**Meet the editor**

Mariano E. Brizzio, MD PhD is a Faculty member at Columbia University's College of Physicians & Surgeons. Born in Buenos Aires, Argentina, Dr Brizzio received his medical degree from the University Of Buenos Aires School Of Medicine in 1989. He completed extensive training in general and cardiovascular surgery in various medical institutions in Buenos Aires, including

residencies in general surgery at the Hospital Churruca-Visca and in cardiovascular surgery at the Instituto Sacre Coeur in 1993 and 1995 respectively, followed by a research fellowship in cardiovascular surgery and the subsequent completion of his PhD degree in 1996. In 2003 he moved to the United States where he completed his fellowship in advance cardiothoracic surgery at the renowned Cleveland Clinic. This was followed three years later whenhe joined Columbia University in New York to continue his clinical and research career in cardiovascular surgery. Dr Brizzio has participated in clinical research in the developing of an artificial heart, minimally invasive cardiothoracic surgery, coronary artery disease and blood conservation techniques.

Contents

**Preface IX** 

Chapter 1 **Antiplatelet Therapy in** 

Chapter 3 **Physiopathology of the** 

Iwao Emura

Chapter 4 **Evolution of Biochemical** 

Chapter 6 **Plaque, Platelets, and Plug –** 

Bambang Irawan

Mariano E. Brizzio

**Cardiovascular Disease – Past, Present and Future 1** 

Chapter 2 **Thrombotic Inception at Nano-Scale 7** 

**Acute Coronary Syndromes 27** 

Chapter 5 **Pathogenesis of Acute Coronary Syndrome,** 

Hamdan Righab, Caussin Christophe, Kadri Zena and Badaoui Georges

Anggoro B. Hartopo, Budi Y. Setianto,

Chapter 7 **Acute Coronary Syndrome Secondary to Acute** 

**Possible Therapeutic Options 99**  Kazuhito Hirata, Tomoya Hiratsuji, Minoru Wake and Hidemitsu Mototake

Suryyani Deb and Anjan Kumar Dasgupta

**Diagnosis of Acute Coronary Syndrome – Impact Factor of High Sensitivity Cardiac Troponin Assays 45**  Amparo Galán, Josep Lupón and Antoni Bayés-Genis

**from Plaque Formation to Plaque Rupture 65** 

Hariadi Hariawan, Lucia K. Dinarti, Nahar Taufiq, Erika Maharani, Irsad A. Arso, Hasanah Mumpuni, Putrika P.R. Gharini, Dyah W. Anggrahini and

**Aortic Dissection – Underlying Mechanisms and** 

**The Pathogenesis of Acute Coronary Syndrome 77** 

### Contents

#### **Preface XI**


X Contents



### Preface

This book has been written with the intention of providing an up-to-the minute review of acute coronary syndromes. Atherosclerotic coronary disease is still a leading cause of death within developed countries and not surprisingly, is significantly rising in others. Over the past decade the treatment of these syndromes has changed dramatically. The introduction of novel therapies has impacted the outcomes and surviving rates in such a way that the medical community need to be up to date almost on a "daily bases".

It is hoped that this book will provide a timely update on acute coronary syndromes and prove to be an invaluable resource for practitioners seeking new and innovative ways to deliver the best possible care to their patients.

> **Mariano E. Brizzio, MD**  Editor in Chief The Valley Heart and Vascular Institute, Ridgewood, New Jersey USA

**1** 

*USA* 

Mariano E. Brizzio

**Antiplatelet Therapy in Cardiovascular** 

Platelet activity has a very important role in the pathogenesis of atherosclerosis disease. In addition to being part of the coagulation system, they contribute to all phases of the atherosclerosis process (1) The "intervention" in the platelet activity has been played a

Aspirin is considered the foundation antiplatelet therapy for patients at risk of cardiovascular events. However, in the last few decades many different agents were introduced to have a more effective antiplatelet action and improve treatment outcomes in

In this chapter you will find a systematic review of all the antiplatelet agents available: mechanism of action, pharmacokinetics, side effects, evidence of effectiveness and their use in clinical settings. A special emphasizes will point out agents that are in investigational

Platelets play a critical role in the normal coagulation system by "preventing" bleeding after blood vessels are damaged. In addition they contribute to different phases of the atherosclerotic process (1). Rupture of a previously formed atherosclerotic plaque exposes collagen, smoothmuscle cells and von Willebrand factor (vWF) all of which trigger platelet activation and massive aggregation (3). The result of this accumulation of platelets is thrombosis. Acute coronary syndrome (ACS) is a consequence of the occlusion of an atherosclerotic vessel by the thrombotic process. As described before, collagen and vWF in addition to thromboxane A2 (TXa2), thrombin and adenosine diphosphate (ADP) are the most powerful platelet activators (4). When a platelet is activated a conformational change occurs in a receptor located in the

platelet membrane called glycoprotein IIb/IIIa which promotes platelet aggregation (5).

sometimes increase the risk of "undesirable" bleeding complications (6).

Antiplatelet agents that target critical steps of the thrombotic mechanism described above have been developed in the last three decades. However, treatment with these agents can

Many anti-platelet agents have been tested and used as an effective treatment in arterial thrombosis. Acetyl salicylic acid, commonly known as **aspirin** was the first anti-platelet

central role in the treatment of coronary artery disease (CAD) (2).

**1. Introduction** 

coronary syndromes.

stage and what are the future perspectives.

**2. The traditional anti-platelet agents** 

**1.1 Platelet mechanisms of action** 

**Disease – Past, Present and Future** 

*The Valley Heart and Vascular Institute, Ridgewood, New Jersey* 

### **Antiplatelet Therapy in Cardiovascular Disease – Past, Present and Future**

Mariano E. Brizzio

*The Valley Heart and Vascular Institute, Ridgewood, New Jersey USA* 

#### **1. Introduction**

Platelet activity has a very important role in the pathogenesis of atherosclerosis disease. In addition to being part of the coagulation system, they contribute to all phases of the atherosclerosis process (1) The "intervention" in the platelet activity has been played a central role in the treatment of coronary artery disease (CAD) (2).

Aspirin is considered the foundation antiplatelet therapy for patients at risk of cardiovascular events. However, in the last few decades many different agents were introduced to have a more effective antiplatelet action and improve treatment outcomes in coronary syndromes.

In this chapter you will find a systematic review of all the antiplatelet agents available: mechanism of action, pharmacokinetics, side effects, evidence of effectiveness and their use in clinical settings. A special emphasizes will point out agents that are in investigational stage and what are the future perspectives.

#### **1.1 Platelet mechanisms of action**

Platelets play a critical role in the normal coagulation system by "preventing" bleeding after blood vessels are damaged. In addition they contribute to different phases of the atherosclerotic process (1). Rupture of a previously formed atherosclerotic plaque exposes collagen, smoothmuscle cells and von Willebrand factor (vWF) all of which trigger platelet activation and massive aggregation (3). The result of this accumulation of platelets is thrombosis. Acute coronary syndrome (ACS) is a consequence of the occlusion of an atherosclerotic vessel by the thrombotic process. As described before, collagen and vWF in addition to thromboxane A2 (TXa2), thrombin and adenosine diphosphate (ADP) are the most powerful platelet activators (4). When a platelet is activated a conformational change occurs in a receptor located in the platelet membrane called glycoprotein IIb/IIIa which promotes platelet aggregation (5).

Antiplatelet agents that target critical steps of the thrombotic mechanism described above have been developed in the last three decades. However, treatment with these agents can sometimes increase the risk of "undesirable" bleeding complications (6).

#### **2. The traditional anti-platelet agents**

Many anti-platelet agents have been tested and used as an effective treatment in arterial thrombosis. Acetyl salicylic acid, commonly known as **aspirin** was the first anti-platelet

Antiplatelet Therapy in Cardiovascular Disease – Past, Present and Future 3

**Antiplatelet agents nowadays**

Modified release dipyridamole is used in conjunction with aspirin (under the trade names Aggrenox in the USA or Asasantin Retard in the UK) in the secondary prevention of stroke and transient ischemic attack. This practice has been confirmed by the ESPRIT trial (9). A triple therapy of aspirin, clopidogrel and dipyridamole has been investigated, but this

Via the mechanisms mentioned above, when given as 3 to 5 min infusion it rapidly increases the local concentration of adenosine in the coronary circulation which causes vasodilation. Vasodilation occurs in healthy arteries, whereas stenosed arteries remain narrowed. This creates a "steal" phenomenon where the coronary blood supply will increase to the dilated healthy vessels compared to the stenosed arteries which can then be detected by clinical symptoms of chest pain, electrocardiogram and echocardiography when it causes ischemia. Flow heterogeneity (a necessary precursor to ischemia) can be detected with gamma cameras and SPECT using nuclear imaging agents such as Thallium-201 and Tc99m-Sestamibi (9). **Terutroban** is a selective antagonist of the thromboxane receptor. It blocks thromboxane induced platelet aggregation and vasoconstriction (11). As of 2010, it is being tested for the secondary prevention of acute thrombotic complications in the Phase III clinical trial. However, the recent publication of the finalized trial PERFORMS shown no clinical advantage in comparison with patients with aspirin monotherapy in preventing strokes (12).

At the time of this publication its use in clinical practice is not approved in the USA.

**Ticlopidine** an anti-platelet drug in the thienopyridine family inhibits platelet aggregation by altering the function of platelet membranes by irreversibly blocking ADP receptors. This

**Inhibits the synthesis of TXa2** 

**Glycoprotein IIb/IIIa antagonist** 

**Direct thrombin Inhibitor** 

**4. Other P2Y 12 antagonist** 

**Protease-activated receptor 1 antagonist** 

combination led to an increase in adverse bleeding events (10).

Aspirin

**TXa2 antagonist**  Dipyridamole Terutroban

**P2Y 12 antagonist** 

Ticlopidine Clopidogrel Prasugrel Ticagrelor Cangrelor

Abciximab Tirobiban Eptifibatide

Vorapaxar

Bivalirudin

agent used and proven to be effective to reduce the incidence of myocardial infarction and stroke in many high risk vascular patients (2).The recurrence of vascular events in patients treated with aspirin alone ranges between 10 – 20% within five years of the initial event (2-7).

Aspirin is effective by blocking the synthesis of TXa2, a powerful platelet activator.

In the last decade, the thienopyridines such as **clopidogrel** have been used to improve outcomes in the treatment of ACS. This anti-platelet agent irreversibly blocks the P2Y12 receptor, precluding the platelet activation by ADP (2). Its anti-platelet mechanism of action clearly differs from aspirin. In the majority of cardiovascular patients the combination of clopidogrel and aspirin has additive beneficial effects when compared with clopidogrel or aspirin alone (8). Clopidogrel also has some limitations, which have prompted the development of newer anti-platelet agents which interact at different sites of the coagulation cascade.

The following figure reflects the site of action of the common antiplatelet agents (figure 1)

#### **3. The thromboxane A2 antagonist**

**Dipyridamole** (Persantine) acts as a thromboxane synthase inhibitor, therefore lowering the levels of TXA2 and thus stops the effects of TXA2 as a platelet activator (9).

Also can causes systemic vasodilation when given at high doses over a short period of time. The latter, due to the inhibition of the cellular reuptake of adenosine into platelets, red blood cells and endothelial cells leading to increased extracellular concentrations of adenosine (9). It also inhibits the enzyme adenosine deaminase, which normally breaks down adenosine into inosine. This inhibition leads to further increased levels of extracellular adenosine, producing a strong vasodilatation (9).

agent used and proven to be effective to reduce the incidence of myocardial infarction and stroke in many high risk vascular patients (2).The recurrence of vascular events in patients treated with aspirin alone ranges between 10 – 20% within five years of the initial

In the last decade, the thienopyridines such as **clopidogrel** have been used to improve outcomes in the treatment of ACS. This anti-platelet agent irreversibly blocks the P2Y12 receptor, precluding the platelet activation by ADP (2). Its anti-platelet mechanism of action clearly differs from aspirin. In the majority of cardiovascular patients the combination of clopidogrel and aspirin has additive beneficial effects when compared with clopidogrel or aspirin alone (8). Clopidogrel also has some limitations, which have prompted the development of newer anti-platelet agents which interact at different sites of the coagulation

The following figure reflects the site of action of the common antiplatelet agents (figure 1)

**Dipyridamole** (Persantine) acts as a thromboxane synthase inhibitor, therefore lowering the

Also can causes systemic vasodilation when given at high doses over a short period of time. The latter, due to the inhibition of the cellular reuptake of adenosine into platelets, red blood cells and endothelial cells leading to increased extracellular concentrations of adenosine (9). It also inhibits the enzyme adenosine deaminase, which normally breaks down adenosine into inosine. This inhibition leads to further increased levels of extracellular adenosine,

levels of TXA2 and thus stops the effects of TXA2 as a platelet activator (9).

Aspirin is effective by blocking the synthesis of TXa2, a powerful platelet activator.

event (2-7).

cascade.

**3. The thromboxane A2 antagonist** 

producing a strong vasodilatation (9).


Modified release dipyridamole is used in conjunction with aspirin (under the trade names Aggrenox in the USA or Asasantin Retard in the UK) in the secondary prevention of stroke and transient ischemic attack. This practice has been confirmed by the ESPRIT trial (9). A triple therapy of aspirin, clopidogrel and dipyridamole has been investigated, but this combination led to an increase in adverse bleeding events (10).

Via the mechanisms mentioned above, when given as 3 to 5 min infusion it rapidly increases the local concentration of adenosine in the coronary circulation which causes vasodilation. Vasodilation occurs in healthy arteries, whereas stenosed arteries remain narrowed. This creates a "steal" phenomenon where the coronary blood supply will increase to the dilated healthy vessels compared to the stenosed arteries which can then be detected by clinical symptoms of chest pain, electrocardiogram and echocardiography when it causes ischemia. Flow heterogeneity (a necessary precursor to ischemia) can be detected with gamma cameras and SPECT using nuclear imaging agents such as Thallium-201 and Tc99m-Sestamibi (9).

**Terutroban** is a selective antagonist of the thromboxane receptor. It blocks thromboxane induced platelet aggregation and vasoconstriction (11). As of 2010, it is being tested for the secondary prevention of acute thrombotic complications in the Phase III clinical trial. However, the recent publication of the finalized trial PERFORMS shown no clinical advantage in comparison with patients with aspirin monotherapy in preventing strokes (12). At the time of this publication its use in clinical practice is not approved in the USA.

#### **4. Other P2Y 12 antagonist**

**Ticlopidine** an anti-platelet drug in the thienopyridine family inhibits platelet aggregation by altering the function of platelet membranes by irreversibly blocking ADP receptors. This

Antiplatelet Therapy in Cardiovascular Disease – Past, Present and Future 5

halted for patients with stroke and mild heart conditions due to safety reasons. It is unknown

**Bivalirudin** (Angiomax) is a specific and reversible intravenous direct thrombin inhibitor. Clinical studies demonstrated consistent positive outcomes in patients with stable angina, unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI), and STsegment elevation myocardial infarction (STEMI) undergoing PCI in 7 major randomized trials (22). Coagulation times and platelet activity return to baseline approximately 1-6 hour

Antiplatelet therapy plays a crucial role in the treatment of coronary patients. The continuous introduction of new agents is geared to improve results in patient ongoing percutaneous coronary interventions. However, the side effects of theses should be monitored closely. In the end, the ideal management of patients with acute coronary syndrome should be to be a collaborative effort between cardiologist and surgeons to assure the best outcomes possible.

[1] Hoffman M et al.Activated factor VII activates Factor IX on the surfaces of activated

[2] Antithrombotic triallist's collaboration. Collaborative meta-analysis of randomized trials

[3] Heemskerk JW. Funtion of glycoprotein VI and intgrelin in the procoagulant response of

[4] Jin, J, Kunapuli, SP. Coactivation of two different G protein-coupled receptors is

[5] Heechler B, et al. The P2Y1 receptor in necessary for adenosine 5'-diphodphate-induced

[6] Brizzio, ME, Shaw, RE, Bosticco B, et al. Use of an Objective Tool to Assess Platelet

[7] de Werf F et al. Dual antiplatelet therapy in high-risk patients. Euro Heart J . 2007:9:D3-

[8] Metha SR, Peters RJG, Bertrand ME, et al., for the Clopidrogel in Unstable angina to

[10] Sprigg N, Gray LJ, England T, et al. (2008). Berger, Jeffrey S.. ed. "A randomised

(ESPRIT): randomised controlled trial". Lancet.2006; 367: 1665–73.

single, collagen-adherent platelets. Throm Hemost 1999;81:782-792

of antiplatelet therapy for prevention of death, myocardial infartion, and stroke in

essential for ADP-induced platelet aggregation. Proc Natl Acad Sci USA

Inhibition Prior to Off-Pump Coronary Surgery to Reduce Blood Usage and Cost.

prevent Recurrent events (CURE) Trial Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-Cure study. Lancet 2001;358:527-33. [9] Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A (May 2006). "Aspirin plus

dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin

controlled trial of triple antiplatelet therapy (aspirin, clopidogrel and

if it will continue.

**8. Conclusions** 

**9. References** 

**7. Direct thrombin inhibitors** 

following cessation of bivalirudin administration (23).

platelets. Blood Coag Fibrinolyis. 1998:9; 61-65.

high risk patients. BMJ 2002;324:71-86

platelet aggregation. Blood 1998;92:152-159

Journ Interv Cardiol. 2011 In press

1998;95:8070-74

D9 MC,

prevents the conformational change of glycoprotein IIb/IIIa which allows platelet binding to fibrinogen (13). It is used in patients in whom aspirin is not tolerated, or in whom dual anti-platelet therapy is desirable (in combination with Aspirin). Because it has been reported to increase the risk of thrombotic thrombocytopenic purpura (TTP) and neutropenia, its use has largely been supplanted by the newer drug, clopidogrel, which is felt to have a much lower hematologic risk (14).

**Prasugrel,** a novel thienopyryridine was approved for clinical use in the USA by the Food and Drug Administration (FDA) in 2010. Unlike clopidogrel, which undergoes a two-step, CYP450-dependent conversion to its active metabolite, prasugrel only requires single-step activation. Prasugrel is a more potent platelet inhibitor with faster action and inhibition. Also, it has been estimated that due to its "easy metabolism" its genetic resistance is less likely (15). In other words, prasugrel has a significantly lower incidence of hyporesponsiveness in comparison with clopidogrel (15). However, the risks of bleeding in these patients are greater than clopidogrel (16).

**Ticagrelor** is the most novel class of anti-platelet drugs, the cyclopentytriazolopyrimides, which also inhibit the P2Y12 receptor as the thienopyryridines. However, it has a simpler and faster metabolism (rapid onset of action) high potency and most importantly reversibility (17). The latter, makes this drug safer in regards of bleeding complications.

**Cangrelor**, an ATP analog, is an investigational intravenous anti-platelet drug. This agent has biphasic elimination and possesses the advantages of high potency, very fast onset of action and very fast reversibility after the discontinuation (16).This gives a considerable advantage over other ADP antagonist in patients who might need immediate surgery. However, after initial treatment, patients who received intravenous infusion of Cangrelor often require continued treatment with one of the oral P2Y12 antagonists, something that one must take into consideration (16).

#### **5. Glycoproteins IIb/IIa antagonist**

**Abciximab**, more known as the ReoPro is an antibody against glycoprotein IIb/IIIa receptor. It had a lot of popularity within interventional cardiologist 10 years ago. It is barely used today. It was replaced by newer IV agents. Abciximab has a plasma half-life of about ten minutes, with a second phase half-life of about 30 minutes. However, its effects on platelet function can be seen for up to 48 hours after the infusion has been terminated, and low levels of glycoprotein IIb/IIIa receptor blockade are present for up to 15 days after the infusion is terminated (18).

**Tirobiban** (Aggrastat) is a synthetic, non-peptide inhibitor acting at glycoprotein (GP) IIb/IIIa receptors. It has a rapid onset and short duration of action after proper intravenous administration. Platelet activity returns to normal 4 to 8 hours after the drug is withdrawn (19). **Eptifibatide** (Integrilin) is the newer anti-platelet drug which inhibits the glycoprotein IIb/IIIa inhibitor. It belongs to the class of the so-called arginin-glycin-aspartat-mimetics and reversibly binds to platelets. Eptifibatide has a short half-life, 3 to 5 hours after the discontinuation platelet activity recovers to normal levels (20).The drug is the third inhibitor of GPIIb/IIIa that has found broad acceptance within interventional cardiologists nowadays.

#### **6. Proteasa-activated receptors antagonist**

**Vorapaxar** (formerly SCH 530348) is a thrombin receptor (PAR-1) antagonist based on the natural product himbacine. It is an experimental pharmaceutical treatment for acute coronary syndrome as a very powerful platelet inhibitor (21).In January 2011, the clinical trial was halted for patients with stroke and mild heart conditions due to safety reasons. It is unknown if it will continue.

#### **7. Direct thrombin inhibitors**

**Bivalirudin** (Angiomax) is a specific and reversible intravenous direct thrombin inhibitor. Clinical studies demonstrated consistent positive outcomes in patients with stable angina, unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI), and STsegment elevation myocardial infarction (STEMI) undergoing PCI in 7 major randomized trials (22). Coagulation times and platelet activity return to baseline approximately 1-6 hour following cessation of bivalirudin administration (23).

#### **8. Conclusions**

4 Acute Coronary Syndromes

prevents the conformational change of glycoprotein IIb/IIIa which allows platelet binding to fibrinogen (13). It is used in patients in whom aspirin is not tolerated, or in whom dual anti-platelet therapy is desirable (in combination with Aspirin). Because it has been reported to increase the risk of thrombotic thrombocytopenic purpura (TTP) and neutropenia, its use has largely been supplanted by the newer drug, clopidogrel, which is

**Prasugrel,** a novel thienopyryridine was approved for clinical use in the USA by the Food and Drug Administration (FDA) in 2010. Unlike clopidogrel, which undergoes a two-step, CYP450-dependent conversion to its active metabolite, prasugrel only requires single-step activation. Prasugrel is a more potent platelet inhibitor with faster action and inhibition. Also, it has been estimated that due to its "easy metabolism" its genetic resistance is less likely (15). In other words, prasugrel has a significantly lower incidence of hyporesponsiveness in comparison with clopidogrel (15). However, the risks of bleeding in these

**Ticagrelor** is the most novel class of anti-platelet drugs, the cyclopentytriazolopyrimides, which also inhibit the P2Y12 receptor as the thienopyryridines. However, it has a simpler and faster metabolism (rapid onset of action) high potency and most importantly reversibility (17). The latter, makes this drug safer in regards of bleeding complications. **Cangrelor**, an ATP analog, is an investigational intravenous anti-platelet drug. This agent has biphasic elimination and possesses the advantages of high potency, very fast onset of action and very fast reversibility after the discontinuation (16).This gives a considerable advantage over other ADP antagonist in patients who might need immediate surgery. However, after initial treatment, patients who received intravenous infusion of Cangrelor often require continued treatment with one of the oral P2Y12 antagonists, something that

**Abciximab**, more known as the ReoPro is an antibody against glycoprotein IIb/IIIa receptor. It had a lot of popularity within interventional cardiologist 10 years ago. It is barely used today. It was replaced by newer IV agents. Abciximab has a plasma half-life of about ten minutes, with a second phase half-life of about 30 minutes. However, its effects on platelet function can be seen for up to 48 hours after the infusion has been terminated, and low levels of glycoprotein IIb/IIIa receptor blockade are present for up to 15 days after the infusion is terminated (18). **Tirobiban** (Aggrastat) is a synthetic, non-peptide inhibitor acting at glycoprotein (GP) IIb/IIIa receptors. It has a rapid onset and short duration of action after proper intravenous administration. Platelet activity returns to normal 4 to 8 hours after the drug is withdrawn (19). **Eptifibatide** (Integrilin) is the newer anti-platelet drug which inhibits the glycoprotein IIb/IIIa inhibitor. It belongs to the class of the so-called arginin-glycin-aspartat-mimetics and reversibly binds to platelets. Eptifibatide has a short half-life, 3 to 5 hours after the discontinuation platelet activity recovers to normal levels (20).The drug is the third inhibitor of GPIIb/IIIa that has found broad acceptance within interventional cardiologists nowadays.

**Vorapaxar** (formerly SCH 530348) is a thrombin receptor (PAR-1) antagonist based on the natural product himbacine. It is an experimental pharmaceutical treatment for acute coronary syndrome as a very powerful platelet inhibitor (21).In January 2011, the clinical trial was

felt to have a much lower hematologic risk (14).

patients are greater than clopidogrel (16).

one must take into consideration (16).

**5. Glycoproteins IIb/IIa antagonist** 

**6. Proteasa-activated receptors antagonist** 

Antiplatelet therapy plays a crucial role in the treatment of coronary patients. The continuous introduction of new agents is geared to improve results in patient ongoing percutaneous coronary interventions. However, the side effects of theses should be monitored closely. In the end, the ideal management of patients with acute coronary syndrome should be to be a collaborative effort between cardiologist and surgeons to assure the best outcomes possible.

#### **9. References**


**2** 

*India* 

**Thrombotic Inception at Nano-Scale** 

Seeing is believing, but the reverse, namely, disbelieving the unseen may often go against the spirit of scientific exploration. This is particularly true for nano-scale objects interacting almost invisibly with biological cells, tissues or organs. Interestingly many of the biological sub-cellular components (e.g. proteins, DNA)have nano-scale dimension. The apparently innocent (chemically inactive) and tiny particulate matter originating from various natural or artificial sources (e.g., pollutant) have been shown to be toxic at different physiological levels. The famous saying by Jeevaka, the legendary physician of the Jataka tales, that there is no herb in the world that is not a drug, however follows. What is toxic in some context have important therapeutic value elsewhere. Nanoparticles do interfere with the thrombo-static equilibrium. While this shift on one hand is a matter of concern, it may provide us a tool to handle or diagnose diseases in which such equilibrium is shifted. One of the finest models to test this dual aspect of the nano-scale objects is Acute Coronary Syndrome (ACS), a leading cause of death in the global scenario. What is known today regarding the effect of nanoscale objects may really be a tip of iceberg and with the advent of smarter nanoparticles one may think of more

ACS is a complex and multi-factorial disease (Badran et al., 2009). ACS is an umbrella like term which includes mainly three diseases i). **ST elevated myocardial infarction (STEMI)**, ii). **Non ST elevated myocardial infarction (NON STEMI),** and iii) **unstable angina**. The

Platelets play a pivotal in manifestation of ACS. Platelets are discoid in shape, with approximate number density 150,000-300,000/µl, and dimension of the order of 2000-4000 nm. Derived from megakaryocyte (figure 1) (Thompson, 1986) they contain mitochondria, peroxisomes, endoplasmic reticulum. They also contain granules and glycogen bodies.

versatile use of nanotechnology in the management of ACS.

**2. Role of platelets in Acute Coronary Syndrome (ACS)** 

patho-physiological event of ACS can be divided into four phases:

a. Atherosclerotic plaque formation. b. Rupture of an unstable plaque. c. The acute ischemic event.

**2.1 Platelet basic physiology** 

d. Long term risk of recurrent coronary event.

**1. Introduction** 

Suryyani Deb and Anjan Kumar Dasgupta *Department of Biochemistry, University of Calcutta* 

dipyridamole) in the secondary prevention of stroke: safety, tolerability and feasibility". PLoS One. 2008 Aug 6;3(8):e2852

