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Describe the components of an atherosclerotic plaque, indicating the factors which lead to plaque formation. Why are such lesions a threat to health?

Atherosclerosis is one of the major diseases of the western world. Indeed it is estimated that 50% of people in the western world die of atherosclerosis related complications. Atherosclerotic plaques consist of both an atheromatous component and a sclerotic component. The atheromatous component is a lipid core at the centre of the lesion which contains lipid filled cells called foam cells and crystals of free cholesterol. The sclerotic component consists of a tough fibrous cap which develops over the lipid core.

The Lipid core and its pathogenesis

The best theory of why atherosclerosis occurs is that of continued damage. The hypothesis is that prolonged and continuous damage to the endothelial lining of a blood vessel is what starts the process. When the endothelial cells become damaged they allow lipoproteins in the blood plasma called LDL to cross into the subendothelial space, which is the space in tunica intima between the basement membrane of the endothelium and the internal elastic lamina. In addition they start expressing surface molecules to which leukocytes and platelets can bind. The specific leukocytes which are very important in atherogenesis are monocytes. These monocytes bind to the surface molecules and translocate into the subendothelial space becoming macrophages.

The macrophages start releasing inflammatory cytokines and importantly oxidising agents. The inflammatory cytokines act as chemotaxic agents drawing more macrophages and other inflammatory cells into the atherosclerotic lesion. Whilst the oxidising agents convert the LDL molecules into oxidised LDL.

Macrophages have an uptake mechanism for LDL called the scavenger receptor pathway. In this pathway macrophages absorb LDL and store it within their cytoplasm. Molecules of oxidised LDL have a particularly high affinity for this pathway. Hence macrophages end up taking up a huge amount of this oxidised LDL. When looked at under the microscope these LDL filled cells look foamy and are hence referred to as foam cells. In addition the oxidised LDL is toxic to the macrophages which ingest it, so many of them undergo necrosis and release the lipid that they were storing into the subendothelial space. This free lipid, which in particular contains large amounts of cholesterol forms crystals in the subendothelial space which are again visible under the microscope. These are two of the main features of the lipid core of atherosclerotic plaques, i.e. the macrophages which have converted into foam cells along with deposits of free cholesterol.

The Fibrous cap

The damaged endothelial cells also start secreting growth factors such as endothelial derived growth factor (commonly referred to as EDGF). They also express a surface membrane protein called Von Willebrand Factor on their luminal membranes. Thrombocytes in the Blood adhere to this Von Willebrand factor and when they do they start secreting Platelet derived Growth factor (PDGF). Both of these growth factors diffuse into the artery wall, through the tunica intima to the tunica media. Here they trigger activity in the smooth muscle cells. They cause smooth muscle cells to dedifferentiate and digest away their contractile infrastructure. These modified cells then migrate along the chemotaxic gradient towards the source of the growth factors. Hence they migrate to just under the basement membrane of the endothelial cells of the blood vessel, i.e. over the lipid core. Some of the smooth muscle cells don’t make it all the way to the endothelium and instead end up absorbing LDL and converting into foam cells.

Once they arrive there, they begin fibroblast like behaviour. They proliferate to make a covering of these dedifferentiated smooth muscle cells over the lipid core and they also start secreting extracellular matrix proteins, such as collagen. Hence a fibrous layer containing these cells forms over the lipid core and this covering is known as the fibrous cap.

Neovascularization

Another central feature of atherosclerotic lesions and one that is important with regards to the complications of atherosclerosis is Neovascularization. Indeed the damaged endothelial cells also start secreting vascular endothelial growth factor (VEGF), which causes the growth of new blood vessel towards the site of the cells which secrete it. Hence blood vessels present in the tunica adventicia, called vasa vasorum, begin to grow branches into the deeper layers of the blood vessel towards the atherosclerotic plaque. Eventually these blood vessels reach the plaque and they typically grow into the shoulder of the plaque. The shoulder refers to the periphery of the plaque, i.e. where it borders with the healthy endothelium.

Risk factors for atherosclerosis

The four main risk factors for the development of atherosclerotic lesions in the walls of your arteries are hypertension, smoking, diabetes mellitus and hyperlipidaemia and we will now address each of these in turn.

Hypertension means too high mean blood pressure. If your blood pressure is too high then your endothelial cells are constantly being exposed to a very large strain. So they are more likely to get damaged and activate the inflammatory response which leads to the formation of an atherosclerotic plaque. This is demonstrated by the fact that the most common site for atherosclerosis to occur is the posterior wall of the abdominal aorta. The pressure that the endothelial cells of the aorta have to endure is very large, because the aorta is the first blood vessel off the heart. But in addition this site is particularly at risk of damaged because it sits anterior to the vertebral column, so every time the heart beats blood is crushing the posterior wall of the aorta against the solid vertebral column and this leads to endothelial damage. If your blood pressure is raised then this crushing will be worsened.

Cigarette smoke contains a huge number of toxins, which the smoker and anyone unfortunate enough to be in their presence breathe in. These chemicals diffuse across the alveolar membrane and into the blood stream. Here they can lead to the damage of the endothelial cells.

In people who suffer from Diabetes mellitus, the blood glucose levels are often unstable and can reach dangerously high levels (hyperglycaemia), because of the lack of control by insulin. These elevated blood glucose levels can directly damage endothelial cells and begin the process of atherosclerosis. Diabetics are particularly at risk of getting atherosclerotic plaques developing in the popliteal arteries in the legs.

Finally Hyperlipidaemias result in much higher blood LDL levels. This means that if the endothelium does become damaged then more LDL will move into across the damaged endothelium into the subendothelial space and the resulting atherosclerotic plaque will be worse than if lipid levels were normal. People who are obese often have extremely high blood lipid levels as well as hypertension and are thus at high risk of atherosclerosis.

Complications of atherosclerosis

There are many ways in which atherosclerosis can lead to complications. Firstly the lesion can lead to stenosis or worse occlusion of blood vessels. It can do this in three ways; either the plaque can gradually grow and narrow the lumen. Or the plaque can ulcerate and then thrombosis can occur on the exposed surface. The resulting thrombus then limits blood flow through the vessel. Or the newly formed blood vessels in the shoulder of the plaque can rupture and lead to intraplaque haemorrhage. This leads to the lipid core swelling as it fills with blood and this swollen lesion can then limit blood flow.

The formation of an atherosclerotic plaque in the aorta is not going to significantly reduce blood flow through that vessel because the aorta is so large. But the second most common site for atherosclerosis to occur is within the coronary arteries and the fourth and fifth most common sites are the carotid arteries and the arteries of the circle of Willis respectively. These arteries have much smaller lumen and the presence of a growing atherosclerotic plaque can seriously limit blood flow to the heart and brain. Hence atherosclerosis in this way can lead to exertional angina pectoris and potential myocardial infarction. Or if the stenosis occurs in an artery supplying the brain then it can potentially lead to occlusive stroke.

The second major complication of atherosclerotic plaques is that they can ulcerate, which is where the fibrous cap becomes detached from the atheromatous portion of the lesion. The process of thrombosis commonly occurs on the exposed surface of the lesion and a thrombus hence forms. As previously discussed this then leads to the stenosis or potentially occlusion of the blood vessel and will result in ischemia and maybe infarction of the tissue which that blood vessel supplies, with serious consequences if it is the brain or the heart. However, another complication is that the thrombus can throw off thromboemboli which can circulate and lodge in other blood vessels. Commonly they lodge in pulmonary vessels causing a pulmonary embolism.

Finally, another complication is that atherosclerosis can lead to aneurysmal dilatation. The atherosclerotic plaque severely weakens the wall of the blood vessel on which it is established and if the blood vessel is under very high pressure from the blood, such as the aorta, this can lead to the blood vessel dilating to a massive size, such as is the case in a triple A. If this ruptures it can lead to major internal haemorrhage and death.

Conclusion

Atherosclerosis is dangerous and very common. By the late teenage years, individuals will have fatty streaks on their aortas, which are speculated to be the forerunners of atherosclerosis. Regular exercise and a healthy diet are thought to lower your risk for developing full-blown atherosclerotic plaques and there is a considerable body of evidence that moderate consumption of resveratrol in red wine also helps.

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Compare and contrast the role of endothelial cells and platelets in haemostasis and coagulation

Haemostasis is the process by which blood vessels with a hole in them produce a stable plug to fill in the hole and prevent haemorrhage. Coagulation is the process by which a soluble protein called fibrinogen, produced by the liver and normally present in the blood is converted into insoluble polymers of fibrin monomers. These fibrin polymers are interwoven into a plug to increase its stability. Both endothelial cells and platelets have essential roles in the processes of haemostasis and coagulation. But as we shall see the role of endothelial cells is more in signalling the need for the formation of a haemostatic plug, whilst platelets actually form the haemostatic plug.

 

The Primary Haemostatic plug

Healthy endothelial cells are incredibly important for preventing the formation of a haemostatic plug in a healthy blood vessel. But if for some reason the endothelial cells are damaged then a primary haemostatic plug forms. When endothelial cells are injured the collagen of the basement membrane of the endothelial cells and the collagen of the extra cellular matrix (depending on how severe the injury is) are exposed on the luminal surface of the blood vessel. In addition the injured endothelial cells begin to produce and secrete a protein called Von Willebrand factor onto the surface of the exposed collagen where it binds. Platelets, also called thrombocytes which are in the circulation possess a surface glycoprotein called gp1B which will bind to the Von Willebrand factor. Hence a layer of platelets will form over the exposed collagen. This is known as platelet adhesion.

 

In addition the exposed collagen will activate the platelets and cause them to secrete granules which are stored in their cytoplasm. These granules contain many substances but some particularly important ones are Thromboxane A2, Serotonin (also called 5-Hydroxytryptamine) and ADP. Both Thromboxane A2 and Serotonin are vasoactive and produce vasoconstriction of the arterioles leading to the damaged blood vessel. Hence less blood will be reaching the damaged wall and this will help to reduce blood loss due to the injury. Similarly injured endothelial cells also take action to try and reduce blood flow to the affected area, but rather than producing a vasoconstrictor, they instead stop secreting the vasodilator Prostacyclin.

 

The final of the products that platelets release is ADP. Platelets have on their surface receptors for ADP and when ADP binds to this receptor it activates the platelet. Activated platelets will then bind to other platelets; specifically they will bind to the platelets which have formed a layer over the exposed collagen, to produce a multilayered structure of platelets. This structure is known as the primary haemostatic plug. The antithrombotic drug Clopidogrel works by binding to the receptor for ADP on the surface of platelets and not stimulating it, i.e. it is an antagonist and simply prevents ADP binding and activating the receptor.

 

Overall with regards to the formation of the primary haemostatic plus we can see that platelets and endothelial cells have vastly different functions. The platelets actually form the structure which will plug the hole. Whilst endothelial cells are essential for preventing the formation of such a structure in healthy blood vessels and ensuring that it is only produced at sites of injury. So their role is more in coordinating haemostasis.

 

 

Coagulation

The purpose of the coagulation cascade is to transform the primary haemostatic plug into a secondary haemostatic plug. A primary haemostatic plug as previously described consists of a multilayered structure of platelets. Whilst a secondary haemostatic plug is a multilayered structure of platelets but with a dense meshwork of fibrin between the platelets holding them in position. The secondary haemostatic plug is far more stable than the primary haemostatic plug and prevents haemorrhage more effectively.

 

In order to produce such a dense meshwork of fibrin it is necessary to turn fibrinogen which is a soluble protein in the blood plasma into these fibrin strands. The enzyme which converts fibrinogen into fibrin monomers is called Thrombin and the inactive precursor of thrombin, called Prothrombin is constitutively present in the blood plasma. Another enzyme called Factor XIIIa then converts the fibrin monomers into Fibrin strands. Hence in order to produce the fibrin strands it is necessary for Prothrombin to be converted into thrombin and the series of reactions by which this conversion occurs is known as the coagulation cascade.

 

Similarly to in the formation of the primary haemostatic plug it is the damaged endothelial tissue which starts the coagulation cascade. Damaged endothelium does this in two ways. The first way is through the intrinsic pathway, when there is damage the protein HMW kinin, standing for heavy molecular weight kinin is produced. This converts factor XII into XIIa. The activated factor XII then in turn activates XI to XIa and XIa activates IX into IXa. Then comes the important stage which is the activation of factor X. Factor X is activated by factor IXa, but it must be in the presence of factor VIIIa, calcium and phospholipids. This is important because it is the activated platelets which release calcium ions and it is also the platelets which act as a surface of phospholipids on which this reaction can occur. Hence this stage means that the coagulation cascade can only occur on platelets surfaces, i.e. it ensures that the fibrin is going to be produced in the primary haemostatic plug.

 

Factor X has two stages of activation. The first we have just seen and the second is done by Factor Va. Once factor X is activated to factor Xa, it will catalyse the conversion of prothrombin to thrombin and hence coagulation can begin. Thrombin then further activated factor V to Va to produce a positive feedback loop.

 

The second pathway by which endothelial cells can activate the coagulation cascade is through the extrinsic pathway. In this pathway, the endothelial cells along with any damaged cells in the interstitum underneath produce a protein called tissue factor. Tissue factor converts factor VII to factor VIIa and factor VIIa can undertake the first portion of factor X activation. Again though this transformation must take place on a phospholipids surface and in the presence of calcium, which helps to ensure that fibrin deposition occurs actually within a primary haemostatic plug and not just in the free circulation.

 

Conclusion

Overall we have seen that in both the formation of the primary haemostatic plug and its conversion to a secondary haemostatic plug, via the coagulation cascade, endothelial cells have a regulatory function. Indeed they help in both cases to ensure that both processes only occur when there is damage. They do this by preventing exposure of the underlying collagen in the case of platelet adhesion and by expressing surface molecules like Antithrombin which inactivates thrombin in the case of coagulation. Platelets on the other hand play a more active role in the case of primary plug formation, since they are the structures which will actually bind together to form the plug. With regards to coagulation they are more similar to endothelial cells and play a guiding role, i.e. they ensure that fibrin deposition happens at the correct site.

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