Introduction
Ischemic heart disease (IHD) remains the major cause of morbidity and mortality in developed countries, and has joined infectious diseases in developing countries as a leading cause of death (WHO 2008). Decades of research have shown conclusively that a number of determinants operating from early childhood onwards, most of them associated with lifestyle, are responsible for IHD.
IHD results when the oxygen demand of the myocardium cannot be met due to an inadequate blood supply. The most common cause of myocardial ischemia is atherosclerosis of epicardial coronary arteries. The major risk factors for atherosclerosis, and therefore IHD, are dyslipidemia (i.e., elevated low-density lipoprotein (LDL) and/or low high-density lipoprotein (HDL)), diabetes mellitus, hypertension, cigarette smoking, poor dietary habits, and lack of physical activity. These risk factors, particularly when more than one co-exists, can progressively damage the vascular endothelium, causing dysregulation of its anti-inflammatory and anti-thrombotic functions. The associated proliferation of underlying fibroblasts and vascular myocytes, together with the accumulation of extracellular matrix and lipids, result in the formation of what are known as atherosclerotic plaques that lead to a reduction in the luminal diameter. Some of the risk factors for atherosclerosis facilitate the development of atherosclerotic plaques, while others sustain or accelerate their formation, producing the clinical manifestations of IHD (Parthasarathy 2008, Garelnabi 2010).
By reducing the lumen of blood vessels, atherosclerosis causes an absolute decrease in myocardial perfusion in the basal state and hinders the required increase in perfusion when the demand for flow is augmented. As this process progressively worsens, the shear stress associated with blood flow through the reduced arterial lumen can cause plaques to erode or rupture, exposing the intimal layer to the luminal contents and thereby promoting frank thrombosis. Platelet activation, mobilization, and recruitment are central to this process. Luminal thrombi can trap red blood cells and acutely reduce coronary blood flow, producing a sudden myocardial ischemic event referred to as an acute coronary syndrome (ACS) that becomes manifest as either unstable angina or myocardial infarction (MI) if there is complete occlusion without prompt reperfusion. MI may also occur with embolization of platelet aggregates and/or atherosclerotic debris from a ruptured plaque.
Coronary blood flow can also be limited by vascular spasm, as well as by congenital abnormalities, such as anomalous origin of the left anterior descending coronary artery from the pulmonary artery, which may cause myocardial ischemia and infarction in infancy, but is very rare in adults.
Patients with IHD can be grouped into two broad categories: those having chronic coronary artery disease (CAD), who most commonly present with stable angina, and those who present with ACSs (i.e., unstable angina and MI). Chronic CAD is most commonly caused by slowly progressive coronary artery atherosclerosis, whereby a narrowing of the lumen of the coronary arteries limits their ability to adequately increase perfusion in response to an increase in demand for oxygen (e.g., during exertion). As the disease progresses in severity, perfusion of the myocardium can become compromised even at rest. ACSs, on the other hand, are the result of acute vasoocclusive events secondary to thrombosis at sites of erosion or rupture of atherosclerotic lesions.
Role of platelets in the etiology and pathophysiology of IHD
Structure of platelets
Blood platelets play an essential role in hemostasis, thrombosis, and coagulation of blood. They are engaged in a complex repertoire of biochemical and molecular activities designed to prevent hemorrhage.
On Wright-Giemsa-stained blood smears, platelets appear as small, anucleate, ovoid or round cells with a pale grayish blue cytoplasm that contains homogeneously distributed purple-red granules. After platelet spreading or aggregation, these dispersed granules become concentrated in the middle of the cell.
When platelet morphology is considered under functional subdivisions rather than purely anatomic terms, there are three major structural zones of the platelet, each related to specific aspect of platelet function. The peripheral zone is involved primarily in adhesion, the solgel zone in contraction, and the organelle zone in secretion.
The volumes of circulating platelets from a single individual are heterogeneous and exhibit a log normal size distribution. Circulating platelets have a volume of 7.06 ± 4.85 ^m3 (femtoliters), a diameter of 3.6 + 0.7 ^m (Mean + SD), and a thickness of 0.9 + 0.3 ^m (Paulus et al. 1979, Frojmovic et al. 1976). Platelet size varies from one individual to another, although abnormally small or large platelets are present only in certain disease states. By scanning electron microscopy, circulating blood platelets appear as flat discs, with smooth contours and rare spiny filopodia, with random openings of a channel system, which invaginates throughout the platelet and is the conduit by which granule contents exocytose after stimulation. Although the platelet is anucleate, transmission electron microscopy reveals a cytoplasm packed with a number of different organelles essential to maintenance of normal hemostasis. Platelets contain four distinct populations of granules: a-granules, dense bodies, lysosomes, and microperoxisomes. a-granules and dense bodies are distinguished morphologically from one another by their electron density as revealed by electron microscopy.
Phospholipids constitute 80% of the total lipid content of platelets, although smaller amounts of neutral lipids and glycolipids are also present. Evidence suggests that these phospholipids move to the outer membrane leaflet after platelet activation, thereby functioning to promote clot formation. Platelet membrane glycoproteins mediate a wide number of adhesive cellular interactions. These glycoproteins function as receptors that can receive signals from outside the platelet, facilitating cell-cell interactions; binding of specific ligands to these receptors results in distinct platelet responses to the external environment. Several other proteins are unique to the platelet, including platelet factor 4 (PF4), low-affinity PF4, P-thromboglobulin (P-TG), and the calcium-binding proteins thrombospondin, calmodulin, and platelet-derived growth factor (PDGF) (Stenberg et al. 1984).
Function and biochemistry of platelets
In terms of dry weight, platelets are composed of approximately 60% protein, 15% lipid, and 8% carbohydrate. Platelet minerals include magnesium, calcium, potassium, and zinc. Platelets contain substantial amounts of vitamin B12, folic acid, and ascorbic acid (Weiss et al. 1968). The concentration of sodium and potassium within the platelet are 39 and 138 mEq, respectively, a gradient against plasma that is maintained by active ion pumping, which derives energy from membrane adenosine triphosphatase of the Ouabain-sensitive, Na+/K+-dependent type. Potassium apparently is distributed in two discrete metabolic compartments (Cooley and Cohen 1967).
Non-stimulated platelets maintain a low cytoplasmic Ca2+ concentration, by limiting Ca2+ transport from plasma and promoting active efflux of this ion from the cell. Two pools of calcium are present in platelets: a rapidly-turning over cytosolic pool that is regulated by sodium-calcium antiporter in the plasma membrane, and a more slowly-exchanging pool that is regulated by a calcium-magnesium-ATPase and is sequestered in a dense tubular system. Platelets are therefore able to transport calcium from the cytosol by moving it against a gradient into the extracellular space or by sequestration in the dense tubular system (Brass 1984, Enouf et al. 1987).
There are several similarities between the energy metabolism of platelets and that of skeletal muscle. Both involve active glycolysis and the synthesis and use of large amounts of glycogen, and in both, the major mediator of intracellular energy use is ATP. Platelets, like muscle cells, are metabolically adapted to expend large amounts of energy rapidly during aggregation, the release reaction, and clot retraction (Karpatkin et al. 1970).
The presence of platelets in the hemostatic plugs that form to prevent bleeding suggests that platelets have a physiological role in hemostasis. Their presence in thrombi and emboli, however, suggests that they may have a pathological role as well. Platelets display certain properties that may be relevant to hemostasis and thrombosis. They have the capacity to adhere to foreign surfaces, they can be induced to aggregate, and they can synthesize or release a number of substances.
Platelet adhesion
The only structures with which platelets normally interact are red cells, white cells, and the endothelial lining of blood vessel walls. All other surfaces are thus foreign to them, but platelets have the ability to adhere to such surfaces. Platelets adhere to subendothelial structures that are exposed when the normal endothelial lining of the blood vessel wall is injured, which causes the deposition of a monolayer of platelets on the surface of the injured vessel. This is followed by the release of pro-coagulation substances, leading to platelet aggregation and formation of a fibrin clot over the adhered layer that results in thrombus formation (Heptinstall and Hanley 1985).
Platelet aggregation
Platelets circulate as disc-shaped cells, but when they come in contact with exposed subendothelium, agonists that activate platelets are exposed, generated, or released. These agonists include collagen, which is present in subendothelium; thrombin, which is generated on the surface of activated platelets and elsewhere; ADP, which is released from damaged red blood cells and secreted from activated platelet-dense granules; circulating epinephrine; and arachidonic acid, which is released from lipid stores in platelets and metabolized to the potent agonist thromboxane A2 (TXA2). These agonists generally cause platelets to change shape such that they form long pseudopodia, followed by platelet aggregation. Aggregation requires activation of platelet integrin adhesion receptor GP Ilb/IIIa so that it can bind fibrinogen or von Willebrand factor (vWF) and link adjacent platelets together in an aggregate. Platelet agonists induce signal transduction events in platelets that cause the above events, although the signal transduction pathways are not completely understood (Leslie et al. 1999).
Platelet release reaction
Platelets store ATP, ADP, Ca2+, and serotonin in dense granules as well as adhesive proteins such as platelet factor 4, P-thromboglobulin, platelet-derived growth factor (PDGF), fibrinogen, fibronectin, thrombospondin, and vWF in a-granules (Siess 1989). Upon activation by agonists, platelets undergo a release reaction, thereby secreting their granular contents. The release reaction is associated with the production of TXA2, and the extent of the secretion depends on the strength of the agonist. Weak agonists (e.g., ADP and epinephrine) require both cyclooxygenase activity and primary aggregation to induce secretion that is observed at low Ca2+ concentrations (Smith et al. 1973, Banga et al. 1986). Agonists of intermediate strength (e.g., platelet activating factor, PAF) can induce secretion in the absence of formation of arachidonic acid metabolism and without primary aggregation. Interestingly, when collagen is added at low concentrations to platelet suspensions, secretion of ATP occurs before the onset of shape change. This secretion is not inhibited by cyclooxygenase blockers, but is sensitive to the extracellular Ca2+ concentration and is a direct consequence of platelet binding to collagen (Siess et al. 1983, Malmgren 1986).
Platelet activation
Some signaling pathways involved in various platelet activation events are reasonably well understood, whereas others are not. Many, but not all platelet agonists activate platelets by occupying seven transmembrane-spanning, G protein-coupled receptors. Activation of these receptors generally results in activation of phospholipase CP (PLC). PLC hydrolyzes phosphatidyl-inositol-4,5-bisphosphate (PIP2), generating inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Both IP3 and DAG appear to play important roles in pathways leading to various aspects of platelet activation. IP3 is believed to interact with specific receptors to induce intracellular Ca2+ release from the dense tubular system, an intracellular Ca2+ storage organelle analogous to the sarcoplasmic reticulum in skeletal muscle. However, the exact mechanism by which this response contributes to platelet aggregation is not entirely clear because IP3-induced platelet aggregation is also dependent on thromboxane A2 (TXA2) production and ADP release (Knezevic et al. 1992). DAG interacts directly with protein kinase C (PKC) and appears to play a crucial role in the pathways of some agonists, leading to the activation of GP IIb/IIIa and fibrinogen binding. Specific inhibitors of PKC block fibrinogen binding and platelet aggregation induced by some agonists. Drivers for platelet activation include the signaling events that occur downstream of receptors for collagen (GP VI and GP Iba), thrombin (PAR1 and PAR4), adenosine diphosphate (ADP; P2Y1 and P2Y12), and thromboxane A2 (TXA2; TP) (Brass 2010).
Platelets are activated and stimulated to synthesize or release a number of substances, namely thrombin, arachidonic acid, PAF, and epinephrine which are of functional importance. When platelet ADP is released from platelet-dense granules during platelet activation by numerous agonists, secreted ADP potentiates the activating effects of other agonists (Hourani and Cusack 1991). ADP causes shape change, granular secretion, and aggregation. However, unlike strong agonists such as thrombin and collagen, ADP induces secretion usually only in conjunction with platelet aggregation. Strong agonists generally stimulate phosphoinositide hydrolysis, increase cytosolic free Ca2+, and induce TXA2 formation.
Platelet receptors and MicroRNA signaling
Platelet receptors are known to interact with external stimuli in the main blood stream leading to the regulation of platelet activation. Platelet adhesion receptors are the key initiators of platelet activation at sites of vascular injury, where platelets become exposed to adhesive proteins in the matrix, or on endothelial cells. Despite significant differences in their functions and signaling pathways, several major platelet adhesion receptors share many similarities in their signal transduction mechanisms (Li et al. 2010). The most studied platelet receptor is platelet integrin GP IIb/IIIa, which is reported to play an essential role in thrombus formation through interactions with adhesive ligands and has emerged as a primary target for the development of anti-thrombotic agents (Hagemeyer and Peter 2010). Successful blockade of this ligand binding has validated GP IIb/IIIa as a therapeutic target in cardiovascular medicine.
MicroRNAs (MiRs) molecules are a novel class of endogenous, small, noncoding RNAs that regulate gene expression via degradation, translational inhibition, or translational activation of their target messenger RNAs (Pan et al. 2010, O’Sullivan et al., 2011). Bioinformatics analysis predicts that each MiR can regulate hundreds of targets, suggesting that they play an essential role in almost every physiological and pathological pathway. Functionally, an individual MiR is important as a transcription factor because it is able to regulate the expression of its multiple target genes. MiRs are short (~20 nucleotides long), single-stranded RNAs initially transcribed by either RNA polymerase II or RNA polymerase III, as a long primary MiR transcript (pre-MiR). It is then cleaved in the nucleus by the microprocessor complex, Drosha-DGCR8, resulting in a precursor hairpin (pre-miRNA) ranging in length from 60 to 110 nucleotides. The pre-MiRNA is exported from the nucleus to the cytoplasm by exportin 5-Ran-GTP. In the cytoplasm, Dicer, a member of the RNase III family, in complex with TRBP, cleaves the pre-MiR hairpin to a 22 base pair MiR duplex.
The mature MiR is incorporated with argonaute (Ago2) proteins into the RNA-induced silencing complex (RISC), where MiR guides the complex to partial complementary binding sites located in the 3′ untranslated region (UTR) of target mRNAs to suppress gene expression. MiRs are able to directly regulate at least 30% of genes in a cell. In addition, other genes may also be regulated indirectly by MiRs. Therefore, MiRs are pivotal regulators in normal development, physiology, and pathology. Recent studies have identified a number of MiRs highly expressed in the vasculature and their expression is dysregulated in diseased vessels (Jamaluddin et al. 2011, Haver et al. 2010, Bonauer et al. 2010, Wierda et al. 2010, Urbich et al. 2008, Fang et al. 2010, Leeper et al. 2011). MiRs are also found to be critical modulators of cell differentiation, contraction, migration, proliferation, and apoptosis. Accordingly, MiRs have emerged as therapeutic targets in disease.
Platelets are also reported to have microRNA population that may regulate its activity. It is well known that platelets have mRNA and mRNA splicing machinery, and translate mRNA into proteins relevant to hemostasis and inflammation (Edelstein and Bray 2011). In silicon analysis work from Edelstein and Bray indicates that each platelet MiR targets an average of 307 distinct mRNAs, concluding in their review that platelet MiRs have ample opportunity to regulate platelet function.
Role of inflammation and oxidative stress in platelet activation
Involvement of inflammation in cardiovascular disease is well defined. Circulating platelets are affected by this metabolic disruption and by inflammatory mediators synthesized and/or released on contact with inflammatory signals. Platelets are known to play a major role in this process and have been identified as targets and players in inflammation-induced cardiovascular disease (Weksler 1983, Nurden 2011). It has been explicitly established that free radicals can cause metabolic disturbances and cell injury in a variety of ways, including lipid peroxidation, hydroxyl radical-induced modification of proteins and nucleic acids, changes in enzyme activity, and carbohydrate damage. Oxidative modification of lipids can be induced in vitro by a wide array of pro-oxidant agents and occurs in vivo during atherosclerosis and several other disease conditions (Parthasarathy et al. 2008). Alterations in the superoxide and glutathione oxidation-reduction system may lead to depleted antioxidant capacity and may result in oxidative stress. Previous studies have suggested that platelets and vascular endothelial cells could be the central target as well as the origin of oxygen free radicals or its metabolites (Dousset et al. 1983). Measuring the end products of lipid peroxidation is one of the most widely accepted assays for oxidative damage. These aldehydic secondary products of lipid peroxidation are generally accepted markers of oxidative stress.
Several studies suggest that the basal release of NO by the endothelium contributes to regulation of the vascular tone (Antoniades et al. 2008), blood flow, and blood pressure. NO inhibits platelet aggregation and adhesion to vascular endothelium. In addition, NO inhibits leukocyte adhesion to endothelium (Petidis et al. 2008). Alteration of cellular calcium homeostasis is also a critical event in ischemic heart injury. NO released by endothelium or synthesized by platelets participates in the regulation of Ca2+ signaling. Elevation of cGMP as a result of the activation of guanylate cyclase by NO stimulates a number of mechanisms that actively decrease calcium levels within the cell (Joseph et al. 1996). Although the NO-cGMP signaling system has been immensely investigated, sparse data is available pertaining to the role of platelet NO activity in coronary artery (CAD). We and others have studied the NO-cGMP system in patients with CAD, particularly the role of oxidative stress and NO-mediated platelet response in IHD (Garelnabi et al. 2010, Ikeda et al. 2000, Garelnabi et al. 2011). These studies have clearly indicated that lipid peroxidation is augmented in patients with ischemic heart disease. The increased oxidative stress seen in these patients was accompanied by platelet activation and impaired antioxidant enzymes activity. On the other hand, platelet aggregation, NO, cGMP, NO synthase activity, plasma NO, and ionized Ca2+ was profoundly increased in CAD. The increases in NO-cGMP components may have resulted as a compensatory response to ameliorate platelet activity and increased Ca2+ levels in CAD patients. Another interesting modulator of platelet activity is the recent description of platelet-derived microparticles (PMP) which are known as a heterogeneous population of vesicles (<1 mm) generated from the plasma membrane upon platelet activation by various stimuli. These PMPs have been shown to not only stimulate the response of platelets, but have also been reported to mediate the intercellular transfer of bioactive molecules such as lipids, surface receptors, and even enzymes (Siljander 2010).
Classes and mechanism of action of antiplatelet drugs
The main goals of pharmacological intervention in patients with IHD are to reduce the occurrence of anginal attacks by minimizing the rise in blood pressure and heart rate associated with physical activity so that patients can go about their daily activities without ischemic episodes. Given the prominent role that thrombosis plays in IHD, antiplatelet therapy is one of the most important modalities used in its treatment.
Antithrombotic drugs used for prevention and treatment of thrombosis include: (1) antiplatelet drugs, (2) anticoagulants, and (3) fibrinolytic agents. Given the predominance of platelets in arterial thrombi, which are the major source of IHD, the treatment and inhibition of arterial thrombosis focus mainly on antiplatelet agents, although anticoagulants and fibrinolytic drugs are often included in the acute setting.
Under normal conditions, the actions of vascular endothelial cells maintain platelets in the bloodstream in an inactive state, largely by their production of nitric oxide (NO) and prostacyclin, but also by their surface expression of adenosine diphosphatase (ADPase), which breaks down ADP released via degranulation of activated platelets. With the occurrence of injury to the vascular endothelium, production of these substances is compromised and certain components of the subendothelial matrix are exposed (e.g., collagen, von Willebrand factor (vWF), and fibronectin) to which platelets adhere via receptors constitutively expressed on their surface (e.g., GP IIb/IIIa). As discussed above, adhered platelets undergo a morphological change and then release the contents of their dense granules (e.g., ADP) and synthesize and release thromboxane A2 (TXA2), both of which serve to recruit and activate surrounding circulating platelets to the site of vascular injury.
Disruption of the vascular wall also exposes underlying cells and matrix that express pro-thrombotic factors to the circulation, which triggers the coagulation cascade. Activated platelets enhance coagulation by binding clotting factors and supporting the assembly of activation complexes that increase thrombin generation, which in addition to converting fibrinogen to fibrin, also acts as a potent platelet agonist and recruits more platelets to the site of vascular injury.
The most abundant receptor on the surface of platelets is GP IIb/IIIa, which undergoes a conformational change upon platelet activation that allows it to bind fibrinogen. Divalent fibrinogen molecules link adjacent platelets together to form aggregates, which are meshed together via fibrin strands generated via the action of thrombin to form a lattice composed of platelets plus fibrin. Antiplatelet drugs target various steps in this process. The most commonly used drugs include cyclooxygenase inhibitors, among which aspirin is the most common, thienopyridines and functionally related drugs, phosphodiesterase inhibitors, adenosine reuptake inhibitors, and GP IIb/IIIa antagonists, all of which are discussed below.
Cyclooxygenase inhibitors
The cyclooxygenases (COXs) are a family of isoenzymes responsible for the biosynthesis of various important and potent pro-inflammatory and pro-thrombotic mediators called eicosanoids, which include prostaglandins, leukotrienes, and thromboxanes. Non-steroidal anti-inflammatory drugs (NSAIDs), like aspirin and ibuprofen, exert their effects through inhibition of COX, and as such they relieve the symptoms of inflammation (e.g., pain, swelling).
COX converts arachidonic acid (AA, an m-6 polyunsaturated fatty acid (PUFA)) to prostaglandin H2 (PGH2), the parent of the eicosanoids, which can then be converted to the other compounds via further enzymatic action that involves radical chemistry and the consumption of molecular oxygen. To date, three distinct COX isoenzymes have been identified: COX-1, COX-2, and COX-3. COX-1 and COX-3 are products of alternative splicing of the same gene, so COX-3 is referred to by some as COX-1b or COX-1 variant (COX-1v). Different tissues express varying levels of the different COXs, and although the isoenzymes basically catalyze the same transformations, selective inhibition can produce a different side-effect profile. COX-1 is nearly ubiquitous among mammalian cells, but COX-2 is undetectable in most normal tissues and is inducible in macrophages upon their activation, as well in endothelial cells at sites of inflammation, where it serves to produce prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. COX-2 is also upregulated in various types of cancers, so it is believed to play a role in oncogenesis.
Both COX-1 and -2 also oxygenate two other essential fatty acids – dihomo-y-linolenic acid (DGLA, ffl-6) and eicosapentaenoic acid (EPA, m-3) – to give eicosanoids with less potent pro-inflammatory properties than those derived from AA. Both DGLA and EPA competitively inhibit oxidation of AA by the COXs, which is believed to be the major mechanism by which dietary sources of DGLA and EPA (e.g., fish oil) can reduce inflammation.
The traditional COX inhibitors are not selective for any particular COX, resulting in widespread inhibition of eicosanoid synthesis that ultimately reduces inflammation, as well as providing antipyretic, antithrombotic, and analgesic effects. However, inhibition of the synthesis of gastroprotective prostaglandins can cause gastric irritation and increases the risk of development of peptic ulcer disease.
The development of selective COX-2 inhibitors was originally aimed at blocking the production of pro-inflammatory prostaglandins while minimizing any effects on platelet and gastric function. Selective inhibition of COX-2 has been accomplished with the "coxibs", which differ in their selectivity for COX-2 relative to COX-1 by selectively binding to a hydrophobic side-pocket on the COX-2 enzyme where a valine takes the place of what is an isoleucine on COX-1, allowing access to an otherwise sterically hindered site that causes inhibition of the enzyme’s function. Since COX-2 is largely expressed selectively in inflamed tissue, there is much less gastric irritation and risk of peptic ulceration associated with COX-2 inhibitors. However, the selectivity of COX-2 causes an imbalance between thromboxane and prostacyclin, resulting in an increased risk of thrombosis, MI, and stroke. Thus, by blocking prostacyclin synthesis without concomitant inhibition of thromboxane A2 (TXA2) production, highly selective inhibitors of COX-2 increase the risk of cardiovascular events. These effects seemed most notable with rofecoxib (Vioxx®) and valdecoxib (Bextra®), which were removed from the market in 2004 and 2005, respectively. Other COX-2 selective NSAIDs, such as celecoxib (Celebrex®), and etoricoxib (Arcoxia®), are still on the market as they continue to be investigated for these adverse effects. Even with short-term use, COX-2 inhibitors have been found to increase the risk of atherothrombosis, most notably manifested as a 2-to-5-fold increased risk of myocardial infarction. Furthermore, high-dose regimens of some traditional NSAIDs such as diclofenac and ibuprofen are associated with a similar increase in risk of vascular events. Thus, although NSAIDs, particularly COX-2 inhibitors, have demonstrated benefits, the risks associated with their use should be seriously considered when prescribing them to a patient having risk factors and/or a personal or family history of IHD.
Aspirin
Aspirin (acetylsalicylic acid, ASA), is the oldest and most widely used antiplatelet drug due to its low cost, wide availability, and proven effectiveness. It is a salicylate drug whose mechanism of action serves as the model of most antiplatelet therapeutic strategies.
Mechanism of action
Aspirin, a non-selective COX inhibitor, is one of the most commonly used drugs in IHD that can reduce the development of thrombosis associated with the rupture of atheromatous plaques. Aspirin interferes with the activation of platelets by irreversibly inhibiting COX, thereby interfering with the biosynthetic pathway of thromboxanes. Unlike other NSAIDs, whose antiplatelet action is transient (i.e., in the order of hours), aspirin irreversibly acetylates COX-1 in platelets, thereby inhibiting the biosynthesis of thromboxane A2 (TXA2) and in that manner producing a long-lived antithrombotic effect (i.e., days, until new platelets are produced by the bone marrow). At higher doses (e.g., 1 g/ d), however, aspirin also inhibits COX-2, which can ultimately produce a prothrombotic effect by inhibiting the synthesis of prostacyclin in endothelial cells.
