Role Of Platelets In Atherothrombosis Research Articles

YIA6: VESSEL WALL, BUT NOT PLATELET, P2Y12 CONTRIBUTES TO EARLY ATHEROGENESIS

The fundamental role of platelets in atherothrombosis is well defined but the extent of their role in early atherogenesis remains unclear. The P2Y12 receptor is responsible for amplifying and sustaining...

Guided antithrombotic therapy: current status and future research direction: report on a National Heart, Lung and Blood Institute working group.

The National Heart, Lung, and Blood Institute (NHLBI) convened a working group to develop a research agenda to enhance the understanding and effectiveness of antithrombotic therapy. The working group brought together cardiologists, hematologists, interventionalists, clinical trialists, genetic epidemiologists, basic scientists, and other stakeholders to review (1) coagulation, platelet activation and aggregation, and antithrombotic therapy; (2) issues surrounding antithrombotic therapy failure – how to define it, how to predict and diagnose it, available tests and how to optimize them; (3) the factors that affect the efficacy, safety, and predictability of antithrombotic therapies; (4) how to optimize antithrombotic therapy, improve on present interventions, and individually tailor therapy to increase efficacy and safety and to avoid failure; and (5) the clinical applicability and cost-effectiveness of individually tailored antithrombotic therapy based on functional and genetic testing. The working group characterized and discussed challenges for guided antithrombotic therapy in 4 domains: therapeutic strategies, antithrombotic metrics, pharmacology and pharmacogenetics, and stakeholders' roles. Overall, the working group identified and prioritized the most pressing clinical needs to focus future research and translational efforts. This report presents highlights of these reviews and a summary of suggested research directions. There has been tremendous progress in the field of thrombosis in the past 2 decades.1–5 The ramifications on cardiovascular care have been profound. A greater appreciation of the central role of platelets in atherothrombosis and an increased understanding of the receptors involved in platelet activation and aggregation have led to pivotal randomized controlled trials (RCTs) of novel agents.6 Many of these agents have been associated with substantial reductions in adverse cardiovascular outcomes. Simultaneously, an appreciation of the complexity of the coagulation cascade and the artificiality of separating it from cellular and platelet interactions has promoted a deeper understanding of thrombosis and, consequently, identification of pharmacological targets to …

Platelet protease-activated receptor antagonism in cardiovascular medicine

Ischemic heart disease remains the number one cause of death in the world despite advances in invasive and pharmacologic therapies. An ongoing area of research is the central role of platelets in atherothrombosis. Many therapeutic strategies have been developed over the last few decades affecting different platelet receptors to alter platelet-mediated thrombosis including targeting the receptors for thromboxane A(2), adenosine diphosphate, and fibrinogen. However, despite the use of pharmacologic agents directed at these pathways, residual morbidity and mortality still exist. Therefore, identifying agents that more favorably balance a reduction in ischemic events while minimizing bleeding events is an ongoing mission. Thrombin is known to be the most potent stimulant of platelet-mediated thrombosis whose action on the platelet is through a family of receptors known as the protease-activated receptors (PARs). Activation through the PAR-1 receptor, in particular, results in an early and intense response by the platelet to thrombin, and it is the primary thrombin receptor on platelets, thus making it a potentially desirable target for therapy. Most recently, two PAR-1 antagonists, atopaxar and vorapaxar, have been tested in clinical trials. Generally, the results show a reduction in ischemic event rates, but an increase in bleeding event rates. This article will summarize the current state of the literature and consider the role these drugs might play in the future for the prevention of ischemic heart disease events.

A contemporary viewpoint on ‘aspirin resistance’

Aspirin is an irreversible inhibitor of platelet prostaglandin synthase activity, and is the most widely prescribed drug for the secondary prevention of cardiovascular disease. In recent years, clinical and laboratory evidence has shown significant individual variability in the response to aspirin and its link to clinical outcome. The term ‘aspirin resistance’ has been introduced to describe situations when clinical or ex-vivo effects of aspirin are less than expected. The accumulating evidence of increased risk of major adverse clinical events (MACE) associated with ‘aspirin resistance’ in the settings of acute coronary syndrome (ACS), stroke, and peripheral arterial disease has stimulated the search for ways of overcoming aspirin resistance. Existence of the link between high on-treatment platelet reactivity and atherothrombotic events suggests the common mechanisms for atherosclerosis progression and thrombotic complications with the platelets, being a key cellular interface between coagulation and inflammation.This review article provides a contemporary view on ‘aspirin resistance’ and discusses its definition, clinical importance, and possible mechanisms in light of recent data on the role of platelets in atherothrombosis.

The Role of Platelets in Atherothrombosis

Platelets have evolved highly specialized adhesion mechanisms that enable cell-matrix and cell-cell interactions throughout the entire vasculature irrespective of the prevailing hemodynamic conditions. This unique property of platelets is critical for their ability to arrest bleeding and promote vessel repair. Platelet adhesion under conditions of high shear stress, as occurs in stenotic atherosclerotic arteries, is central to the development of arterial thrombosis; therefore, precise control of platelet adhesion must occur to maintain blood fluidity and to prevent thrombotic or hemorrhagic complications. Whereas the central role of platelets in hemostasis and thrombosis has long been recognized and well defined, there is now a major body of evidence supporting an important proinflammatory function for platelets that is linked to host defense and a variety of autoimmune and inflammatory diseases. In the context of the vasculature, experimental evidence indicates that the proinflammatory function of platelets can regulate various aspects of the atherosclerotic process, including its initiation and propagation. The mechanisms underlying the proatherogenic function of platelets are increasingly well defined and involve specific adhesive interactions between platelets and endothelial cells at atherosclerotic-prone sites, leading to the enhanced recruitment and activation of leukocytes. Through the release of chemokines, proinflammatory molecules, and other biological response modulators, the interaction among platelets, endothelial cells, and leukocytes establishes a localized inflammatory response that accelerates atherosclerosis. These inflammatory processes typically occur in regions of the vasculature experiencing low shear and perturbed blood flow, a permissive environment for leukocyte-platelet and leukocyte-endothelial interactions. Therefore, the concept has emerged that platelets are a central element of the atherothrombotic process and that future therapeutic strategies to combat this disease need to take into consideration both the prothrombotic and proinflammatory function of platelets.

The Influence of Intermittent Hypoxemia on Platelet Activation in Obese Patients with Obstructive Sleep Apnea

Literature regarding platelet function in obstructive sleep apnea (OSA) has considerable limitations. Given the central role of platelets in atherothrombosis and the known cardiovascular risk of OSA, we hypothesized that OSA severity is predictive of platelet function, independent of known comorbidities. Obese subjects, without comorbidities, underwent overnight, in-lab polysomnography. The following morning, 5 biomarkers of platelet activation were measured by whole-blood flow cytometry at baseline and in response to agonists (no stimulation, stimulation with 5 μM ADP agonist, and stimulation with 20 μM ADP agonist): platelet surface P-selectin, activated glycoprotein (GP) IIb/IIIa, and GPIb receptor expression, platelet-monocyte aggregation (PMA) and platelet-neutrophil aggregation (PNA). Of the 77 subjects, 47 were diagnosed with OSA (median apnea-hypopnea index [AHI] of 24.7 ± 28.1/h in subjects with OSA and 3.0 ± 3.9/h in subjects without OSA, p < 0.001). The groups were matched for body mass index, with a mean body mass index of 40.3 ± 9.6 kg/m(2) in subjects with OSA and 38.9 ± 6.0 kg/m(2) in subjects without OSA (p = 0.48). A comparison of time spent with an oxygen saturation of less than 90% showed that subjects who had 1 minute or more of desaturation time per hour of sleep had lower GPIb fluorescence in circulating platelets, as compared with those subjects who had less than 1 minute of desaturation time per hour of sleep; similar findings were observed following 5 μM and 20 μM of ADP stimulation, as compared with control vehicle, suggesting higher levels of circulating platelet activity. In multivariate analyses, only nocturnal hypoxemia and female sex predicted agonist response. Platelet surface P-selectin, platelet surface-activated GPIIb/IIIa, PMA, and PNA were not significantly correlated with markers of OSA. In obese patients with OSA, platelet activation is associated with greater levels of oxygen desaturation, compared with matched control subjects. Metrics other than AHI (e.g., hypoxemia) may determine OSA-related thrombotic risk.

Role of Platelets in Atherothrombosis

Platelets play a pivotal role in atherothrombosis and therefore are primary targets of antithrombotic therapy. They release an array of agonists, such as adenosine diphosphate (ADP); adhesive molecules, such as P-selectin, thrombospondin, fibrinogen, and von Willebrand factor; coagulation factors; and growth factors. In turn, they present transmembrane receptors for a plethora of agonists and ligands. Heterodimeric glycoproteins of the integrin family bind extracellular matrix and plasma proteins; mediate adhesion, activation, spreading, and aggregation; and facilitate intercellular bidirectional signal transduction. Glycoprotein IIb/IIIa is the most abundant platelet integrin and membrane surface glycoprotein. Glycolipids, heparins, proteoglycans, tetraspanins, and a multitude of other molecules, such as tumor necrosis factor-alpha, CD40L, growth arrest-specific 6, Eph receptor tyrosine kinases, and signaling lymphocytic activation molecule receptors, have been implicated in atherothrombosis. ADP promotes platelet aggregation by binding to platelet surface receptors P2Y(1) and P2Y(12); the thienopyridines inhibit aggregation by binding covalently to P2Y(12). Thrombin, a potent initiator of platelet aggregation, activates platelets by cleaving protease-activated receptors (PARs) PAR-1 and PAR-4 and further propagates its effect by activating nearby platelets. A number of pharmacologic agents with antiplatelet actions have been developed, but the search continues for agents that strike an optimal balance between control of thrombosis and serious bleeding.

Continuum of Care in the Treatment of ST-Segment Elevation Myocardial Infarction (STEMI): Importance of Platelet and Coagulation Inhibition

ST-segment elevation myocardial infarction (STEMI) is a serious manifestation of atherothrombosis. Platelets play an important role in the pathogenesis of atherothrom-bosis, and the use of antiplatelet agents is associated with substantial improvements in clinical outcome. Current guidelines for the management of patients with STEMI stress the importance of using antiplatelet agents as an integral part of acute and long-term therapy. However, these and other recommended therapies are frequently underutilized. In-hospital quality improvement initiatives have been shown to substantially improve adherence to guideline-recommended therapies at the time of discharge. This review discusses the role of platelets in atherothrombosis and describes the medical management of patients with STEMI, highlighting current guideline recommendations, adherence in clinical practice, and the impact of quality improvement programs in maintaining the continuum of care into the ambulatory setting.

Platelet Activation and Atherothrombosis

This review of the role of platelets in atherothrombosis illuminates the surprisingly numerous activities of these tiny, anucleate cells and stresses their participation in the inflammatory component of atherothrombosis. The information is presented in the context of the prevention of atherothrombosis by antiplatelet agents now in clinical use.

New perspectives on von Willebrand factor functions in hemostasis and thrombosis

The adhesive protein, von Willebrand factor (VWF), mediates the initiation and progression of thrombus formation at sites of vascular injury by means of specific interactions with extracellular matrix components and platelet receptors. The essential biologic properties of VWF have been elucidated, with progress particularly in the areas of genetic regulation, biosynthesis, and specific bimolecular interactions. The three-dimensional structure of selected domains has been solved, but our understanding of detailed structure-function relationships is still fragmented, partly because of the complexity and size of the VWF molecule. The biomechanical properties of the interaction between the VWF A1 domain and the platelet receptor glycoprotein (GP) Ibalpha also are better known, but we can still only hypothesize how this adhesive bond can oppose the fluid dynamic effects of rapidly flowing blood to initiate thrombus formation and contribute to platelet activation. Elucidating the details of VWF and GPIbalpha function will lead to a more satisfactory definition of the role of platelets in atherothrombosis, since hemodynamic forces greatly influence responses to vascular injury in stenosed and partially occluded arteries. Progress in this direction is also aided by rapidly expanding novel information on the mechanisms that regulate VWF multimer size in the circulation, a topic of relevance to explain microvascular thrombosis and, perhaps, arterial thrombosis in general. Developments in these areas of research will refine our understanding of the role played by VWF in vascular biology and pathology.