Introduction Of Myocardial Infarction

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Fifteen years ago the Gruppo Italialono per lo Studio della Streptochianasi nell'Infarto Miocardico (GISSI) trial firmly established the benefit of fibrinolytic therapy in acute myocardial infarction (1). Several years later, the importance of adjunctive antiplatelet therapy with aspirin was demonstrated in the Second International Study of Infarct Survival (ISIS-2) (2). The need for concomitant anticoagulant therapy with heparin remains less clear, but indirect evidence in the setting of fibrin-specific lytics has led to widespread adoption (3,4).

However, pharmacologic reperfusion for acute ST-elevation myocardial infarction is limited by the fact that infarct-related artery patency is achieved in only 60-80% of patients at 90 min, and Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 is achieved in only 30-55% of patients (5). Moreover, even after successful thrombolysis, reocclusion occurs in 5-10% of patients and is associated with increased morbidity and mortality (5,6). Third-generation bolus fibrinolytics such as reteplase and tenecteplase appeared to be more effective than alteplase in angiographic studies (7-10), but these patency data have not translated into lower mortality rates in large phase III clinical trials (11,12).

Thus, attention has shifted to optimizing adjunctive antithrombotic therapy. It is well recognized that there are several important limitations to our current antiplatelet and anticoagulant agents, namely aspirin and unfractionated heparin. Aspirin is only a weak inhibitor of platelet activation, allowing platelet activation to occur by cyclooxygenase-independent pathways (13). Persistent platelet activation leads to platelet aggregation,

From: Contemporary Cardiology: Management of Acute Coronary Syndromes, Second Edition Edited by: C. P. Cannon © Humana Press Inc., Totowa, NJ

creating platelet-rich coronary thrombi which are relatively resistant to thrombolysis (14) and to further stimulation of the clotting cascade by providing a catalytic surface for coagulation factor interactions (15). Heparin has several major limitations to being an ideal anticoagulant. First, although heparin is able to inactivate fluid-phase thrombin, it is unable to inactivate fibrin monomer-bound (16) or clot-bound (17) thrombin. Second, heparin is inactivated by platelet factor 4 and heparinases, both of which are released by activated platelets (18). Third, heparin is a heterogeneous mixture with highly variable pharmacokinetics (19). Fourth, treatment with heparin can be complicated by heparin-induced thrombocytopenia (20).

Along with these pharmacodynamic and pharmacokinetic limitations to our current adjunctive therapy, there is evidence that a hypercoagulable state exists during acute coronary syndromes that may persist as far as 6 mo out (21). Furthermore, thrombolysis may even potentiate this hypercoagulable state. Thrombolytic therapy has been shown to cause platelet activation (22,23), increased thrombin generation (24-26), and increased thrombin activity (27,28), that heparin may not be able to adequately suppress (25,29-31). The mechanisms underlying this hypercoagulable state and its potentiation by thrombolysis are incompletely understood, but may involve clot digestion leading to thrombin liberation (32), reexposure of prothrombotic lesions, or direct effects on the coagulation cascade (33).

Thus, research efforts have focused on developing new antiplatelet and anticoagulant agents that are capable of overcoming the above limitations and achieving higher rates of infarct-related artery patency and lower rates of reocclusion and, thereby, enable us to reduce the morbidity and mortality still associated with acute myocardial infarction.

PLATELET INHIBITION Platelet Activation and Aggregation

Platelets play a key role in initiating coronary artery thrombosis (13,34,35). Damage to the vessel wall exposes the subendothelial matrix and allows platelet adhesion through glycoprotein (GP) Ib binding to von Willebrand factor (vWF), GP Ia binding to collagen, and other adhesion molecule interactions (36). Platelets can then be activated by a variety of agonists including thrombin, adenosine diphosphate (ADP), collagen, and thromboxane A2 (TXA2) (Fig. 1). There are three main signal transduction path-

Fig. 1. A greatly simplified schematic depicting platelet adhesion, activation, and aggregation and the sites of action of antiplatelet agents. Platelet adhesion is mediated primarily by collagen binding to GP Ia and vWF binding to GP Ib. Platelet activation is extremely complex and only incompletely understood. Three major pathways have been identified. One pathway involves stimulation of PLC by agonists such as TXA2, thrombin, serotonin (5-HT), platelet-activating factor (PAF), and collagen. PLC converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,3,5-triphosphate (IP3) and diacyl glycerol (DAG). Increased levels of IP3 causes translocation of calcium from intracellular storage sites to the cytosol, which, with the help of calmodulin, leads to the activation of a variety of enzymes including myosin light chain kinase (MLCK). The other product of PLC activity is DAG, which activates protein kinase C (PKC). These two kinases, MLCK and PKC, phosphorylate, respectively, myosin light chain (MLC) and a 47-kDA protein (p47), ultimately leading to platelet activation. Another pathway involves stimulation of PLA by agonists such as ADP and epinephrine (epi). PLA liberates arachidonic acid (AA) from membrane phospholipids. AA is then converted by cyclooxyge-nase (CO) to PGH2, which can then be converted either into TXA2 by thromboxane synthase (TxS)

Pgi2 Cell Cycle

or into PGI2 by prostacyclin synthase. TXA2 is a platelet activator and a vasoconstrictor. A third pathway involves adenylate cyclase which, when inhibited by thrombin, ADP, or epi, leads to decreased levels of cyclic adenosine monophosphate (cAMP) and consequent depression of the PLC pathway described above. The end result of activation of any of these three pathways is to induce platelet activation specifically by bringing about cytoskeletal rearrangement, granule release, and the activation of GPIIb/IIIa. Platelet aggregation then occurs through fibrinogen binding to GP Ilb/IIIa receptors on different platelets. The sites of action of platelet inhibitors is shown using open arrowheads and dashed lines. Addional abbreviations: (+), receptors which lead to activation of adenylate cyclase; (—), receptors which lead to inhibition of adenylate cyclase; A, ADP receptor; E, epinephrine receptor; TX, TXA2 receptor; T, thrombin receptor; S, 5-HT receptor; P, PAF receptor; ATP, adenosine triphosphate; 5'AMP, 5' adenosine monophosphate; PD, phosphodiesterase.

Table 1 Antiplatelet Agents

Platelet adhesion inhibitors: Glycoprotein Ib inhibitors vWF inhibitors Platelet activation inhibitors: Cyclooxygenase inhibitors Aspirin NSAIDs Sulfinpyrazone ADP antagonists (i.e., thienopyridine derivatives) Ticlopidine Clopidogrel

Thromboxane inhibitors (i.e., synthase inhibitor and receptor antagonist)

Ridogrel Dipyridamole Prostacyclin and analogues Thrombin inhibitors Platelet aggregation inhibitors: Glycoprotein IIb/IIIa inhibitors

Monoclonal antibodies (e.g., abciximab) Synthetic peptide compounds (e.g., eptifibatide) Nonpeptide mimetics (e.g., tirofiban)

ways: (i) activation of phospholipase C (PLC) (e.g., by thrombin, collagen, and TXA2) leads to an increase in intraplatelet calcium concentration and subsequent phosphoryla-tion and activation of downstream signal transducers; (ii) activation of phospholipase A2 (PLA2) (e.g., by ADP) leads to an increase in arachidonic acid levels with subsequent conversion to TXA2; and (iii) inhibition of adenylate cyclase (e.g., by ADP and epi-nephrine) leads to a decrease in cyclic adenosine monophosphate (which normally antagonizes the activity of PLC) (36-39). Importantly, platelet activation can occur through both TXA2-dependent and TXA2-independent pathways. Regardless of the pathway, platelet activation results in changes in morphology (36), degranulation, induction of procoagulant activity (15), and activation of the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor (37). The final step, platelet aggregation, occurs when fibrinogen molecules bind to the activated GP IIb/IIIa receptor and connect platelets to one another (40). Thus, platelet inhibition can occur by interfering with any one of these steps (Fig. 1 and Table 1) (41-43).

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