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Seminars in Thrombosis and Hemostasis Apr 2016Platelets are the smallest blood cells, numbering 150 to 350 × 10(9)/L in healthy individuals. The ability of activated platelets to adhere to an injured vessel... (Review)
Review
Platelets are the smallest blood cells, numbering 150 to 350 × 10(9)/L in healthy individuals. The ability of activated platelets to adhere to an injured vessel wall and form aggregates was first described in the 19th century. Besides their long-established roles in thrombosis and hemostasis, platelets are increasingly recognized as pivotal players in numerous other pathophysiological processes including inflammation and atherogenesis, antimicrobial host defense, and tumor growth and metastasis. Consequently, profound knowledge of platelet structure and function is becoming more important in research and in many fields of modern medicine. This review provides an overview of platelet physiology focusing particularly on the structure, granules, surface glycoproteins, and activation pathways of platelets.
Topics: Blood Platelets; Hemostasis; Humans; Models, Biological; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Platelet Membrane Glycoproteins; Signal Transduction; Thrombosis
PubMed: 26926581
DOI: 10.1055/s-0035-1564835 -
Cardiovascular Toxicology Feb 2020Globally, one of the major causes of death is the cardiovascular disease (CVD), and platelets play an important role in thrombosis and atherosclerosis that led to death.... (Review)
Review
Globally, one of the major causes of death is the cardiovascular disease (CVD), and platelets play an important role in thrombosis and atherosclerosis that led to death. Platelet activation can be done by different molecules, genes, pathways, and chemokines. Lipids activate platelets by inflammatory factors, and platelets are activated by receptors of peptide hormones, signaling and secreted proteins, microRNAs (miRNAs), and oxidative stress which also affect the platelet activation in older age. In addition, surface molecules on platelets can interact with other cells and chemokines in activated platelets and cause inflammation thrombosis events and CVD. However, these molecules activating platelets or being activated by platelets can be suggested as the markers to predict the clinical outcome of CVD and can be targeted to reduce thrombosis and atherosclerosis. However, hindering these molecules by other factors such as genes and receptors can reduce platelet activation and aggregation and targeting these molecules can control platelet interactions, thrombosis, and CVD. In addition, dual therapy with the receptor blockers and novel drugs results in better management of CVD patients. Overall, our review will emphasize on the molecules involved in the activation of platelets and on the molecules that are activated by platelets in CVD and discuss the molecules that can be blocked or targeted to reduce the thrombosis events and control CVD.
Topics: Animals; Blood Platelets; Cardiovascular Diseases; Humans; Molecular Targeted Therapy; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Signal Transduction
PubMed: 31784932
DOI: 10.1007/s12012-019-09555-4 -
Circulation Jan 2021PCSK9 (proprotein convertase subtilisin/kexin 9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein cholesterol by...
BACKGROUND
PCSK9 (proprotein convertase subtilisin/kexin 9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein cholesterol by degrading low-density lipoprotein receptor. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, and the underlying mechanisms, as well, still remain unclear.
METHODS
We detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, α-granule release, spreading, and clot retraction. These studies were complemented by in vivo analysis of FeCl-injured mouse mesenteric arteriole thrombosis. We also investigated the underlying mechanisms. Using the myocardial infarction (MI) model, we explored the effects of PCSK9 on microvascular obstruction and infarct expansion post-MI.
RESULTS
PCSK9 directly enhances agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, P-selectin release from α-granules, spreading, and clot retraction. In line, PCSK9 enhances in vivo thrombosis in a FeCl-injured mesenteric arteriole thrombosis mouse model, whereas PCSK9 inhibitor evolocumab ameliorates its enhancing effects. Mechanism studies revealed that PCSK9 binds to platelet CD36 and thus activates Src kinase and MAPK (mitogen-activated protein kinase)-extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase, increases the generation of reactive oxygen species, and activates the p38MAPK/cytosolic phospholipase A2/cyclooxygenase-1/thromboxane A signaling pathways downstream of CD36 to enhance platelet activation, as well. Using CD36 knockout mice, we showed that the enhancing effects of PCSK9 on platelet activation are CD36 dependent. It is important to note that aspirin consistently abolishes the enhancing effects of PCSK9 on platelet activation and in vivo thrombosis. Last, we showed that PCSK9 activating platelet CD36 aggravates microvascular obstruction and promotes MI expansion post-MI.
CONCLUSIONS
PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, and MI expansion post-MI, as well, by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors or aspirin abolish the enhancing effects of PCSK9, supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.
Topics: Animals; Aspirin; Blood Platelets; CD36 Antigens; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; PCSK9 Inhibitors; Platelet Activation; Platelet Aggregation; Proprotein Convertase 9; Thrombosis
PubMed: 32988222
DOI: 10.1161/CIRCULATIONAHA.120.046290 -
Current Pharmaceutical Design 2018Coronary artery disease (CAD) is a disease progressing over many years. Genetic factors, as well as the exposure to risk factors, are continuously leading to endothelial... (Review)
Review
BACKGROUND
Coronary artery disease (CAD) is a disease progressing over many years. Genetic factors, as well as the exposure to risk factors, are continuously leading to endothelial dysfunction, vascular alterations and, eventually, organ damage, major cardiovascular events and deaths. Oxidative stress, platelet hyperactivity and low-grade inflammation are important modulators in this context, contributing to plaque formation. Since platelet activation plays a critical role in the development and progression of atherothrombotic events, the inhibition of platelet hyperactivity may contribute to decreased atherothrombotic risk. The consumption of bioactive foods, and plant-derived polyphenols in particular, might impart anti-thrombotic and cardiovascular protective effects.
METHODS
Aim of this work is to focus on the potential of dietary derived polyphenols to reduce platelet hyperactivity or hypercoagulability in addition to discussing their possible complementary anti-platelet therapeutic potential. All the relevant publications on this topic were systematically reviewed.
RESULTS
Various studies demonstrated that polyphenol supplementation affects platelet aggregation and function in vitro and in vivo, mainly neutralizing free radicals, inhibiting platelet activation and related signal transduction pathways, blocking thromboxane A2 receptors and enhancing nitric oxide production. Experimental data concerning the effect of dietary polyphenols on platelet aggregation in vivo are poor, and results are often conflicting. Only flavanols clearly mirrored in vivo showed the efficacy in vitro in modulating platelet function.
CONCLUSION
Dietary polyphenols, and above all flavanols contained in cocoa and berries, reduce platelet activation and aggregation via multiple pathways. However, more controlled interventional studies are required to establish which doses are required as well as what circulating concentrations are sufficient to induce functional antiplatelet effects.
Topics: Animals; Dietary Supplements; Humans; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Polyphenols
PubMed: 29119922
DOI: 10.2174/1381612823666171109104600 -
Comprehensive Physiology Jun 2018This overview article for the Comprehensive Physiology collection is focused on detailing platelets, how platelets respond to various stimuli, how platelets interact... (Review)
Review
This overview article for the Comprehensive Physiology collection is focused on detailing platelets, how platelets respond to various stimuli, how platelets interact with their external biochemical environment, and the role of platelets in physiological and pathological processes. Specifically, we will discuss the four major functions of platelets: activation, adhesion, aggregation, and inflammation. We will extend this discussion to include various mechanisms that can induce these functional changes and a discussion of some of the salient receptors that are responsible for platelets interacting with their external environment. We will finish with a discussion of how platelets interact with their vascular environment, with a special focus on interactions with the extracellular matrix and endothelial cells, and finally how platelets can aid and possibly initiate the progression of various vascular diseases. Throughout this overview, we will highlight both the historical investigations into the role of platelets in health and disease as well as some of the more current work. Overall, the authors aim for the readers to gain an appreciation for the complexity of platelet functions and the multifaceted role of platelets in the vascular system. © 2017 American Physiological Society. Compr Physiol 8:1117-1156, 2018.
Topics: Animals; Blood Platelets; Humans; Platelet Activation; Platelet Adhesiveness; Vascular Remodeling
PubMed: 29978900
DOI: 10.1002/cphy.c170049 -
Arteriosclerosis, Thrombosis, and... Apr 2017
Topics: Blood Platelets; Humans; Neovascularization, Pathologic; Platelet Activation; Tamoxifen
PubMed: 28330945
DOI: 10.1161/ATVBAHA.117.309105 -
Blood Nov 2023Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing the...
Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing the leakage of blood cells from the vessel. There has been a paucity in the development of new drugs to target platelet reactivity. Recently, the oxylipin 12(S)-hydroxy-eicosatrienoic acid (12-HETrE), which is produced in platelets, was shown to limit platelet reactivity by activating the prostacyclin receptor. Here, we demonstrated the synthesis of a novel analog of 12-HETrE, known as CS585. Human blood and mouse models of hemostasis and thrombosis were assessed for the ability of CS585 to attenuate platelet activation and thrombosis without increasing the risk of bleeding. Human platelet activation was assessed using aggregometry, flow cytometry, western blot analysis, total thrombus formation analysis system, microfluidic perfusion chamber, and thromboelastography. Hemostasis, thrombosis, and bleeding assays were performed in mice. CS585 was shown to potently target the prostacyclin receptor on the human platelet, resulting in a highly selective and effective mechanism for the prevention of platelet activation. Furthermore, CS585 was shown to inhibit platelet function in human whole blood ex vivo, prevent thrombosis in both small and large vessels in mouse models, and exhibit long-lasting prevention of clot formation. Finally, CS585 was not observed to perturb coagulation or increase the risk of bleeding in the mouse model. Hence, CS585 represents a new validated target for the treatment of thrombotic diseases without the risk of bleeding or off-target activation observed with other prostaglandin receptor agonists.
Topics: Animals; Humans; Mice; Receptors, Epoprostenol; Oxylipins; Platelet Activation; Blood Platelets; Hemostasis; Thrombosis; Hemorrhage; Platelet Aggregation
PubMed: 37624927
DOI: 10.1182/blood.2023020622 -
Frontiers in Immunology 2021In 2019 10 million people developed symptomatic tuberculosis (TB) disease and 1.2 million died. In active TB the inflammatory response causes tissue destruction, which... (Review)
Review
In 2019 10 million people developed symptomatic tuberculosis (TB) disease and 1.2 million died. In active TB the inflammatory response causes tissue destruction, which leads to both acute morbidity and mortality. Tissue destruction in TB is driven by host innate immunity and mediated enzymes, chiefly matrix metalloproteinases (MMPs) which are secreted by leukocytes and stromal cells and degrade the extracellular matrix. Here we review the growing evidence implicating platelets in TB immunopathology. TB patients typically have high platelet counts, which correlate with disease severity, and a hypercoagulable profile. Platelets are present in human TB granulomas and platelet-associated gene transcripts are increased in TB patients versus healthy controls. Platelets most likely drive TB immunopathology through their effect on other immune cells, particularly monocytes, to lead to upregulation of activation markers, increased MMP secretion, and enhanced phagocytosis. Finally, we consider current evidence supporting use of targeted anti-platelet agents in the treatment of TB due to growing interest in developing host-directed therapies to limit tissue damage and improve treatment outcomes. In summary, platelets are implicated in TB disease and contribute to MMP-mediated tissue damage their cellular interactions with other leukocytes, and are potential targets for novel host-directed therapies.
Topics: Blood Platelets; Extracellular Matrix; Humans; Immunity, Innate; Inflammation; Leukocytes; Platelet Activation; Platelet Aggregation Inhibitors; Signal Transduction; Tuberculosis
PubMed: 34093524
DOI: 10.3389/fimmu.2021.631696 -
Cardiovascular & Hematological... 2018Ischemia is a multifactorial disorder in which several genetic and environmental factors are involved. Platelets are the major causative agents of this disease because... (Review)
Review
BACKGROUND
Ischemia is a multifactorial disorder in which several genetic and environmental factors are involved. Platelets are the major causative agents of this disease because their elevated activity and aggregation would increase the risk of atherosclerosis and thrombosis, as well as ischemia. A number of polymorphisms in platelet receptors can increase the risk of ischemia and single-nucleotide polymorphisms (SNPs) have been detected in platelets. In addition, polymorphisms in other genes have been shown to cause platelet adhesion and aggregation that plays a role in ischemia. Patients respond differently to anti-platelet drugs which are used to treat patients with ischemia. Polymorphisms affect patients' responses to anti-platelet drugs, for instance, by increasing platelet activity and causing resistance of platelets to these drugs. Diagnosis of these polymorphisms can greatly contribute to better prediction of prognosis and response to treatment of patients, leading to more effective therapeutic strategies and a proper approach to ischemia.
CONCLUSION
In this review, we have evaluated the role of polymorphisms involved in platelet activation and development of ischemia.
Topics: Atherosclerosis; Blood Platelets; Humans; Ischemia; Platelet Activation; Platelet Aggregation
PubMed: 29577867
DOI: 10.2174/1871529X18666180326121239 -
Pathologie-biologie Dec 2015The protein kinase C (PKC) family has been implicated in several physiological processes regulating platelet activation. Each isoform of PKC expressed on platelets, may... (Review)
Review
The protein kinase C (PKC) family has been implicated in several physiological processes regulating platelet activation. Each isoform of PKC expressed on platelets, may have a positive and/or negative role depending on the nature and concentration of the agonist. Mice lacking PKCα show much reduced thrombus formation in vivo, while PKCθ(-/-) showed inhibition of aggregation in response to PAR4. On the other hand, PKCδ by associating with Fyn, inhibits platelet aggregation. In addition, PKCβ by interacting with its receptor RACK1 has been implicated in the primary phases of signaling via the αIIbβ3 and finally PKCɛ appears to be involved in platelet function downstream GPVI. The present review discusses the latest observations relevant to the role of individual PKC isoforms in platelet activation and thrombus formation.
Topics: Animals; Humans; Isoenzymes; Mice; Mice, Knockout; Platelet Activation; Platelet Aggregation; Protein Kinase C; Thrombosis
PubMed: 26476932
DOI: 10.1016/j.patbio.2015.09.001