Antiplatelet therapy: thrombin receptor antagonists

Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. Multiple pathways contribute to platelet activation. Aspirin, an irreversible inhibitor of thromboxane A2 synthesis, in combination with clopidogrel, an inhibitor of P2Y(12) adenosine diphosphate platelet receptors, represent the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and for those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations. Thrombin is one of the most important platelet activators. The inhibition of protease-activated receptor 1 showed a good safety profile in preclinical studies. In fact, phase II studies with vorapaxar (SCH530348) and atopaxar (E5555) showed no increase of bleeding events in addition to the current standard-of-care of antiplatelet therapy. Although the results of phase III trials for both drugs are awaited, this family is a promising new addition to the current clinical practice for patients with atherothrombotic disease, not only as an alternative, but also as additional therapy.     

Anti-inflammatory effects of anti-platelet treatment in atherosclerosis

Atherosclerosis is considered an inflammatory disease. T-cells, macrophages, and mast cells infiltrate atherosclerotic plaques and platelets play an essential role releasing inflammatory mediators that stimulate plaque progression. This is important in acute coronary syndromes but it is also the mechanism involved in plaque progresion and endothelial dysfunction. Antiplatelet drugs exert their effects not only by inhibition of platelet aggregation but also through their antiinflammatory effect. Aspirin, thyenopiridines and GPIIb/IIIa inhibitors have antiinflammatory properties that involve different mechanisms of action, especially related to the blockade of platelet activation and platelet-leukocyte interactions. Testing platelet function in addition to assessing levels of inflammatory markers, and not only the risk of bleeding, could help in decision-making to balance the risk-benefit of anti-thrombotic treatment. Different clinical settings are associated with variable inflammatory states, and this could be, in part, responsible for variable response to treatment.     

The Role of Oral Antiplatelet Agents in Atherothrombotic Disease

Atherothrombosis involves the mutually interactive dual mechanistic processes of atherosclerotic plaque progression and thrombus formation. In the setting of acute plaque rupture, resultant thrombus formation precipitates acute ischemic events such as acute coronary syndromes (ACS), stroke, and transient ischemic attack. Peripheral arterial disease is also a manifestation of atherothrombotic disease, and occurs both acutely and as a result of underlying disease progression. Atherothrombotic disease is highly prevalent and imposes a substantial burden on the community. For example, coronary artery disease was the single greatest cause of mortality among men and women in the US and accounted for an estimated US dollars 142.1 billion in health costs in 2005. Activated platelets are the prime mediators of arterial thrombus formation. This review discusses the evidence supporting the use of oral antiplatelet agents with other risk prevention strategies in the long-term secondary prevention of atherothrombotic disease. The most widely used oral antiplatelet agent is aspirin (acetylsalicylic acid), and both aspirin and clopidogrel have proven roles in the management of atherothrombotic disease. Clopidogrel should also be used in combination with aspirin in patients with non-ST-segment elevation ACS and those undergoing percutaneous coronary intervention. Recent data suggest that clopidogrel may have a significant role, with or without fibrinolytic therapy, in the immediate management of ST-segment elevation ACS.     

The pharmacodynamics of antiplatelet compounds in thrombosis treatment

Introduction: As it is importance to understand the involvement of platelets in the initiation and propagation of thrombosis, antiplatelet drugs have come to the forefront of atherothrombotic disease treatment. Dual antiplatelet therapy of aspirin plus clopidogrel has its benefits, but it also has its limitations with regard to its pharmacologic properties and adverse effects. For these reasons, within the last decade or so, the investigation of novel antiplatelet agents has prospered.

Areas covered: In this review, we discuss the unique pharmacodynamic properties of several antiplatelet drugs with their possible potential molecular of mechanisms on inhibiting platelet aggregation.

Expert opinion: Considering multiple synergetic pathways of platelet activation and their close interplay with coagulation, the current treatment strategies are not only based on platelet inhibition, they also rely on the attenuation of procoagulant activity, inhibition of thrombin generation, and enhancement of clot dissolution. Current guidelines recommend various antiplatelet agents in addition to aspirin for patients with acute coronary syndromes. The advantages of these agents, as repute mortality, may be associated with off-target effects of the drug. Hence, further studies are required to facilitate the physician’s choice of the most appropriate antiplatelet agents for each patient for thrombosis treatment.     

Antiplatelet therapies: from aspirin to GPIIb/IIIa-receptor antagonists and beyond

This review discusses recent advances in antiplatelet therapies, comparative analysis between the antiplatelet/ antithrombotic efficacy of various antiplatelet strategies and that of platelet glycoprotein GPIIb/IIIa-receptor antagonists, issues in the development of chronic anti-GPIIb/IIIa-receptor therapy and potential adjunct strategies using GPIIb/IIIa-receptor antagonists. Acute coronary syndromes are secondary to unstable angina, ST-segment elevation, and acute myocardial infarction. These involve the rupture of a vulnerable atherosclerotic plaque, leading to platelet adhesion, activation and aggregation at the site of rupture. Several studies suggest that complex or ulcerated plaques, which might promote further thrombotic events, can persist for more than one month after the acute event. These data suggest the potential added benefit of chronic oral therapy with antiplatelet drugs beyond the well-documented benefit of acute intravenous use of various GPIIb/IIIa-receptor antagonists. However the efficacy–safety ratio or the risk–benefit ratio for chronic oral antiplatelet therapy needs to be defined. Both aspirin and clopidogrel are available for chronic oral use. By contrast, there are tremendous challenges ahead with the oral GPIIb/IIIa-receptor antagonists because of their lack of expected benefit over aspirin. However, much still remains to be defined with regard to the optimization of current and future antiplatelet therapies or their optimized combinations.     

Inhibition of platelet activation and aggregation

It has recently been established that platelets are involved at all stages of atherosclerotic disease. A major platelet mediated process is the acute vessel closure at the site of atherosclerotic plaque rupture and there is emerging evidence for platelet adhesion to endothelial cells in the early stage of atherosclerotic disease. This, through engagement of other cells, leads to the development of the atherosclerotic plaque. Beside dietary, cholesterol- and lipid-lowering, and other pharmaceutical approaches antiplatelet therapy plays an important part in the treatment of atherosclerosis and its multifarious clinical manifestations. Antiplatelet therapy and the currently approved substances for oral (acetylsalicylic acid, dipyridamole, cilostazol, ticlopidin and clopidogrel) and parenteral (acetylsalicylic acid, abciximab, eptifibatide and tirofiban) administration are discussed in the following section. Attention is given to each single agent and its mechanism of action. Differences in pharmacodynamic and pharmacokinetic properties are elucidated and outlook on future antiplatelet strategies is discussed.     

The role of tirofiban in the management of coronary artery disease

Glycoprotein IIb/IIIa receptor antagonists are potent antiplatelet agents by inhibiting the final common pathway of platelet aggregation. Tirofiban binds specifically to the glycoprotein IIb/IIIa receptor resulting in immediate and extensive inhibition of platelets. Studies have shown that intravenous administration of tirofiban in combination with aspirin and heparin reduces major adverse cardiac events in patients undergoing percutaneous coronary intervention and in those patients with acute coronary syndromes. Large randomised trials using tirofiban demonstrate early clinical and long-term survival benefit in all patient subgroups including high-risk patients undergoing urgent percutaneous coronary intervention, patients undergoing elective intracoronary stent placement and in the medical management of acute coronary syndromes. The use of high-dose bolus tirofiban may provide additional protection in patients at highest risk, whereas the role of tirofiban in the facilitation of primary angioplasty is less well defined. Similar to the other glycoprotein IIb/IIIa receptor antagonists, tirofiban increases the risk of haemorrhagic complications. However, the risk of serious bleeding, including intracranial haemorrhage, remains low and tirofiban does not appear to increase the risk of thrombocytopenia. Overall, the use of tirofiban in coronary artery disease has been shown to be effective, has an acceptable safety profile and is potentially cost-effective.     

Microvascular thrombosis: an exciting but elusive therapeutic target in reperfused acute myocardial infarction

The beneficial effects of restoration of coronary flow in patients with acute myocardial infarction may be hampered by inadequate tissue perfusion. Among other factors, it is likely that platelets contribute substantially to this phenomenon. Platelets may compromise blood flow at the microvascular level by forming a part of microemboli, by adhering to reperfused, capillary or venular endothelium or to attached leukocytes, by releasing substances producing vasoconstriction, or through toxic effects. Patients with acute coronary syndromes have an increased number of circulating activated platelets, and this systemic platelet activation has been related to the presence and extent of myocardial necrosis. The mechanisms of platelet deposition to reperfused microvessels are not fully understood, but likely involve the interaction between adhesion molecules such as selectins or glycoproteins expressed on these cells upon activation and their ligands on the surface of endothelial cells or polymorphonuclear leukocytes. While these interactions are potentially important therapeutic targets in acute myocardial infarction, reducing platelet deposition and increasing myocardial salvage by direct effects on the microvasculature is still challenging with the existing armamentarium of antiplatelet agents. This review summarizes the current knowledge on the mechanisms of platelet-mediated myocardial damage after reperfusion and the effects of pharmacological interventions aimed to reduce microvascular platelet deposition and platelet-mediated myocardial injury.     

Advancing the Battle Against Acute Ischemic Syndromes: A Focus on the GP IIb-IIIa Inhibitors

Platelet aggregation and thrombus formation, resulting from disruption of a coronary artery plaque, play a critical role in the pathology of acute coronary syndromes. Currently, aspirin and heparin are administered to decrease platelet aggregation. The discovery of the platelet integrin receptor α_IIbβ₃, also known as the platelet glycoprotein (GP) IIb-IIIa receptor, is a breakthrough in antiplatelet therapy. The GP IIb-IIIa receptor is responsible for the crucial binding of fibrinogen to platelets, leading to cross-links between platelets and further platelet aggregation. Since the introduction of abciximab, the first GP IIb-IIIa-receptor antagonist, several other nonantibody agents have been studied for use in percutaneous transluminal coronary angioplasty and also in stent placement, treatment of unstable angina, and myocardial infarction.     

Recognition, pathophysiology, and management of acute myocardial infarction.

New insights into the pathophysiology of atherosclerotic plaques leading to acute myocardial infarction (MI) are discussed, along with new diagnostic and treatment strategies. Ischemic heart disease represents a continuum from stable angina to unstable angina to non-Q-wave MI to Q-wave MI. Patients whose angina becomes unstable are classified as having acute coronary syndrome (ACS). It was formerly believed that thrombosis leading to critical occlusion of coronary arteries at the site of atherosclerotic plaque rupture was the common cause of ischemic heart disease. It is now thought that even lesions that do not critically occlude coronary arteries can cause MI. ACS can be caused by the rupture of an unstable atherosclerotic plaque. Vulnerable plaques are usually those causing only mild to moderate stenosis and having a lipid-rich core and a thin, macrophage-dense, collagen-poor fibrous cap. Factors affecting plaque rupture include mechanical injury, circadian rhythm, inflammation, and infection. Progressive thrombosis and vasospasm may follow plaque rupture. The diagnosis of MI starts with the recognition of symptoms of myocardial ischemia that are new or different from the usual pattern. Agents used to prevent or treat plaque rupture and its complications include thrombolytics, antiplatelet agents, antithrombotics, beta-blockers, angiotensin-converting-enzyme (ACE) inhibitors, and nitrates. Once patients survive the acute phase of MI, long-term therapy for prevention of future events begins. Post-MI patients should receive aspirin, beta-blockers, and an ACE inhibitor indefinitely; modification of cardiovascular risk factors is also important. Greater understanding of the pathophysiology of ACS has led to strategies to limit the progression of atherosclerosis and to improve survival and function after an acute event.     

Ticlopidine and clopidogrel: Antithrombotic agents that block ADP-mediated platelet activation

Summary Ticlopidine and clopidogrel are orally active antiplatelet agents that block ADP-mediated platelet activation. The proaggregatory effects of other platelet agonists are also attenuated by administration of ticlopidine or clopidogrel; however, this generalized inhibition of platelet activation may arise from interference with the synergy between platelet-derived ADP and other proaggregatory agents. Ticlopidine and clopidogrel do not display antiplatelet activity when added to blood or purified platelets; hence, biotransformation of these agents appears to be a prerequisite for inhibition of platelet activation. The purported active derivatives have not been identified. A variety of preclinical and clinical investigations have demonstrated that ticlopidine and clopidogrel are useful for the treatment and/or prevention of platelet-dependent thrombotic disorders.     

Monitoring antiplatelet therapy: What is the best method?

Platelet function tests measure different aspects of platelet function, which include adherence, activation, aggregation and secretion. Clinically, the goal of platelet function testing is to provide information about the platelet contribution to the risk of thrombotic or haemorrhagic events and the optimisation of antiplatelet therapy. The important clinical questions are whether an antiplatelet agent is having the desired effect on platelet inhibition (effectiveness) and whether the patient has sufficient residual platelet function to avoid bleeding (safety). The role of aspirin (acetylsalicylic acid) and thienopyridines is well established in the management of patients with coronary artery disease and in the setting of coronary interventions. The last several years have demonstrated the unequivocal effectiveness of intravenously administered platelet glycoprotein (GP) IIb/IIIa antagonists in the management of acute coronary syndromes and in the setting of percutaneous coronary interventions. With the increasing use of these GPIIb/IIIa antagonists, it is becoming more important clinically to measure platelet inhibition with these agents. This paper reviews major techniques and instrumentation for platelet monitoring and discusses the goals of the best method.     

Clopidogrel and aspirin in cardiovascular medicine: responders or not--current best available evidence

Dual antiplatelet therapy represents an important advance for patients with established coronary artery disease. It is an important strategy for patients with acute coronary syndromes and those undergoing percutaneous transcatheter coronary interventions. Clopidogrel effectively inhibits ADP-induced platelet activation and aggregation by selectively and irreversibly blocking the P2Y(12) receptor on the platelet membrane. Aspirin works by irreversibly acetylating the cyclooxygenase (COX-1) enzyme, thus suppressing the production of thromboxane A(2) (TxA(2)) and inhibiting platelet activation and aggregation. Variable platelet response and potential resistance to therapy has emerged with aspirin and clopidogrel. The definitions of antiplatelet agents variability in responsiveness and nonresponsiveness are discussed. Clopidogrel and aspirin responsiveness as they are measured in the laboratory by various techniques (platelet aggregometry and point-of-care assays such as platelet function analyzer [PFA-100] and rapid platelet function assay [RPFA]) are evaluated. The mechanisms responsible for variations in responsiveness to antiplatelet agents such as clinical, cellular and genetic factors are defined. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as myocardial infarction, stroke or death. The therapeutic interventions to deal with nonresponsiveness are reported, although specific recommendations are not clearly established. In the future, routine measurement of platelet function in patients with cardiovascular disease may become the standard of care. Personalized antithrombotic treatment strategies may be determined by ex-vivo measurements that identify critical pathways influencing thrombotic risk in the individual patient.     

On-treatment platelet reactivity: State of the art and perspectives

High on-clopidogrel platelet reactivity (HcPR) during dual-antiplatelet therapy is a marker of vascular risk, in particular stent thrombosis, in patients with acute coronary syndromes (ACS). Genetic determinants (CYP2C19*2 polymorphism), advanced age, female gender, diabetes and reduced ventricular function are related to a higher risk to develop HcPR. In addition, inflammation and increased platelet turnover, as revealed by the elevated percentage of reticulated platelets in patients’ blood, that characterize the acute phase of acute coronary syndromes, are associated with HcPR. To overcome the limitation of clopidogrel, new antiplatelet agents (prasugrel and ticagrelor) were developed and the demonstration of their superiority over clopidogrel was obtained in the two randomized trials, TRITON TIMI 38 and PLATO. Emerging evidence is accumulating on the role of high-on aspirin platelet reactivity (HaPR), especially in the clinical context of diabetes. Finally, the presence of new, potent antiplatelet drugs has shifted the focus from thrombotic to bleeding risk. Recent data document that low on-treatment platelet reactivity (LPR) is associated with a significantly higher bleeding risk. Due to the current possibility to choose between multiple antiplatelet strategies, the future perspective is to include in the management of ACS, in addition to clinical data and classical risk factors, the definition of platelet function during treatment in order to set a tailored therapy.     

Matrix metalloproteinase inhibition with tetracyclines for the treatment of coronary artery disease

Coronary artery disease is caused by atherosclerosis – a progressive arterial inflammatory disease that is responsible for significant global mortality and morbidity through the development of the acute coronary syndromes: sudden cardiac death, acute myocardial infarction and unstable angina. These clinical entities share a common pathophysiology: rupture of atherosclerotic plaque resulting in abrupt complete or partial thrombotic obstruction of coronary blood flow. Matrix metalloproteinases (MMP), through their central role in tissue remodeling and inflammation, are secreted by inflammatory cells of the atherosclerotic plaque and are capable of degrading all the extracellular matrix components of the fibrous cap that separates the atherosclerotic lesion from blood flow in the arterial lumen. Plaque rupture occurs when the circumferential tensile stresses in the artery overwhelm the structural integrity of the progressively degraded, thinned and weakened fibrous cap of the atherosclerotic lesion. Tetracyclines inhibit MMPs through their ability to chelate zinc. Subantimicrobial doses of doxycycline have been shown to reduce inflammation and inhibit MMP activity in patients with coronary artery disease. Further investigation is warranted to assess the potential clinical risks and benefits of MMP inhibition with tetracyclines or other agents in the treatment of coronary artery disease.     

Dual antiplatelet therapy for prevention of recurrent ischemic events.

The advantages of dual antiplatelet therapy over monotherapy in preventing recurrent ischemic events are examined. Atherosclerosis is an insidious systemic process involving multiple vascular beds, including the cerebral, coronary, and peripheral arteries. Atherosclerotic plaque rupture is one of the inciting events in the progression of platelet activation, aggregation, and thrombus formation. Patients with any clinical manifestation of atherosclerosis are vulnerable to others in different vascular beds since the disease develops throughout the vasculature, and different vascular events have common predisposing risk factors. Ischemic coronary heart disease and cerebrovascular disease are two of the three most frequent causes of death in the United States. The efficacy of aspirin in the secondary prevention of myocardial infarction (MI) and stroke has been demonstrated in numerous trials. While dipyridamole has not been linked with a greater odds reduction than aspirin in the development of MI, stroke, and vascular death, ticlopidine and clopidogrel have been associated with a greater reduction in the development of acute MI, stroke, and vascular death than aspirin. Clinical trials evaluating the efficacy and safety of combination antiplatelet therapy in the prevention of recurrent ischemic events are ongoing. The rationale for using a combination of two mechanistically different antiplatelet agents is supported by ex vivo and clinical studies. Inhibition of platelet aggregation and thrombus formation is enhanced with dual antiplatelet therapy. Combination antiplatelet regimens with different mechanisms of action to inhibit multiple sites in the thrombotic pathway may further improve long-term clinical outcomes. Dual antiplatelet therapy may have advantages over monotherapy in the prevention of recurrent ischemic events.     

Endothelial dysfunction, impaired endogenous platelet inhibition and platelet activation in diabetes and atherosclerosis

Platelet activation induces rapid thrombus formation at a ruptured atherosclerotic plaque leading to acute vessel occlusion and a fatal or non-fatal cardiovascular event. More recent evidence suggests that activated platelets play an additional central role during the initiation of atherosclerosis, essentially facilitating leukocyte adhesion and recruitment. Endothelial dysfunction is a common and early feature of cardiovascular diseases characterized by reduced bioavailability of prostacyclin and nitric oxide (NO). Subsequently impaired endogenous platelet inhibition causes platelet activation in pre-atherosclerotic vascular disease resulting in enhanced platelet susceptibility to agonists released from the inflamed endothelium. Platelet adhesion to inflammatory, dysfunctional endothelium precedes leukocyte adhesion. Indeed, adherent activated platelets are mandatory for leukocyte recruitment in the early phases of atherosclerosis under arterial flow conditions. Increased expression of chemokines in atherosclerotic plaques and the inflamed endothelium initiates and facilitates pro-inflammatory processes in leukocytes and the vascular wall. Apart from their chemotactic properties, some chemokines such as fractalkine contribute to platelet activation. Moreover, fractalkine induces leukocyte recruitment to inflamed endothelial cells under arterial flow by activating adherent platelets. An aggressive form of atherosclerosis is found in patients with diabetes. Since diabetes is currently considered as a risk equivalent for coronary artery disease, the interaction between oxidative stress, endothelial dysfunction, impaired endogenous platelet inhibition and platelet activation is discussed in the light of diabetes. Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke.     

Natural phenolic compounds as cardiovascular therapeutics: potential role of their antiinflammatory effects

A number of epidemiological studies have shown that diets rich in plant-derived phenolic compounds reduce the risk of coronary heart disease. The chronic antioxidant and hypolipidemic activities of these compounds have important roles in prevention of lipoprotein oxidation and atherosclerotic lesion development. In recent years, it has been recognized that inflammation is directly involved in development of cardiovascular disease and clinical events such as atherosclerotic plaque rupture (which is the trigger of acute coronary syndrome), arterial restenosis, and myocardial ischemia-reperfusion injury. Phenolic compounds have significant antiinflammatory effects, including inhibition of adhesion molecule, cytokine and chemokine gene expression; inhibition of platelet function; augmentation of endothelial nitric oxide release; suppression of smooth muscle activation; and other effects on proinflammatory factors such as endothelin and matrix metalloproteinases. However, direct evidence of acute therapeutic benefits of phenolic compounds in cardiovascular disorders remains sparse. This review attempts to integrate the inflammatory mechanisms involved in these cardiovascular diseases with recent findings on the antiinflammatory effects of phenolic compounds. Findings from the limited in vivo studies in this regard are discussed. It is suggested that searching for novel phenolic compounds with higher specificity and efficacy may represent a fruitful approach in development of new cardiovascular therapeutics.     

Pathophysiology of platelet resistance to anti-aggregating agents in insulin resistance and type 2 diabetes: implications for anti-aggregating therapy

The insulin resistance syndrome, which presents among its many facets obesity and type 2 diabetes mellitus, is a major risk factor for cardiovascular events. Thus, therapeutic guidelines recommend multifactorial treatment programs including, especially in the presence of type 2 diabetes, antiplatelet drugs. Few data, however, are available about the protective effect of antiplatelet therapy in both obese and type 2 diabetic patients. Furthermore, some reports showed a decreased sensitivity to the platelet antiaggregating effect of acetylsalicylic acid in diabetic patients. In the first part of this review, we focused our attention to alterations of platelets from insulin resistant subjects with or without type 2 diabetes, underlining that platelet hyperactivation is explained, at least in part, by: i) a reduced sensitivity to agents exerting an inhibitory modulation of platelet responses, ii) an altered intracellular milieu with elevated cytosolic Ca2+, iii) an enhanced thromboxane A2 synthesis, and iv) an increased number and/or function of GPIIb/IIIa complexes on platelet membranes. Furthermore, oxidative stress, which increases isoprostane production from arachidonic acid, may be involved in platelet hyperactivation, since isoprostanes activate platelets by interplaying with thromboxane receptors. These defects explain why antiplatelet therapy for both chronic atherosclerotic vascular disease and acute coronary syndromes should be specifically tailored in obese, insulin resistant subjects, especially in the presence of type 2 diabetes mellitus. Thus, in the second part of this review we carried out a critical overview of the clinical trials in subjects with metabolic syndrome and type 2 diabetes mellitus with or without macroangiopathy.     

Expression of Platelet Surface Receptors and Early Changes in Platelet Function in Patients with STEMI Treated with Abciximab and Clopidogrel versus Clopidogrel Alone

BACKGROUND: Platelets play a crucial role in the pathogenesis of acute coronary syndromes (ACS). The efficacy of antiplatelet treatment is pivotal in the success of percutaneous coronary intervention (PCI) performed in patients with ACS. OBJECTIVE: The aim of the study was to investigate the effects of clopidogrel with or without abciximab on the expression of platelet surface receptors and platelet function in patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI. MATERIALS AND METHODS: Thirty patients with STEMI were included in the study. During acute primary coronary intervention, patients received aspirin (acetylsalicylic acid) and clopidogrel in a loading dose of 300mg. Clopidogrel was the only antiplatelet therapy used by nine patients (group B). Twenty-one patients (group A) received additional abciximab. Blood samples were collected and analyzed twice: before and up to 22 hours after administration of antiplatelet therapy. The platelet aggregation was established as primary platelet-related hemostasis (closure time [CT] assessed using the PFA100 system). The absolute number of platelet surface antigens as CD41a, CD42a, CD42b, CD61, and CD62P were determined by flow cytometry analysis. RESULTS: The study revealed a statistically significant increase in CT induced by adenosine diphosphate and adrenaline (epinephrine) +130 seconds (p < 0.0001) and +94 seconds (p < 0.0001), respectively, in group A patients post-therapy. While in group B the parameters of CT did not change after treatment. In addition, the absolute number of CD41a antigens (glycoprotein [GP] IIb/IIIa) increased significantly after treatment in group A. No significant changes were observed after treatment in the expression of CD62P (P-selectin) antigens in either treatment group. There was a significant reduction in the percentage of CD62P-positive platelets in group B after antiplatelet therapy. CONCLUSIONS: The absolute number of GP IIb/IIIa receptors increases and platelets are not activated up to 12 hours after cessation of abciximab therapy. Treatment of STEMI patients undergoing PCI with a loading dose of clopidogrel reduces the percentage of active platelets but does not influence the CT.