness in the wall: probable predisposing factor of saccular berry aneurysms around the circle of Willis Systemic hypertension -> microaneurysms (Charcot Bouchard) in cerebral arterioles from arteriolar damage (hyaline

arteriolosclerosis) Traumatic arterial injury

N.B. Aortic dissection is frequently, but incorrectly, referred to as dissecting aneurysm. Aortic dissection arises in the thoracic aorta, most commonly as a result of systemic hypertension or Marfans syndrome. Blood dissects into and travels in the outer media. The vessel is generally not dilated.

AORTIC DISSECTION Aortic dissection refers to the phenomenon of blood entering the vessel wall, generally from a tear in the intima, and dissecting along the wall in the media (usually at the junction of the inner 2/3 and outer 1/3) for a variable distance. The intimal tear is usually in the thoracic aorta, usually the ascending part. Those in the ascending aorta have an especially high mortality rate due a variety of potentially life threatening complications: Aortic rupture -> hypovolaemic shock Retrograde rupture into the pericardial cavity -> haemopericardium and cardiac tamponade Weakening and dilatation of the aortic valve ring leading to acute incompetence of the valve and acute cardiac failure Continuation of the dissection around branches of the aorta leading to external compression of the vessels e.g. coronary

arteries (-> myocardial ischaemia or infarction), cerebral arteries (-> cerebral ischaemia or infarction)

Alternatively, blood may re-enter the vessel lumen, even as far down as the iliac arteries. Patients may survive for many years with such re-entrant dissections. The dissection track usually ultimately becomes dilated. Risk factors The main risk factor is systemic hypertension. Certain hereditary diseases of connective tissue also pose a risk, the main one being Marfans syndrome. In Marfans syndrome the elastic tissue of the aortic media fragments and proteoglycans accumulate (cystic medionecrosis). Other less common risk factors include bicuspid aortic valve, aortic coarctation (both associated with similar changes in the media), aortitis of any cause (e.g. giant cell arteritis) and in the 3rd trimester of pregnancy. Atherosclerosis is relatively less important though may be present incidentally. DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM Major clinical problem Thrombi form within deep veins of the lower limbs +/- pelvis and mainly cause problems from embolisation to the

pulmonary artery or its branches in the lungs Risk factors for DVT

Slowing of blood flow e.g. Restricted mobility e.g. elderly, post surgical, unconscious, long plane flights Cardiac failure Hyperviscosity e.g. polycythaemia External pressure on veins Leg fractures in plaster cast (may be trauma also)

Hypercoagulability of blood e.g. Post-operative and post-traumatic states, burns Certain genetic abnormalities including mutations in the gene for coagulation factor V Certain malignancies, especially adenocarcinoma of the pancreas, probably via the release of procoagulant

substances Myocardial infarction Certain chemotherapeutic agents High oestrogens: peri-partum, oral contraceptives Antiphospholipid antibody syndrome Nephrotic syndrome Obesity

Local endothelial injury e.g. Trauma Surgical injury Smoking

Some patients may have several risk factors. NOT atherosclerosis Signs/symptoms of DVT About 50% are asymptomatic as there are alternative pathways for venous drainage Others have variable redness, pain, warmth, swelling of calf Outcomes: pulmonary embolism, chronic venous insufficiency (varicose veins, leg discomfort, characteristic skin changes, non-healing leg ulcers). Pulmonary embolism The vast majority of pulmonary emboli arise from thrombi formed in the systemic veins, particularly from pelvic and deep femoral veins. Effects depend on: size of embolus, presence or absence of underlying lung and cardiovascular disease

Large or numerous -> Sudden collapse and death (if > 60% of vascular bed occluded) Acute cor pulmonale, shock

Medium sized Cough, breathlessness, acute cor pulmonale Pulmonary infarction:

Relatively uncommon due to the dual blood supply of the lung. More likely if there is underlying lung and cardiovascular disease

Peripheral in lung, haemorrhagic Haemoptysis, pleuritic chest pain and pleural rub (from associated inflammation) +/-pleural effusion

Small May be clinically silent (small emboli) Multiple small emboli over time may lead to pulmonary hypertension and chronic cor pulmonale