Platelets thromboxane synthesis

Bydlowski, S.P., D Amico, E.A., and Chamone, D.A. 1991. An aqueous extract of guarana (Paullinia cupana) decreases platelet thromboxane synthesis. Braz. J. Med. Biol. Res. 24, 421-424. 

Aspirin s permanent inactivation of the anucleate platelet is also responsible for the cumulative effect seen with repeated daily dosing below 100 mg (25). Daily administration of 30 to 50 mg of aspirin has been shown to lead to complete suppression of platelet thromboxane synthesis in 7 to 10 days (25, 30, 31). This, in turn, leads to inhibition of platelet aggregation and prolongation of the bleeding time, a clinical test often useful in identifying patients with platelet functional defects for further study and characterization (28,32). 

Hanley SP, Bevan J, Cockbill SR, Heptinstall S. Differential inhibition by low-dose aspirin of human venous prostacyclin synthesis and platelet thromboxane synthesis. Lancet 1981 1(8227) 969-71. 

PGI2. In vitro stndies have shown that COX-2 expression is up-regulated in endothelial cells by laminar shear stress (73). Furthermore, selective COX-2 inhibitors reduce systemic PGI-2 production in healthy volunteers (74). The clinical implications of these observations are unknown. In theory, COX-2 selective NSAIDs might increase the risk of thromboembolic cardiovascular events because of preferential inhibition of endothehal prostacychn synthesis without corresponding inhibition of platelet thromboxane synthesis, but no rehable data are available on the occurrence of cardiovascnlar events in patients treated with COX-2 selective or non-selective NSAIDs. 

Other investigators have shown that oily garlic extracts, which contain ajoene, are able to inhibit enzymes necessary for arachidonic acid conversion to thromboxane (Srivastava anad Tyagi, 1993). Makheja et al. (1979) demonstrated the effect of garlic oil on platelet thromboxane synthesis. Human and rabbit platelets were incubated with garlic oil, resulting in almost complete... 

Grimm, L.J., Knapp, D.R., Senator, D. and Halushka, P. (1981). Inhibition of platelet thromboxane synthesis by 7-(l-imidazolyl) heptanoic acid dissociation from inhibition of aggregation. Thrombosis Res., 24, 307-317... 

All NSAIDs except aspirin inhibit cyclooxygenase reversibly. Inhibition by aspirin, caused by the covalent acetylation of the enzyme, is irreversible. In platelets most NSAIDs block thromboxane synthesis more than that of prostacyclin and the overall effect is therefore inhibition of platelet aggregation. This effect is already noticeable at low doses. Because of the irreversible nature of the enzyme inhibition by aspirin and the fact that in platelets the novo enzyme synthesis is not possible the aggregation inhibitory effects of aspirin last several days. 

Thrombus Formation. The thromboxanes, especially TXA2, cause platelet aggregations that result in blood clot formation.73 It is unclear whether excessive thrombus formation (as in deep vein thrombosis or coronary artery occlusion) is initiated by abnormal thromboxane production. Certainly, inhibition of thromboxane synthesis will help prevent platelet-induced thrombus formation in individuals who are prone to specific types of excessive blood clotting.84... 

Garlic (Allium sativum) is thought to have several beneficial cardiovascular effects, such as lowering blood pressure and serum lipid, and antithrombotic activity. Garlic oil has been reported to interrupt thromboxane synthesis, thereby inhibiting platelet function. 

A sequence within the cytoplasmic tail of GpIIb independently activates platelet aggregation and thromboxane synthesis. 

Israds SJ, Odaibo FS, Robertson C, McMillan EM, McNicol A. Defident thromboxane synthesis and respcHise in platelets from premature infants PedialrRes 1997 41 218-23... 

VanRollins M. (1995). Epoxygenase metabolites of docosahexaenoic and eicosi >elItaenoic acids inhibit platelet aggregation at concentrations below those affecting thromboxane synthesis. J. Pharmacol. Ejqytl. TherapeuL 274,798-804. 

PG synthesis involves four steps (Figme 2). The first two steps are common to all cells involved in prostaglandin synthesis while the final two steps are cell-specific (14-16). Release of the substrate, arachidonic acid, from membrane phospholipid stores by phospholipase is the initial event in prostaglandin synthesis, and this is followed by formation of the common PG intermediate, PGHj catalyzed by PGH synthase. At this point, rearrangement of PGH to form either stabk (PGD / Ej/ F, ) or unstable (platelet thromboxane - TxA, endothelial prostacyclin - PGy products takes place. The final step, also cell-specific, involves breakdown of the active compounds to irractive metabolites. 

Antiplatelet effect is due to permanent inactivation of COX in platelets, preventing synthesis of thromboxane. Being non-nucleated, platelets cannnot regenerate the enz)mie as can nucleated cells, and the resumption of thromboxane production is dependent on the entry of new platelets into the circulation (platelet life-span is 8 days). Thus continuous antiplatelet effect is readily achieved with low doses. 

COX-2 inhibitors inhibit the synthesis of prostacyclin in the vascular wall but not platelet thromboxane production. They could therefore theoretically increase the risk of cardiovascular events by shifting the hemostatic balance toward a prothrombotic state. However, it is not clear that theory has much impact on reality. 

Makheja AN, Vanderhoek JY, Bailey JM. Inhibition of platelet aggregation and thromboxane synthesis by onion and garlic. Lancet 1979 1 781. 

An in vitro study demonstrated that the concentrations of an aqueous extract of garlic required to inhibit ADP, epinephrine, and collagen-induced platelet aggregation were much less than those needed to inhibit thromboxane production (Srivastava, 1984). This finding suggests that inhibition of thromboxane synthesis is not the only mechanism by which garlic inhibits platelet aggregation. 

Dietary intake of n-6 fatty acids such as linoleic acid, and n-3 fatty acids, such as the fish oils eicosapentanoic acid and docosahexaenoic acid, lowers plasma cholesterol and antagonizes platelet activation, but the fish oils are much more potent in this regard [26]. In particular, n-3 fatty acids competitively inhibit thromboxane synthesis in platelets but not prostacyclin synthesis in endothelial cells. These fatty acids have also been shown to have other potentially anti-atherogenic effects, such as inhibition of monocyte cytokine synthesis, smooth muscle cell proliferation, and monocyte adhesion to endothelial cells. While dietary intake of n-3 fatty acid-rich fish oils appears to be atheroprotective, human and animal dietary studies with the n-6 fatty acid linoleic acid have yielded conflicting results in terms of effects on both plasma lipoproteins and atherosclerosis. Indeed, excess amounts of both n-3 and n-6 fatty acids may actually promote oxidation, inflammation, and possibly atherogenesis (M. Toberek, 1998). In this context, enzymatic and non-enzymatic oxidation of linoleic acid in the sn-2 position of LDL phospholipids to 9- and 13-hydroxy derivatives is a key event in LDL oxidation (Section 6.2). 

The antiplatelet action of aspirin results from the fact that inhibition of thromboxane synthesis is essentially permanent in platelets they lack the machinery for new protein synthesis. In contrast, inhibition of prostacyclin synthesis in the vascular endothelium is temporary because these cells can synthesize new enzyme. Inhibition of prostaglandin synthesis also results in important anti-inflammatory effects. Inhibition of synthesis of fever-inducing prostaglandins in the brain produces the antipyretic action of NSAIDs. Closure of a patent ductus arteriosus in an otherwise normal infant can be accelerated with a potent NSAID such as indomethacin. 

B. Mechanism of Action Aspirin and other NSAIDs inhibit thromboxane synthesis by blocking the enzyme cyclooxygenase. Thromboxane is a potent stimulator of platelet aggregation. Aspirin is particularly effective because it irreversibly inactivates the enzyme. Because the platelet lacks the machinery for synthesis of new protein, inhibition by aspirin persists until new platelets are formed (several days). Other NSAIDs cause a less persistent antiplatelet effect (hours). 

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