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Physiology (Bethesda, Md.) Mar 2017Upon blood vessel injury, platelets are exposed to adhesive proteins in the vascular wall and soluble agonists, which initiate platelet activation, leading to formation... (Review)
Review
Upon blood vessel injury, platelets are exposed to adhesive proteins in the vascular wall and soluble agonists, which initiate platelet activation, leading to formation of hemostatic thrombi. Pathological activation of platelets can induce occlusive thrombosis, resulting in ischemic events such as heart attack and stroke, which are leading causes of death globally. Platelet activation requires intracellular signal transduction initiated by platelet receptors for adhesion proteins and soluble agonists. Whereas many platelet activation signaling pathways have been established for many years, significant recent progress reveals much more complex and sophisticated signaling and amplification networks. With the discovery of new receptor signaling pathways and regulatory networks, some of the long-standing concepts of platelet signaling have been challenged. This review provides an overview of the new developments and concepts in platelet activation signaling.
Topics: Animals; Blood Platelets; Cyclic GMP; Humans; Inflammation; Integrins; Mice; Platelet Activation; Platelet Adhesiveness; Signal Transduction; Thrombosis
PubMed: 28228483
DOI: 10.1152/physiol.00020.2016 -
Arteriosclerosis, Thrombosis, and... Apr 2017
Topics: Blood Platelets; Humans; Neovascularization, Pathologic; Platelet Activation; Tamoxifen
PubMed: 28330945
DOI: 10.1161/ATVBAHA.117.309105 -
Platelets Feb 2022While it is clear that platelets interact with viruses, the ramifications and mechanisms of those interactions are still being defined for each type of viral infection....
While it is clear that platelets interact with viruses, the ramifications and mechanisms of those interactions are still being defined for each type of viral infection. HIV/AIDS represents a potentially unique example of how viremia affects platelets since the increasing efficacy of antiretroviral therapeutics (ART) has made it a chronic disease that increases the risk of cardiovascular disease. In this opinion article, we discuss some of the open questions about how platelets interact with HIV. What happens to a virion once it binds a platelet? What is the nature of virus-induced platelet activation? Are platelets a normal part of the immune response to viremia that has been co-opted to increase the spread of HIV? The answers to these and similar questions will help define how platelet-directed therapeutics might be used in treating HIV/AIDS patients.
Topics: Blood Platelets; HIV Infections; Humans; Platelet Activation
PubMed: 35086429
DOI: 10.1080/09537104.2021.2019695 -
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 -
Microbiology Spectrum Dec 2022Streptococcus bovisStreptococcus equinus complex (SBSEC) is a common cause of infective endocarditis (IE). For IE-pathogens, the capacity to activate and aggregate...
Streptococcus bovisStreptococcus equinus complex (SBSEC) is a common cause of infective endocarditis (IE). For IE-pathogens, the capacity to activate and aggregate platelets is believed to be an important virulence mechanism. While the interactions between bacteria and platelets have been described in detail for many Gram-positive pathogens, little research has been carried out with SBSEC in this respect. Twenty-six isolates of the four most common species and subspecies of SBSEC identified in bacteremia were collected, and interactions with platelets were investigated in platelet rich plasma (PRP) from three donors. Aggregation was studied using light-transmission aggregometry and platelet activation using flow cytometry detecting surface upregulation of CD62P. Platelets and serum were treated with different inhibitors to determine mechanisms involved in platelet aggregation and activation. Twenty-two of 26 isolates induced aggregation in at least one donor, and four isolates induced aggregation in all three donors. In PRP from donor 1, isolate SL1 induced a rapid aggregation with a median time of 70 s to reach 50% aggregation. Blockade of the platelet Fc-receptor or enzymatic cleavage of IgG abolished platelet activation and aggregation. The capacity for bacteria-induced platelet aggregation was also shown to be transferable between donors through serum. SBSEC mediates platelet aggregation in an IgG and IgG-Fc-receptor dependent manner. Bacterial activation of platelets through this pathway is common for many bacteria causing IE and could be a potential therapeutic target for the prevention and treatment of this infection. The capacity of bacteria to activate and aggregate platelets is believed to contribute to the pathogenesis of IE. The Streptococcus bovis/Streptococcus equinus complex (SBSEC) contains known IE-pathogens, but there is limited research on the different subspecies ability to interact with platelets and what signaling pathways are involved. This study reports that 22 of 26 tested isolates of different subspecies within SBSEC can induce aggregation, and that aggregation is host dependent. The Fc-IgG-receptor pathway was shown essential for platelet activation and aggregation. To the best of our knowledge, this is the first study that reports on platelet interactions of SBSEC-isolates other than Streptococcus gallolyticus subspecies as well as the first study to report of mechanisms of platelet interaction of SBSEC-isolates. It adds SBSEC to a group of bacteria that activate and aggregate platelets via the platelet Fc-receptor. This could be a potential therapeutic target for prevention of IE.
Topics: Streptococcus bovis; Platelet Activation; Platelet Aggregation; Blood Platelets; Immunoglobulin G
PubMed: 36374116
DOI: 10.1128/spectrum.01861-22 -
The Journal of Pharmacology and... May 2019Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but fewer endogenous inhibitors of platelets, such as prostacyclin and nitric...
Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but fewer endogenous inhibitors of platelets, such as prostacyclin and nitric oxide (NO), have been identified. Acetylcholinesterase inhibitors, such as donepezil, can cause bleeding in patients, but the underlying mechanisms are not well understood. We hypothesized that acetylcholine is an endogenous inhibitor of platelets. We measured the effect of acetylcholine or analogs of acetylcholine on human platelet activation ex vivo. Acetylcholine and analogs of acetylcholine inhibited platelet activation, as measured by P-selectin translocation and glycoprotein IIb IIIa conformational changes. Conversely, we found that antagonists of the acetylcholine receptor, such as pancuronium, enhance platelet activation. Furthermore, drugs inhibiting acetylcholinesterase, such as donepezil, also inhibit platelet activation, suggesting that platelets release acetylcholine. We found that NO mediates acetylcholine inhibition of platelets. Our data suggest that acetylcholine is an endogenous inhibitor of platelet activation. The cholinergic system may be a novel target for antithrombotic therapies.
Topics: Acetylcholine; Blood Platelets; Humans; Nitric Oxide; Platelet Activation; Receptors, Cholinergic
PubMed: 30765424
DOI: 10.1124/jpet.118.253583 -
Handbook of Experimental Pharmacology 2012This chapter summarizes current ideas about the intracellular signaling that drives platelet responses to vascular injury. After a brief overview of platelet activation... (Review)
Review
This chapter summarizes current ideas about the intracellular signaling that drives platelet responses to vascular injury. After a brief overview of platelet activation intended to place the signaling pathways into context, the first section considers the early events of platelet activation leading up to integrin activation and platelet aggregation. The focus is on the G protein-mediated events utilized by agonists such as thrombin and ADP, and the tyrosine kinase-based signaling triggered by collagen. The second section considers the events that occur after integrin engagement, some of which are dependent on close physical contact between platelets. A third section addresses the regulatory events that help to avoid unprovoked or excessive platelet activation, after which the final section briefly considers individual variations in platelet reactivity and the role of platelet signaling in the innate immune response and embryonic development.
Topics: Animals; Blood Platelets; Calcium; GTP-Binding Proteins; Humans; Platelet Activation; Platelet Adhesiveness; Signal Transduction
PubMed: 22918727
DOI: 10.1007/978-3-642-29423-5_3 -
Platelets May 2020Platelets are small, anucleated effector cells that play an important role in linking the hemostatic and inflammatory processes in the body. Platelet function is known... (Review)
Review
Platelets are small, anucleated effector cells that play an important role in linking the hemostatic and inflammatory processes in the body. Platelet function is known to be altered under various inflammatory conditions including aging. A gain in platelet function during aging can increase the risk of thrombotic events, such as stroke and acute myocardial infarction. Anti-platelet therapy is designed to reduce risk of serious cerebrovascular and cardiovascular events, but the adverse consequences of therapy, such as risk for bleeding increases with aging as well. Age-associated comorbidities such as obesity, diabetes, and hyperlipidemia also contribute to increased platelet activity and thus can enhance the risk of thrombosis. Therefore, identification of unique mechanisms of platelet dysfunction in aging and in age-associated comorbidities is warranted to design novel antiplatelet drugs. This review outlines some of the current areas of research on aging-related mechanisms of platelet hyperactivity and addresses the clinical urgency for designing anti-platelet therapies toward novel molecular targets in the aging population.
Topics: Aged; Aging; Animals; Blood Platelet Disorders; Blood Platelets; Comorbidity; Humans; Inflammation; Oxidative Stress; Platelet Activation; Risk Factors; Signal Transduction; Thrombosis
PubMed: 31524038
DOI: 10.1080/09537104.2019.1665641 -
Platelets Feb 2022Influenza infection has long been associated with prothrombotic outcomes in patients and platelets are the blood component predominantly responsible for thrombosis. In... (Review)
Review
Influenza infection has long been associated with prothrombotic outcomes in patients and platelets are the blood component predominantly responsible for thrombosis. In this review, we outline what is known about influenza interaction with human platelets, virion internalization, and viral RNA sensing, and the consequent impact on platelet function. We further discuss activation of platelets by IgG-influenza complexes and touch upon mechanisms of environmental platelet activation that relate to prothrombotic outcomes in patients during infection.
Topics: Blood Platelets; Humans; Influenza, Human; Platelet Activation
PubMed: 34369285
DOI: 10.1080/09537104.2021.1961710 -
Journal of Thrombosis and Haemostasis :... Aug 2023The response of platelets to activating stimuli and pharmaceutical agents varies greatly within the normal population. Current platelet function tests are used to...
BACKGROUND
The response of platelets to activating stimuli and pharmaceutical agents varies greatly within the normal population. Current platelet function tests are used to measure end-point levels of platelet activation without taking the speed at which platelets activate into account, potentially missing vital metrics to characterize platelet reactivity.
OBJECTIVES
To identify variability, to agonists and among individuals, in platelet activation kinetics and assess the impact of this on thrombus formation.
METHODS
We have developed a bespoke real-time flow cytometry assay and analysis package to measure the rate of platelet activation over time using 2 parameters of platelet activation, fibrinogen binding and P-selectin exposure.
RESULTS
The rate of platelet activation varied considerably within the normal population but did not correlate with maximal platelet activation, demonstrating that platelet activation rate is a separate and novel metric to describe platelet reactivity. The relative rate of platelet response between agonists was strongly correlated, suggesting that a central control mechanism regulates the rate of platelet response to all agonists.
CONCLUSION
For the first time, we have shown that platelet response rate corresponds to thrombus size and structure, wherein faster responders form larger, more densely packed thrombi at arterial, but crucially not venous, shear. We have demonstrated that the rate of platelet activation is an important metric in stratifying individual platelet responses and will provide a novel focus for the design and development of antiplatelet therapy, targeting high-shear thrombosis without exacerbating bleeding at low shear.
Topics: Humans; Platelet Activation; Thrombosis; Blood Platelets; Platelet Function Tests; Arteries; Platelet Aggregation
PubMed: 37085037
DOI: 10.1016/j.jtha.2023.03.044