Commonest cause of death in the Western world ( about 1/3 of total mortality).
117,000 deaths in 2002 in the UK, more than any other single disease process at an enormous cost to the NHS - £1.73 billion in 1999.
Death rates falling 44% over last 10 years but less than other western countries.
Over 20% males < 60 years may have evidence of early IHD.
Atherothrombosis * is a Leading Cause of Death Worldwide †1 1. The World Health Report 2001. Geneva: WHO; 2001. Mortality (%) *Cardiovascular disease, ischemic heart disease and cerebrovascular disease † Worldwide defined as Member States by WHO Region (African, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific)
Troponins are very sensitive and cardiospecific markers but can be raised in cardiac damage due to other causes. eg PE, myocarditis.
Troponin levels are not an early marker of cardiac damage and although levels in some patient rise at 3-4 hours the test is most diagnostically useful at 12 hours post symptoms, particular for ruling out cardiac damage.
Atherothrombosis is characterized by a sudden (unpredictable) atherosclerotic plaque disruption (rupture or erosion) leading to platelet activation and thrombus formation
Atherothrombosis is the underlying condition that results in events leading to myocardial infarction, ischemic stroke, and vascular death
Plaque rupture 1 Plaque erosion 2 1. Falk E et al. Circulation 1995; 92: 657–71. 2. Arbustini E et al . Heart 1999; 82: 269–72. Shows a disrupted coronary plaque with occlusive thrombosis superimposed Shows plaque erosion with acute coronary thrombosis
The Development of Atherothrombosis – a Generalized and Progressive Process Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Plaque rupture acts as the stimulus for thrombus formation If non occlusive, ischaemic symptoms are temporary Thrombosis can contribute to plaque growth through the formation and resolution of subclinical platelet thrombi Plaque rupture Platelet activation and aggregation Non-occlusive thrombus
Occlusive thrombus Healing and resolution Plaque growth
Atherothrombosis and Microcirculation Adapted from: Topol EJ, Yadav JS. Circulation 2000; 101: 570–80, and Falk E et al . Circulation 1995; 92: 657–71. Thrombus formation on a plaque is a dynamic process in which platelets aggregate then dis-aggregate This leads to embolization of platelet aggregates from evolving thrombus. These can be occlusive and are pro-inlammatory Particulate matter is also shed, this can cause block in the microvasculature leading to cardiac insufficiency or vascular dementia Plaque rupture Microvascular obstruction Embolization
Identifying Those at Risk of Atherothrombosis 1,2 1. Yusuf S et al . Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.
Atherothrombosis is characterized by a sudden plaque disruption leading to platelet activation and thrombus formation 1
Atherothrombosis is the common pathological link between all major clinical manifestations of vascular disease: myocardial infarction, ischemic stroke and peripheral arterial disease 2
Patients with clinical manifestations of atherothrombosis in one vascular bed are not only at risk of a recurrent event in the same arterial distribution, but also at risk of developing ischemic events in other vascular beds 3
Atherothrombosis is one of the leading causes of death worldwide 4
1. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. 2. Nenci GG. Eur Heart J 1999; 1(suppl A): A27–A30. 3. Lichtman JH et al. Circulation 2002; 105: 1082–7. 4. The World Health Report 2001. Geneva: WHO; 2001.
The Role of Platelets in Atherothrombotic Disease
Hemostatic Plug Formation Adapted from: Ferguson JJ. The Physiology of Normal Platelet Function . In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice . London: Martin Dunitz; 2000: pp.15–35. Primary hemostasis (termination of bleeding)is the process of platelet plug formation at the site of injury (occurs within seconds) Secodary hemostasis describe the reactions in the coag system that result in a fibrin clot (minutes) fibrin strands strengthen the plug (important in larger vessels to prevent further bleeding Thrombin AGGREGATION Fibrin Hemostatic clot Clotting Platelet Aggregation 0 min 10 min 5 min SECONDARY PRIMARY COAGULATION
Platelet Adhesion and Activation Aggregation of platelets into a thrombus Platelets Endothelial cells Platelets adhering to subendothelial space Platelet thrombus Normal platelets in flowing blood Platelets adhering to damaged endothelium and undergoing activation Subendothelial space Adapted from: Ferguson JJ. The Physiology of Normal Platelet Function . In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice . London: Martin Dunitz; 2000: pp.15–35. Platelet relationship with the vessel wall is crucial. Normally they do not adhere. But an injury like a ruptured plaque will cause them to adhere Adherance is promoted by a platelet collagen receptor. This interaction is stabilised by VWF allows platelets to remain attached despite high shear forces. Fibrinogen then links adjacent platelets There are many things that can cause activation ADP, serotonin, thromboxane. They also activate the coagulation cascade producing thrombin which further stimulates platelets
Platelet Aggregation Adapted from: Kuwahara M et al. Arterioscler Thromb Vasc Biol 2002; 22: 329–34. VWF makes the platelets change shape, they look like rolling balls. They become “inside out” which release factors that change shape to a hemisphere FIRM, BUT REVERSIBLE ADHESION IRREVERSIBLE ADHESION Scanning electron micrograph of discoid, dormant platelets Activated, aggregating platelets illustrating fibrin strands Flowing disc-shaped platelet Rolling ball-shaped platelet Hemisphere-shaped platelet Spreading platelet
Key Mediators in Platelet Adhesion, Activation and Aggregation Adhesion 1. Ferguson JJ. The Physiology of Normal Platelet Function . In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice . London: Martin Dunitz; 2000: pp.15–35. INJURY
Plaque Disruption Leading to Atherothrombosis Formation Adapted from: Falk E et al. Circulation 1995; 92: 657–71. Size and composition of the clot varies with the site of injury. Thombus formation can cause an acute event (MI) or contribute to long term progression of vascular disease A small fissure can result in a mural thrombus that partially occludes the vessel contributing to plaque growth Macrophage Tissue factor Fibrin Aggregated platelets BLOOD FLOW
Inflammatory Modulators Produced by Platelets 1. Libby P, Simon DI. Circulation 2001; 103: 1718–20. 2. von Hundelshausen P et al . Circulation 2001; 103: 1772–7. 3. Wever RMF et al . Circulation 1998; 97: 108–12. 4. Hermann A et al . Platelets 2001; 12: 74–82. 5. Robbie L, Libby P. Ann N Y Acad Sci 2001; 947: 167–79.
Stimulate smooth muscle cell biosynthesis
Nitric oxide 3
Effects on monocyte, leucocyte, endothelium, and smooth muscle cells
(CD40 ligand) 1,4
Regulates macrophage and smooth muscle cell functions
Influences macrophage adhesion to endothelial cell
Platelet-factor 4 1
Mediates shear-resistant arrest of monocytes to endothelium
Rupture or erosion of an atherosclerotic plaque exposes the thrombogenic core of the lesion and lead to adhesion and aggregation of platelets and thrombus formation 1
A large rupture typically results in the formation of a large thrombus that completely occludes the vessel, resulting in an acute vascular event 2
A smaller rupture may result in a mural thrombus that partially or transiently occludes the artery, causing acute ischemia and, in the long term, contributing to progression of atherothrombosis 2
Platelets produce several inflammatory modulators and may play a significant role in atherosclerotic development 3
1. Ferguson JJ. The Physiology of Normal Platelet Function . In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice . London: Martin Dunitz; 2000: pp.15–35. 2. Falk E et al. Circulation 1995; 92: 657–71. 3 . Libby P, Simon DI. Circulation 2001; 103: 1718–20.