Platelets atherosclerosis

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

LDL when oxidized is recognized to play a crucial role in the development of atherosclerosis. It was thought that flavonoids could also protect LDL against oxidation, especially by limiting the degradation of vitamin E, the main antioxidant in LDL. Other beneficial effects of flavonoids have been reported inhibition of platelet... 

Weber C. Platelets and chemokines in atherosclerosis partners in crime. Circ Res 2005 96(6) 612-616. 

Platelets play a role in each of the mechanisms of normal hemostasis vasoconstriction, formation of the platelet plug, and blood coagulation. However, they are also involved in pathological processes that lead to atherosclerosis and thrombosis (formation of a blood clot within the vascular system). Antiplatelet drugs interfere with platelet function and are used to prevent the development of atherosclerosis and formation of arterial thrombi. 

Ar-(4-ChIorobenzyI)-7-substituted-4-oxo-4//-pyrazino[l,2-tf]pyrimidine-3-carboxarnidcs have been claimed as compounds to treat atherosclerosis and restenosis <2004W02004/019933> and as antiviral agents, particularly against herpes viruses <2002W02002/004444>. The mesoionic pyrazino[l,2-tf]pyrimidine 95 exhibited platelet aggregation inhibitory activity <2000BMC1917>. 

N. Kasuya, Y. Kishi, S. Sakita, F. Numano, and M. Isobe, Acute vigorous exercised primes enhanced NO release in human platelets. Atherosclerosis 161, 225-232 (2002). 

The aggregation of platelets contributes to the development of atherosclerosis and to the formation of acute thrombus. The activated platelets that adhere to the vascular endothelium generate lipid peroxides and oxygen free radicals, inhibiting the endothelial formation of prostacyclin and nitric oxide. 

Iron-stimulated free radical-mediated processes are not limited to the promotion of peroxidative reactions. For example, Pratico et al. [188] demonstrated that erythrocytes are able to modulate platelet reactivity in response to collagen via the release of free iron, which supposedly catalyzes hydroxyl radical formation by the Fenton reaction. This process resulted in an irreversible blood aggregation and could be relevant to the stimulation by iron overload of atherosclerosis and coronary artery disease. 

In carotid atherosclerosis, plaques may rupture, resulting in collagen exposure, platelet aggregation, and thrombus formation. The clot may cause local occlusion or may dislodge and travel distally, eventually occluding a cerebral vessel. 

Fig. 9.1. A dysfunctional or injured endothelium is at the basis for initiation of and progression to atherosclerosis. Several mechanisms, such as adhesion molecules or liberation of von Willebrand factor (vWf, upper panel), determine a series of phenomena, including platelet activation and aggregation. This participation of platelets involves the implication of molecules like glycoprotein Ilb/IIIa, fibrinogen, and von Willebrand factor. The endothelium also acts as a source of signals that regulate local functions, including VSMCs (lower panel). A list of the most relevant messengers produced by a functional and a dysfunctonal endothelium is presented in the lower panel...

Many studies have shown that ginseng has a protective effect on the development of atherosclerosis that may lead to myocardial infarction and other cardiovascular diseases. The preventive effects on cardiovascular diseases of ginseng include its potential antihypertensive and antiatherosclerotic effects. Ginsenosides are likely to be responsible for some of these effects as they have been shown to have inhibitory effects on platelet aggregation and to suppress thrombin formation as well as an effect on blood vessel contraction. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Arterial thrombi (white thrombi) are formed initially from both platelets and fibrin in medium-sized arteries on the basis of atherosclerosis. These thrombi can lead to symptoms of, among others, myocardial ischemia and myocardial infarction. The treatment is primarily aimed at prevention of thrombus formation with platelet aggregation inhibitors. For the treatment of myocardial infarction thrombolytic agents are used and for secondary prevention both oral anticoagulants and anti-platelet drugs are employed. 

Clopidogrel is indicated for prevention of vascular ischaemic events in patients with symptomatic atherosclerosis. It is also used, along with aspirin, for the prevention of thromboembolism after placement of an intracoronary stent. Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loading-dose is usually administered. Although rare, severe neutropenia and also thrombotic thrombocytopenic purpura may occur. 

CN125 Vas Dias, F. W., M. J. Gibney, and T. G. Taylor. The effect of polyunsatu-rated fatty acids on the n-3 and n-6 series on platelet aggregation and platelet and aortic fatty acid composi-tion in rabbits. Atherosclerosis 1982 43(2-3) 245-257. 

Bordia A. Effect of garlic on platelet aggregation in vitro. Atherosclerosis 1978 30 355-360. 

A significant body of evidence suggests that the calcium channel blockers may interfere with platelet aggregation in vitro and prevent or attenuate the development of atheromatous lesions in animals. Clinical studies have not established their role in human blood clotting and atherosclerosis. 

Our most common lethal disease is atherosclerosis, which causes constriction and blockage of arteries of the heart, brain, and other organs. In the United States, Europe, and Japan half of all deaths can be attributed to this ailment.a,b There seems to be a variety of causes. However, there is agreement that the disease begins with injury to the endothelial cells that form the inner lining of the arteries.3/C/d This is followed by the aggregation of blood platelets at the sites of injury and infiltration of smooth muscle cells, which may be attracted by 12-hydrox-yeicosotetraenoic acid and other chemoattractants formed by activated platelets.c "Foam cells" laden with cholesterol and other lipids appear, and the lesions enlarge to become the characteristic plaques (atheromas). 

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