Thrombosis and platelet

Roth GJ, Calverley DC Aspirin, platelets, and thrombosis theory and practice. Blood 1994 83 885. 

RothGJ, CalverieyDC Aspirin, platelets and thrombosis. Theory and practice. Blood 1 885,1994. 

Bom, G. V. R., 1974, Research on the mechanisms of the intravascular adhesion of circulating cells, in Platelets and Thrombosis (S. Sherry and A. Scriabine, eds.), pp. 113-126 University Park Press, Baltimore. 

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. 

Platelets play a central role in primary hemostasis. They are also important in pathological processes leading to thrombosis. Antiplatelet drugs are primarily directed against platelets and inhibit platelet activation by a number of different mechanisms. They are used for the prevention and treatment of thrombotic processes, especially in the arterial vascular system. 

Due to the pivotal role of platelets in thrombus formation, especially in the arterial system, inhibition of platelet function has become a central pharmacological approach. Antiplatelet drugs are given in order to prevent and treat thromboembolic diseases such as coronary heart disease, peripheral and cerebrovascular disease. They have also revolutionized the procedures of invasive coronary interventions as they reduce the risk of restenosis and thrombosis. 

We shall first describe the coagulation pathway leading to the formation of fibrin. Then we shall briefly describe some aspects of the involvement of platelets and blood vessel walls in the overall process. This separation of clotting factors and platelets is artificial, since both play intimate and often mutually interdependent roles in hemostasis and thrombosis, but it facifitates description of the overall processes involved. 

Hemostasis and thrombosis are complex processes involving coagulation factors, platelets, and blood vessels. 

Early studies indicate that combined GP Ilb/IIIa inhibition with rt-PA thrombolysis may improve clinical and MRI outcomes after acute ischemic stroke, with an acceptable safety prohle. The dual targeting of platelets and hbrin by combination therapy may provide synergistic benefits, including increased arterial recanalization, reduced microvascular thrombosis, reduced arterial reocclusion, and less rt-PA-mediated blood-brain barrier injury and secondary activation of the coagulation system. 

Describe the processes of hemostasis and thrombosis, including the role of the vascular endothelium, platelets, coagulation cascade, and thrombolytic proteins. 

By far the most widely measured marker of hemostatic activation is D-dimer, which is a product formed by the action of plasmin on cross-linked fibrin (95). D-dimer levels in plasma are generally elevated in DIC. The consumption of platelets and coagulation proteins as a result of thrombin generation leads to the deposition of fibrin thrombi at multiple organ sites. This triggers fibrinolysis with an increase in the formation of fibrin degradation products, which can cause bleeding at multiple sites. Because DIC can have a variety of causes and may coexist with systemic fibrinolysis, such as in pulmonary embolism or deep vein thrombosis, the d-Dimer test is not specific for DIC (95). 

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. 

BAY 41-2272 is a novel non-NO-based soluble GC activator. It produced a marked inhibition of platelet aggregation in washed platelets and PRP, however, with much lower potency in PRP. Both NO and prostacyclin exhibited synergistic activity with BAY 41-2272 to inhibit platelet aggregation. In vivo, BAY 41-2272 significantly reduced blood pressure in rats, but it had only a small effect on FeCl3-induced thrombosis [107]. 

The rat carotid artery injured by a balloon catheter has been widely used as a model of angioplasty. The rat model is a proliferation model without foam cells (93). This form of injury causes immediate coagulation and thrombosis cascade in which platelets adhere, spread, and degranulate on the denuded surface of the artery, and approximately 24 hours later SMC begin to proliferate. Liposomal BPs, clodronate, and alendronate were injected to male sabra rats, 15 and 3mg/kg, respectively (52,69,76). Marked neointimal formation and decreased luminal area were observed in control animals. Neointima/media (N/M) ratio was 1.3 0.2, and luminal stenosis was 44 3%. LC and LA suppressed intimal growth when administered intravenously on day -1 and day 6. N/M ratios were reduced by 60% and 69% for LC and LA, respectively. 

The plasma level of fatty acids in a fed subject is between 0.3 and 0.5 mmol/L. As discussed above, the maximal safe level is about 2 mmol/L. This is not usually exceeded in any physiological condition since, above this concentration, that of the free (not complexed with albumin) fatty acids in the blood increases markedly. This can then lead to the formation of fatty acid micelles which can damage cell membranes the damage can cause aggregation of platelets and interfere with electrical conduction in heart muscle (Chapter 22). The cells particularly at risk are the endothelial cells of arteries and arterioles, since they are directly exposed to the micelles, possibly for long periods of time. Two important roles of endothelial cells are control of the diameter of arterioles of the vascular system and control of blood clotting (Chapter 22). Damage to endothelial cells could be sufficiently severe to interfere with these functions i.e. the arterioles could constrict, and the risk of thrombosis increases. Both of these could contribute to the development of a heart attack (Chapter 22) (Box 7.4). 

Figure 22.5 (a) Injury to endothelial cells can lead to thrombosis. Healthy endothelial cells secrete two factors that inhibit thrombus formation (i) prostacyclins, which inhibit aggregation of platelets and (ii) a factor that facilitates conversion of plasminogen to plasmin. Injury to endothelial cells can facilitate thrombosis since (i) they do not secrete prostacyclins (ii) they do not secrete plasminogen activator and (iii) they secrete a factor that stimulates thrombosis. (b) Diagram of an atheroscle-rosed artery containing a thrombus. A thrombus is blocking the lumen of the artery that is not totally blocked by plaque. 

Arterial thrombosis. The formation of an aggregate of blood factors (thrombus), primarily platelets and fibrin, with entrapment of cellular elements in the arteries. Arthritis. Inflammation of a joint. 

Some polyphenols inhibit platelet aggregation reducing the risk of thrombosis [171-173]. This effect may be due to a series of interaction of flavonoids in different biochemical pathways, such as by inhibition of cyclooxygenase and lipoxygenase, that are involved in the arachidonic acid metabolism in the platelets, or by inhibition of the formation of tromboxane and of the receptor function of the same [173-176]. Regular consumption of wine, tea and chocolate has been associated to the reduction of platelet aggregation, cardio-vascular diseases and thrombosis [171,177-179]. 

Demrow HS, Slane PR, Folts JD. 1995. Administration of wine and grape juice inhibits in-vivo platelet activity and thrombosis in stenosed canine coronary arteries. Circulation 91 1182-1188. 

Packham MA, Role of platelets in thrombosis and hemostasis, CanJ Physiol Pharmacol 1994 72 278-284. 

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