Platelet cyclooxygenase

A thrombotic tendency is present in diabetes due to an imbalance between prostacyclin and thromboxane. Lipid peroxides and newly generated free radicals are thought to inhibit the vasodilator and anti-platelet effects of endothelial-derived prostacyclin, but stimulate platelet cyclooxygenase activity, thereby promoting the production of thromboxane A2. This leads to vasoconstriction and platelet aggregation - the concept of peroxide vascular tone (Halliwell and Gutteridge, 1989). 

B. Presystemic inactivation of platelet cyclooxygenase by acetylsalicylic acid... 

Far out the most important agent in this group is aspirin, a cyclooxygenase inhibitor which is discussed in more detail in Chapter 26. Its unique properties as a platelet aggregation inhibitor are brought forward by the fact that while platelet cyclooxygenase is irreversibly inhibited at low doses of aspirin the synthesis in endothelium of prostacyclin, a platelet aggregation inhibitor itself, recovers more quickly. 

C. Aspirin inhibits platelet cyclooxygenase. Abciximab, a monoclonal antibody, binds to and inhibits the platelet glycoprotein Ilb/IIIa receptor. Dipyridamole inhibits platelet cyclic AMP phosphodiesterase and raises cyclic AMP levels. Eptifibatide binds to the glycoprotein Ilb/IIIa complex. 

The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins (Figure 36-2). Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while most non-COX-selective NSAIDs are reversible inhibitors. 

Pederson, A.K. and G.A, FitzGerald Dose-Related Kinetics of Aspirin Presystemic Acetylation of Platelet Cyclooxygenase, N. Eng. J. Med., 1206 (November 6, 1984). 

Berg J, Christoph T, Widema M, Bodenteich A (1997) Isoenzyme-specific cyclooxygenase inhibitors A whole cell assay system using the human erythroleukemic cell line HEL and the human monocytic cell line Mono Mac 6. J Pharmacol Toxicol Meth 37 179-186 Boopathy R, Balasubramanian AS (1988) Purification and characterization of sheep platelet cyclooxygenase. Biochem J 239 371-377... 

Malmsten C, Hambert M, Svensson J, et al. Physiological role of an endoperoxide in human platelets hemostatic defect due to platelet cyclooxygenase deficiency. Ptoc Natl Acad Sd USA 1975 72 1446-1450. 

Horellou MH, Lecompte T, Leaubier C, et al. Familial and constitutional bleeding disorder due to platelet cyclooxygenase defidency. Am J Hematol 1983 14 1-9. 

Patrono C, Cidiattcuii G, Patrigiani P, et al. Clinical pharmacology of platelet cyclooxygenase inhibition. 

Based on several randomized trials, aspirin has become the preferred antiplatelet agent in the treatment of aU ACSs. Early aspirin administration to all patients without contraindications within the first 24 hours of hospital admission is a quality care indicator (see Table 16-3). The antiplatelet effects of aspirin are mediated by inhibiting the synthesis of thromboxane A2 through an irreversible inhibition of platelet cyclooxygenase-1. Following the administration of a non-enteric-coated formulation, aspirin rapidly (<10 minutes) inhibits thromboxane A2 production in the platelets. Aspirin also has anti-inflammatory actions, which decrease C-reactive protein and also may contribute to its effectiveness in ACS. In patients undergoing PCI, aspirin prevents acute thrombotic occlusion during the procedure. 

Aspirin has emerged as a very nsefnl antithrombotic agent because of its action against platelet cyclooxygenase activity. 

Honn KV, Steinert BW, Moin K, Onoda JM, Taylor JD, Sloane BF. The role of platelet cyclooxygenase and lipoxygenase pathways in tumor cell induced platelet aggregation. Biochem Biophys Res Commun. 145 (1987) 384—389. 

VITAMIN E AND PLATELET AGGREGATION a-Tocopherol, a natural antioxidant, inhibits platelet aggregation and release. The effect of vitamin E is dne to a redaction in platelet cyclooxygenase activity and inhibition of lipid peroxide formation. It is believed that snpplementing the diet with vitamin E could play a role in the treatment of thromboembolic disease, especially if it is given in conjnnc-tion with an inhibitor of platelet aggregation. 

With either low-dose or high-dose aspirin, both endothelial and platelet cyclooxygenase are rendered inactive. Endothelial cells are capable of synthesizing new enzyme, as opposed to platelets. Thus, the inhibition of prostacyclin production is only temporary, while inhibition of... 

Aspirin irreversibly acetylates platelet cyclooxygenase, rendering it inactive. Thus, thromboxane A, is no longer formed, decreasing platelet adhesion. 

Which of the following is a reversible inhibitor of platelet cyclooxygenase ... 

Aspirin, an irreversible inhibitor of platelet cyclooxygenase, has been shown to prevent recurrence of transient ischemic attacks and ischemic stroke. The answer is (B). 

The pharmacologic basis for an antiplatelet effect of aspirin was described by John Vane in 1971 (18). Because the platelet cyclooxygenase is irreversibly acetylated by aspirin, a single dose of 325 mg aspirin obliterates thromboxane synthesis by all platelets then in the circulation. Mrrltiple... 

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