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Platelets 2011ADP plays an important role in hemostasis and thrombosis. The P2Y12 receptor, activated by ADP, plays a central role in platelet activation and thrombus formation. Thus,... (Review)
Review
ADP plays an important role in hemostasis and thrombosis. The P2Y12 receptor, activated by ADP, plays a central role in platelet activation and thrombus formation. Thus, the P2Y12 receptor has been an effective target for antithrombotic drugs.
Topics: Adenosine Diphosphate; Animals; Blood Coagulation; Blood Platelets; Fibrinolytic Agents; Humans; Membrane Proteins; Mice; Platelet Activation; Platelet Aggregation; Purinergic Agents; Receptors, Purinergic P2; Signal Transduction; Thrombosis
PubMed: 21231822
DOI: 10.3109/09537104.2010.497231 -
BMC Medicine Nov 2020Antiretroviral therapy (ART) alters platelet reactivity, and as a consequence, patients living with HIV may be at an increased risk of cardiovascular disease (CVD). The... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antiretroviral therapy (ART) alters platelet reactivity, and as a consequence, patients living with HIV may be at an increased risk of cardiovascular disease (CVD). The current evidence on platelet activation levels in patients with HIV remains inconclusive. We therefore aimed to systematically synthesise evidence on the association of platelet activation in HIV-infected patients on successful treatment.
METHODS
Electronic databases were searched from inception until November 2019. Studies were included if the primary or secondary outcome of the study was to assess platelet activation in HIV-infected patients on ART. The primary outcome of this review included the levels of platelet activation. The pooled effect estimates were calculated using a random-effects meta-analysis model.
RESULTS
We identified 30 studies comprising of 2325 participants. The pooled estimates showed elevated levels of platelet activation in treatment-naïve HIV-infected patients compared to uninfected controls (Hedges' g 2.00 [95%CI 1.05, 2.94]; z = 4.12, p < 0.0001). These remained elevated despite successful ART (Hedges' g 2.05 [95%CI 0.58, 3.52]; z = 2.71, p = 0.0067).
CONCLUSION
The levels of platelet activation are elevated in treatment-naïve HIV-infected patients, and these persist during successful ART. Further studies should assess the clinical relevance of monitoring the levels of platelet activation in HIV-infected patients on ART.
Topics: Anti-Retroviral Agents; Cardiovascular Diseases; HIV Infections; Humans; Platelet Activation
PubMed: 33203400
DOI: 10.1186/s12916-020-01801-9 -
Journal of Internal Medicine Jan 1996
Review
Topics: Animals; Arteriosclerosis; Aspirin; Blood Platelets; Hemostasis; Humans; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Thrombosis
PubMed: 8551196
DOI: 10.1046/j.1365-2796.1996.331661000.x -
Vascular Pharmacology 2012The Ca(2+)-activated proteases or calpains, play a crucial role in a spectrum of physiological processes such as cytoskeletal remodeling, cellular signaling, cell... (Review)
Review
The Ca(2+)-activated proteases or calpains, play a crucial role in a spectrum of physiological processes such as cytoskeletal remodeling, cellular signaling, cell migration, apoptosis, cell survival and platelet activation, by the proteolytic cleavage of target proteins. Rather than eliciting protein degradation the calpains are responsible for their modification (e.g. activation, inhibition or altered sensitivity to intracellular signals) and therefore make a significant impact on intracellular signaling. Maintained calpain activation is known to be associated with disease development and in platelet calpains are involved in both physiological platelet activation as well as pathological platelet hyper-activation.
Topics: Animals; Apoptosis; Blood Platelets; Calpain; Cell Movement; Cell Survival; Humans; Platelet Activation; Platelet Aggregation; Signal Transduction
PubMed: 22386643
DOI: 10.1016/j.vph.2012.02.009 -
Na(+)/H(+) exchanger in the regulation of platelet activation and paradoxical effects of cariporide.Experimental Neurology Oct 2015Platelets are anucleated cell fragments derived from mature megakaryocytes and function in hemostasis when the endothelium is injured. Hemostasis involving platelets can... (Review)
Review
Platelets are anucleated cell fragments derived from mature megakaryocytes and function in hemostasis when the endothelium is injured. Hemostasis involving platelets can be divided into four phases: adhesion, activation, secretion, and aggregation. Platelet activation requires a rise in intracellular Ca(2+) concentrations and results in both a morphological change and the secretion of platelet granule contents. Na(+)/H(+) exchanger isoform 1 (NHE1) regulates the intracellular pH (pHi) and the volume of platelets. In addition, NHE1 plays a large role in platelet activation. Thrombus generation involves NHE1 activation and an increase in [Ca(2+)]i, which results from NHE1-mediated Na(+) overload and the reversal of the Na(+)/Ca(2+) exchanger. Cariporide (HOE-642), a potent NHE1 inhibitor, has inhibitory effects on the degranulation of human platelets, the formation of platelet-leukocyte-aggregates, and the activation of the GPIIb/IIIa receptor (PAC-1). However, despite the demonstrated protection against myocardial infarction as mediated by cariporide in patients undergoing coronary artery bypass graft surgery, the EXPEDITION clinical trial revealed that cariporide treatment increased mortality due to thromboembolic stroke. These findings suggest that a better understanding of NHE1 and its effect on platelet function and procoagulant factor regulation is warranted in order to develop therapies using NHE inhibitors.
Topics: Animals; Anti-Arrhythmia Agents; Blood Platelets; Cerebrovascular Disorders; Clinical Trials as Topic; Guanidines; Humans; Platelet Activation; Sodium-Hydrogen Exchangers; Sulfones
PubMed: 25595121
DOI: 10.1016/j.expneurol.2014.12.023 -
Thrombosis Research Feb 2021The ability to measure changes in platelet reactivity is important to identify novel aspects of platelet biology and develop targeted therapeutics to prevent bleeding or...
BACKGROUND
The ability to measure changes in platelet reactivity is important to identify novel aspects of platelet biology and develop targeted therapeutics to prevent bleeding or thrombosis. Current platelet function testing allows for single agonist analysis at a time. The ability to phenotype platelets in a single assay with multiple agonists and adhesion substrates could yield more insights into altered pathways than are feasible with current approaches. We hypothesized platelet electrical resistance (PER) could be used for more comprehensive phenotyping of platelets.
METHODS
Platelets were isolated from male and female healthy donors (age 39.6 ± 6.9) and septic patients (age 44.0 ± 13.5). PER 96-well plates were coated with various substrates, including fibrinogen and collagen. Platelets were added to the coated plates in the presence or absence of thrombin or convulxin. Platelet activation and spreading was monitored by measuring changes in electrical impedance.
RESULTS
Platelets adhesion to fibrinogen and collagen increased impedance. In addition, impedance increased in response to thrombin or convulxin. No changes in impedance were observed in the absence of platelets or when wells were uncoated, indicating changes in impedance were directly due to platelet adhesion and activation. Inhibiting integrin αIIbβ3 decreased impedance when fibrinogen was used as a substrate, consistent with platelet-dependent effects. Platelets from septic patients caused increased impedance compared to healthy donors, demonstrating this assay can be used to assess platelet hyperreactivity.
CONCLUSION
PER can be applied as a high throughput tool to measure platelet reactivity in health and disease, where platelet activation is increased.
Topics: Adult; Blood Platelets; Electric Impedance; Female; Fibrinogen; Humans; Male; Middle Aged; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex
PubMed: 33360636
DOI: 10.1016/j.thromres.2020.12.012 -
Expert Review of Cardiovascular Therapy Jul 2004Platelets play a central role in the pathogenesis of atherosclerosis and thrombosis. Platelet adhesion and aggregate formation are critical events that occur in unstable... (Review)
Review
Platelets play a central role in the pathogenesis of atherosclerosis and thrombosis. Platelet adhesion and aggregate formation are critical events that occur in unstable coronary syndromes. Platelet activation precedes the formation of homotypic and heterotypic aggregates. In the last 10 years, researchers have described the presence of activated platelets in the systemic circulation in various cardiovascular disease states, particularly acute coronary syndromes. This review describes the evidence for platelet activation in acute myocardial ischemic syndromes, describes the pathophysiology responsible for its occurrence, and discusses how platelet activation and reactivity may affect the use of concomitant drug therapies and patient prognosis.
Topics: Fibrinolytic Agents; Humans; Myocardial Ischemia; Platelet Activation; Platelet Membrane Glycoproteins; Syndrome; Treatment Outcome
PubMed: 15225113
DOI: 10.1586/14779072.2.4.535 -
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 -
Journal of Thrombosis and Haemostasis :... Apr 2020Succinate is a Krebs cycle intermediate whose formation is enhanced under metabolic stress, and for which a selective sensor GPR91 has been identified on various cell...
BACKGROUND
Succinate is a Krebs cycle intermediate whose formation is enhanced under metabolic stress, and for which a selective sensor GPR91 has been identified on various cell types including platelets. Platelet-derived eicosanoids play pivotal roles in platelet activation/aggregation, which is key to thrombus formation and progression of atherothrombosis.
OBJECTIVES
This study aims to decipher the molecular mechanism(s) and potential involvement of eicosanoids in succinate enhanced platelet activation/aggregation.
METHODS
We used liquid chromatography-mass spectrometry (LC-MS)/MS-based lipid mediator profiling to identify eicosanoids regulated by succinate. We ran light transmittance aggregometry and flow cytometry to assess platelet aggregation, P-selectin expression, and platelet-polymorphonuclear leukocyte (PMN) adherence. Various pharmacological tools were used to assess the contributions of GPR91 signalling and eicosanoids in platelet aggregation.
RESULTS
Succinate and two types of synthetic non-metabolite GPR91 agonists-cis-epoxysuccinate (cES) and Cmpd131-potentiated platelet aggregation, which was partially blocked by a selective GPR91 antagonist XT1. GPR91 activation increased production of 12-hydroxy-eicosatetraenoic acid (12-HETE), thromboxane (TX) A , and 12-hydroxy-heptadecatrienoic acid (12-HHT) in human platelets, associated with phosphorylation of cytosolic phospholipase A (cPLA ), suggesting increased availability of free arachidonic acid. Blocking 12-HETE and TXA synthesis, or antagonism of the TXA receptor, significantly reduced platelet aggregation enhanced by GPR91 signalling. Moreover, platelet-PMN suspensions challenged with succinate exhibited enhanced transcellular biosynthesis of leukotriene C (LTC ), a powerful proinflammatory vascular spasmogen.
CONCLUSION
Succinate signals through GPR91 to promote biosynthesis of eicosanoids, which contribute to platelet aggregation/activation and potentially vascular inflammation. Hence, GPR91 may be a suitable target for pharmacological intervention in atherothrombotic conditions.
Topics: Blood Platelets; Humans; Leukotriene C4; Platelet Activation; Platelet Aggregation; Thromboxane A2
PubMed: 31930602
DOI: 10.1111/jth.14734 -
Platelets Apr 2021The core structure of the extracellular basement membrane is made up of self-assembling networks of collagen and laminin which associate with each other through the...
The core structure of the extracellular basement membrane is made up of self-assembling networks of collagen and laminin which associate with each other through the bridging adapter proteins including the sulfated monomeric glycoprotein nidogen. While collagen and laminin are known to support platelet adhesion and activation via β1 integrins and glycoprotein (GP) VI, respectively, whether nidogen contributes to platelet activation and hemostasis is unknown. In this study, we demonstrate that recombinant human nidogen-1 supports platelet adhesion and stimulates platelet activation in a phospholipase-C γ-2 (PLCγ2), Src and Syk kinase-dependent manner downstream. Platetet adhesion to nidogen-1 was inhibited by blocking the platelet receptors GPVI and β1 integrins. Platelet adhesion to nidogen-1 activated the IκB kinase (IKK) complex, while pharmacological inhibition of IKK blocked platelet spreading on nidogen. Taken together our results suggest that nidogen may play a redundant role in hemostasis by activating platelets downstream of GPVI.
Topics: Humans; Membrane Glycoproteins; Platelet Activation; Platelet Adhesiveness
PubMed: 32233694
DOI: 10.1080/09537104.2020.1745170