Pharmacodynamic Properties of Antiplatelet Agents

Current Knowledge and Future Perspectives

Kallirroi I Kalantzi; Maria E Tsoumani; Ioannis A Goudevenos; Alexandros D Tselepis


Expert Rev Clin Pharmacol. 2012;5(3):319-336. 

In This Article

Cyclooxygenase-1 Inhibitors

One of the consequences of platelet activation is the liberation of arachidonic acid (AA) from the sn-2 position in membrane phospholipids by cytosolic phospholipase A2. AA is then converted to the unstable intermediates prostaglandin (PG) G2/H2. In platelets, both reactions are catalyzed by the enzyme PGH synthase-1, which exhibits cyclooxygenase (COX)-1 and hydroperoxidase activities. COX-1 activity converts AA to PGG2, which is then converted to PGH2 by the hydroperoxidase activity of PGH synthase-1 (Figure 1). PGH synthase-1 is colloquially termed as COX-1. In platelets PGH2 is subsequently metabolized to TxA2 by TxA2 synthase. In endothelial cells PGH2 is metabolized to prostaglandin I2 (PGI2) by PGI2 synthase and in other tissues to various prostanoids by tissue-specific isomerases (Figure 1). TxA2 is a potent platelet agonist.[4] Inhibition of COX-1 significantly inhibits TxA2-dependent platelet activation; however, it leaves other platelet-activation pathways largely unaffected. Aspirin is an irreversible inhibitor of COX-1 and has for many decades represented the cornerstone of antiplatelet therapy. An alternative to aspirin is triflusal (Figure 1).

Figure 1.

Arachidonic acid metabolism and the effect of cyclooxygenase-1 inhibitors. Arachidonic acid (AA) is liberated from the sn-2 position of membrane phospholipids by cytosolic PLA2. AA is then converted to the unstable intermediates prostaglandin G2/H2. In platelets, both reactions are catalyzed by the enzyme PGH synthase-1, which exhibits COX-1 and HOX activities. COX-1 activity converts AA to PGG2, which is then converted to PGH2 by the HOX activity of PGH synthase-1. In platelets, PGH2 is subsequently metabolized to TxA2 by the TxA2 synthase. In endothelial cells, PGH2 is metabolized to PGI2 by the PGI2 synthase and in other tissues to various prostanoids by tissue-specific isomerases. Inhibition of COX-1 by aspirin and triflusal significantly inhibits TxA2 formation and TxA2-dependent platelet activation; however, it leaves other platelet activation pathways largely unaffected. COX-1: Cyclooxygenase-1; HOX: Hydroperoxidase; PGG2: Prostaglandin G2; PGH2: Prostaglandin H2; PGI2: Prostaglandin I2; PLA2: Phospholipase A2; TxA2: Thromboxane A2.


Aspirin (acetyl salicylic acid) has remained, for over 50 years, the cornerstone of antiplatelet therapy owing to its proven clinical benefit and very good cost–effectiveness profile. Aspirin selectively and irreversibly acetylates the hydroxyl group of a single serine residue at position 529 within the polypeptide chain of PGH synthase-1. Thus, aspirin inhibits COX-1 activity but it does not affect the hydroperoxidase activity of PGH synthase-1. By blocking COX-1, the production of TxA2 is reduced, leading to reduced platelet aggregation.[5]

For the complete inhibition of platelet aggregation by aspirin, it is necessary to inhibit TxA2 production by >90%, which can be achieved by a dosage as high as 30 mg/day. When platelets are exposed to aspirin, COX-1 is deactivated and remains inactive for the remaining lifespan of the platelet, namely 7–10 days. This is owing to the fact that these cells are anucleate and thus unable to synthesize new, active COX-1. Thus the restoration of normal platelet function after aspirin administration occurs only with the production of new platelets. It should be noted that one seventh of the platelets in the circulation are renewed every 24 h; therefore, up to 30% of circulating platelets may show normal TxA2 production after aspirin discontinued for 48 h.[6] Consequently, aspirin administration on a daily basis should be preferred rather than administration every second day. It must be stressed that in low doses aspirin does not affect the action of endothelial cell COX-1 and therefore does not reduce the production of PGI2, which has many beneficial effects including potent antiplatelet effects.[6]

Aspirin improves clinical outcome in all cardiovascular (CV) syndromes in primary and secondary prevention, including acute events. In high-risk patients, aspirin substantially reduces the risk of vascular death by approximately 15% and nonfatal vascular events by approximately 30%, as has been reported by a meta-analysis of over 100 large-scale randomized trials.[7] The efficacy of aspirin in the primary prevention of CV events is more modest and its recommendation in this setting is highly debated owing to the fact that ischemic benefit may be offset by bleeding complications. Despite the universal use of aspirin, its optimal dose for efficacy and safety remains debatable. In this regard, the CURRENT-OASIS 7 trial showed that a daily aspirin dose of 300 mg has similar outcomes for efficacy, without a difference in the risk of major bleeding complication when it is compared to a daily dose of 75 mg in patients with an acute coronary syndrome (ACS). In the absence of recurrent ischemia, low aspirin dose could be the treatment of choice for maintenance therapy in all patients following ACS, irrespective of whether an invasive or medical approach is undertaken.

Several studies in the last few years have suggested that a proportion of patients (5–65%) exhibit a hyporesponsiveness (resistance) to aspirin treatment that could be associated with recurrent ischemic events.[8,9] The aspirin resistance may also be due to high plasmatic activities of kallikrein that could result in enhanced thrombin generation in response to vascular injury.[10,11] However, measurements of the COX-1 activity in platelets of patients treated with aspirin show that biochemical aspirin resistance is observed in less than 1% of patients.[12] Consequently, aspirin resistance may result from several causes, such as low compliance, interference with NSAIDs and protein glycation occurring in Type 2 diabetes mellitus. Increased platelet turnover observed in various diseases such as ACS, peripheral arterial disease and diabetic angiopathy, associated with faster re-appearance of newly formed, nonaspirinated platelets, may also account for aspirin resistance.[13] The role of genetic factors in aspirin resistance is controversial. Several studies have focused on the COX-1-encoding gene PTGS1. However, inconsistent results have been reported on the associations between single-nucleotide polymorphisms within PTGS1 and biochemical resistance to aspirin. The COX-2 enzyme in inflammatory cells has been suggested to play a part in aspirin resistance. Preliminary pharmacogenomic analyses have shown associations between polymorphisms in PTGS2, the gene encoding COX-2, and aspirin's effectiveness in reducing the levels of the stable TxA2 metabolite TxB2.[14]


Triflusal, or 2-(acetyloxy)-4-(trifluoromethyl) benzoic acid, is an antiplatet agent with a chemical structure similar to aspirin, but with a different pharmacokinetic and pharmacodynamic profile. The drug is administered orally and its bioavailability ranges from 83 to 100%.[15] It binds almost entirely (99%) to plasma proteins and readily crosses organic barriers. Triflusal is deacetylated in the liver, forming its main metabolite 2-hydroxy-4-trifluoromethyl benzoic acid (HTB). In contrast to the inactive aspirin metabolite salicylic acid, HTB exhibits antiplatelet activity and has a long plasma half-life of approximately 40 h.[16] Triflusal irreversibly inhibits COX-1 and reduces TxA2 production, but to a lesser extent compared with aspirin (Figures 1 & 2). It inhibits COX-1 and AA metabolism selectively in platelets, preserving PGI2 synthesis in vascular endothelial cells.[15] In addition to inhibiting the platelet COX-1 activity, triflusal and in particular HTB inhibit phosphodiesterase, the enzyme that degrades the cyclic nucleotides cAMP and cGMP, both of which inhibit platelet function.[17]

Figure 2.

Sites of action of antiplatelet agents used in clinical practice or under investigation. Aspirin and triflusal irreversibly inhibit COX-1 and reduce TxA2 production, leading to reduced platelet aggregation. P2Y12 receptor antagonists inhibit platelet function by blocking the effects of ADP at P2Y12 receptors. Thromboxane receptor antagonists target TP. GPIIb/IIIa antagonists block the binding of Fg to the activated platelet integrin-receptor αIIbβ3. Dipyridamole and cilostazol are inhibitors of PDE, an enzyme that catalyzes the hydrolysis of the cyclic nucleotides cAMP and cGMP. The PAR-1 antagonists vorapaxar and atopaxar bind to PAR-1 with high affinity and block thrombin-induced platelet aggregation. AA: Arachidonic acid; AC: Adenylate cyclase; COX-1: Cyclooxygenase-1; Fg: Fibrinogen; PAR: Protease-activated receptor; PDE: Phosphodiesterase; TP: Thromboxane and prostaglandin endoperoxide receptor; TxA2: Thromboxane A2.

Triflusal has similar efficacy to aspirin for the secondary prevention of vascular events in patients with acute myocardial infarction and stroke, while it reduces the incidence of intracranial and gastrointestinal hemorrhage compared with aspirin.[18] It should be noted that triflusal is well tolerated in patients with aspirin-induced asthma.[19] The efficacy of triflusal over clopidogrel for secondary prevention of stroke among patients with CYP2C19 polymorphisms will be determined in the ongoing MAESTRO trial.[201]


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