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International Journal of Molecular... Apr 2024Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial... (Review)
Review
Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.
Topics: Humans; Thrombosis; Blood Platelets; Hemostasis; Platelet Activation; Animals; Platelet Adhesiveness; Platelet Aggregation
PubMed: 38732019
DOI: 10.3390/ijms25094800 -
Journal of Cellular and Molecular... Apr 2020HNG, a highly potent mutant of the anti-Alzheimer peptide-humanin, has been shown to protect against ischaemia-reperfusion (I/R) injury. However, the underlying...
HNG, a highly potent mutant of the anti-Alzheimer peptide-humanin, has been shown to protect against ischaemia-reperfusion (I/R) injury. However, the underlying mechanism related to platelet activation remains unknown. We proposed that HNG has an effect on platelet function and thrombus formation. In this study, platelet aggregation, granule secretion, clot retraction, integrin activation and adhesion under flow conditions were evaluated. In mice receiving HNG or saline, cremaster arterial thrombus formation induced by laser injury, tail bleeding time and blood loss were recorded. Platelet microtubule depolymerization was evaluated using immunofluorescence staining. Results showed that HNG inhibited platelet aggregation, P-selectin expression, ATP release, and α β activation and adhesion under flow conditions. Mice receiving HNG had attenuated cremaster arterial thrombus formation, although the bleeding time was not prolonged. Moreover, HNG significantly inhibited microtubule depolymerization, enhanced tubulin acetylation in platelets stimulated by fibrinogen or microtubule depolymerization reagent, nocodazole, and inhibited AKT and ERK phosphorylation downstream of HDAC6 by collagen stimulation. Therefore, our results identified a novel role of HNG in platelet function and thrombus formation potentially through stabilizing platelet microtubules via tubulin acetylation. These findings suggest a potential benefit of HNG in the management of cardiovascular diseases.
Topics: Adenosine Triphosphate; Animals; Blood Coagulation; Blood Platelets; Histone Deacetylase 6; Humans; Intracellular Signaling Peptides and Proteins; Mice; Microtubules; P-Selectin; Platelet Activation; Platelet Aggregation; Signal Transduction; Thrombosis
PubMed: 32174022
DOI: 10.1111/jcmm.15151 -
International Journal of Molecular... Nov 2021Cardiovascular disease is strongly influenced by platelet activation. Platelet activation and thrombus formation at atherosclerotic plaque rupture sites is a dynamic... (Review)
Review
Cardiovascular disease is strongly influenced by platelet activation. Platelet activation and thrombus formation at atherosclerotic plaque rupture sites is a dynamic process regulated by different signaling networks. Therefore, there are now focused efforts to search for novel bioactive compounds which target receptors and pathways in the platelet activation process while preserving normal hemostatic function. The antiplatelet activity of numerous fruits and vegetables and their multiple mechanisms of action have recently been highlighted. In this review, we review the antiplatelet actions of bioactive compounds via key pathways (protein disulfide isomerase, mitogen-activated protein kinases, mitochondrial function, cyclic adenosine monophosphate, Akt, and shear stress-induced platelet aggregation) with no effects on bleeding time. Therefore, targeting these pathways might lead to the development of effective antiplatelet strategies that do not increase the risk of bleeding.
Topics: Animals; Blood Platelets; Hemorrhage; Hemostasis; Humans; Phytochemicals; Plaque, Atherosclerotic; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombosis
PubMed: 34830261
DOI: 10.3390/ijms222212380 -
Oxidative Medicine and Cellular... 2021Recent studies have shown that the red cell distribution width- (RDW-) to-platelet (PLT) count ratio (i.e., RPR) and the mean platelet volume (MPV)/PLT ratio (i.e. MPR)...
OBJECTIVE
Recent studies have shown that the red cell distribution width- (RDW-) to-platelet (PLT) count ratio (i.e., RPR) and the mean platelet volume (MPV)/PLT ratio (i.e. MPR) are more sensitive markers of atherosclerosis-connected risk than RDW and PLT alone. The present study is aimed at investigating the oxidative stress status and these two new markers of platelet activation in two different heart surgery modalities: cardiopulmonary bypass (CPB) and off-pump coronary artery bypass (OPCAB). We also aimed to test the possible relationship between RPR and MPR, respectively, and the severity and complexity of atherosclerotic plaque, measured as Syntax Score. . A total of 107 patients encompassed this prospective study (i.e., 60 patients in CPB group and 47 patients in OPCAB). Blood samples were drawn at several time intervals: before skin incision (t1), immediately after intervention (t2), 6 h (t3), 24 h (t4), 48 h (t5), and 96 h after cessation of the operation (t6).
RESULTS
The values of RPR and MPR were similar in CPB and OPCAB before surgery and started to rise in t2 (i.e., immediately after the intervention). This increase lasted to t5 (i.e., 48 hours after the intervention), when it became the highest. After that, both markers started to regress about the 96 hour after the beginning of surgery. Nominal values of both indices were higher in CPB than in OPCAB in all study points after the surgery. Furthermore, a significantly higher level of antioxidative parameters (i.e., total sulfhydryl groups and paraoxonase 1) in the OPCAB group compared to the CPB group was noted at t5 study point (i.e., 48 hours after the surgery), whereas no significant difference was noted in prooxidant levels (i.e., lipid hydroperoxides and advanced oxidation protein products) between these groups at this study point. MPR and RPR correlated positively with Syntax Score at several study points after the surgery completion. Syntax Score, MPR, and RPR showed good clinical accuracy in surgery-related complication prediction ((AUC = 0.736), 95 CI (0.616-0.856), = 0.003)).
CONCLUSION
When combined, MPV, RDW, and platelet count, such as MPR and RPR, could be good predictors of coronary artery disease status, regarding the aspect of joint inflammation, oxidative stress, and thrombosis.
Topics: Coronary Artery Bypass; Female; Humans; Male; Middle Aged; Oxidative Stress; Platelet Activation
PubMed: 34257821
DOI: 10.1155/2021/8915253 -
International Journal of Cardiology Jan 2017Lipid lowering therapy constitutes the basis of cardiovascular disease therapy. The purpose of this study was to investigate effects of ezetimibe, a selective inhibitor...
PURPOSE
Lipid lowering therapy constitutes the basis of cardiovascular disease therapy. The purpose of this study was to investigate effects of ezetimibe, a selective inhibitor of intestinal cholesterol absorption, on platelets and endothelial cells in an in vitro endothelial cell model.
METHODS
After a 24h incubation period with ezetimibe (concentrations 1, 50, 100 and 1000ng/ml), human umbilical vein endothelial cells (HUVEC) were stimulated for 1h with lipopolysaccharide (LPS) and were then incubated in direct contact with activated platelets. Following this, the expression of CD40L and CD62P on platelets, and the expression of ICAM-1, VCAM-1, uPAR, and MT1-MMP on endothelial cells were measured by flow cytometry. Supernatants were analysed by enzyme linked immunosorbent assay for soluble MCP-1, IL-6 and MMP-1.
RESULTS
The increased expression of uPAR on endothelial cells by proinflammatory stimulation with LPS and by direct endothelial contact with activated platelets was significantly reduced through pre-incubation with 100ng/ml and 1000ng/ml ezetimibe (p<0.05). Platelets directly incubated with ezetimibe but without endothelial cell contact showed significantly reduced CD62P and CD40L surface expression (p<0.05). Ezetimibe had no significant effects on HUVEC expression of MT1-MMP, ICAM-1 and VCAM-1 and on CD40L expression on platelets in direct contact with endothelial cells. Levels of soluble IL-6 in HUVEC supernatants were significantly lower after pre-incubation with ezetimibe.
CONCLUSION
In this in vitro analysis, ezetimibe directly attenuates platelet activation and has significant endothelial cell mediated effects on selected markers of atherosclerosis.
Topics: Anticholesteremic Agents; Cells, Cultured; Dose-Response Relationship, Drug; Ezetimibe; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Platelet Activation; Receptors, Urokinase Plasminogen Activator
PubMed: 27818020
DOI: 10.1016/j.ijcard.2016.09.122 -
Blood Reviews Sep 2019Platelets play a major role in primary hemostasis and thrombus formation. After vascular injury, platelets adhere to injured site and rapidly change their shape that... (Review)
Review
Platelets play a major role in primary hemostasis and thrombus formation. After vascular injury, platelets adhere to injured site and rapidly change their shape that switches the resting platelets to active state. Activated platelets aggregate and secrete biologically active intermediate substances that further potentiate platelet activation through autocrine as well as paracrine mechanisms. The activated platelet expresses certain proteins that are not seen on the resting platelets, thus these proteins serve as markers of platelet activation. Other subsequent events of platelet activation include release of microvesicles and formation of complexes with other circulating cells, like monocytes and neutrophils. Platelet activation markers are useful tools in evaluating risk factors of thrombosis in a variety of clinical conditions. Increased platelet activation has been associated with various pathological conditions such as acute coronary syndrome, stroke, peripheral vascular disease and other inflammatory diseases. The advancement in technologies helps in determining the status of platelet activation in such clinical conditions. This article focuses on the sources, mechanism and diagnosis of platelet activation and their clinical implications.
Topics: Humans; Platelet Activation; Risk Factors; Thrombosis
PubMed: 31133440
DOI: 10.1016/j.blre.2019.05.007 -
Medicinal Chemistry (Shariqah (United... 2016Platelets are involved in haemostasis and vessel integrity under physiologic conditions, and in thrombosis under disease states. Platelet activation upon stimulation... (Review)
Review
Platelets are involved in haemostasis and vessel integrity under physiologic conditions, and in thrombosis under disease states. Platelet activation upon stimulation with various agonists in vitro and in vivo, is strongly dependent on an increase of intracellular Ca(2+) concentration. The latter results from Ca(2+) release by the dense tubular system (DTS), and Ca(2+) entry from the extracellular space. Recent advances in identification of the molecular mechanisms involved in these processes are described in this review, along with potential targets for pharmacologic interventions in disease states.
Topics: Animals; Blood Platelets; Calcium; Fibrinolytic Agents; Humans; Platelet Activation; Thrombosis
PubMed: 26411604
DOI: 10.2174/157340641202160208195923 -
Clinical Hemorheology and... 2023To investigate the clinical value of platelet and inflammatory factor activation in vascular endothelial injury in hypertension.
OBJECTIVE
To investigate the clinical value of platelet and inflammatory factor activation in vascular endothelial injury in hypertension.
METHODS
A total of 120 hypertension patients diagnosed in our hospital from December 2019 to June 2021 were enrolled as study objects (Hypertension group); besides, another cohort of 60 healthy people undergoing physical examination at the same period were recruited as the controls (Control group). Next, the baseline clinical characteristics of subjects in the two groups were recorded and compared. Specifically, a hematology analyzer was adopt for detecting the mean platelet volume (MPV), platelet distribution width (PDW) and platelet hematocrit (PCT); ELISA for the level of IL-6, IL-8 and TNF-α; PHILIPS EPIQ 7 C (a device assessing endothelial vasodilator function in a non-invasive fashion) for reactive hyperemia index (RHI); univariate and multivariate regression analysis for risk factors triggering endothelial dysfunction; and Spearman correlation analysis for the correlation of platelet activation indicators and inflammatory factor level with vascular endothelial function.
RESULTS
Compared with the Control group, the patients in the Hypertension group exhibited higher levels of MPV, PDW, PCT, inflammatory factors (IL-6, IL-8 and TNF-α) and lower RHI. Moreover, Spearman correlation analysis showed a significant negative correlation of MPV, PDW, PCT, IL-6, IL-8 and TNF-α level with RHI level. In addition, univariate and multivariate regression analysis presented that MPV, PCT, IL-8 and TNF-α were risk factors for vascular endothelial dysfunction.
CONCLUSION
The activation of platelet and inflammatory factor is closely related to vascular endothelial function injury in patients with hypertension. To be specifically, platelet and inflammatory factor activation can effectively reflect the vascular endothelial function injury in patients with hypertension and has high clinical value.
Topics: Humans; Interleukin-6; Interleukin-8; Tumor Necrosis Factor-alpha; Platelet Count; Blood Platelets; Mean Platelet Volume; Platelet Activation; Essential Hypertension; Hypertension
PubMed: 36463438
DOI: 10.3233/CH-221638 -
Undersea & Hyperbaric Medicine :... 2020Platelets are the most easily altered type of peripheral blood cell in decompression sickness (DCS), which can feature decreased platelet count and the appearance of...
Platelets are the most easily altered type of peripheral blood cell in decompression sickness (DCS), which can feature decreased platelet count and the appearance of platelet microparticles in plasma. We hypothesized that DCS results in platelet activation in the bloodstream. The present study was carried out on 45 rabbits. The platelet count and concentration of plasma platelet markers were determined in 35 rabbits; the platelet shape was observed under scanning electron microscope in 10 rabbits. All indexes were collected at two points: 24 hours before the simulated dive and 30 minutes after the simulated dive. Platelet count decreased noticeably after DCS, from 380.10 ± 73.61 (G/L) to 330.23 ± 115.72 (G/L), a change of approximately -13.49 ± 25.57 (%). Platelet count was further decreased in the severe DCS group (a change of -45.99 ± 18.57%). Platelet count after DCS was proportional to the survival time of the rabbits after DCS. The concentration of two plasma platelet markers (PF4 and BTG) did not demonstrate statistically significant change at 30 minutes after DCS. However, platelet shape was changed, and the following features were observed: oblong, distortion, flattening shape, sticking together, mixing of membrane, and abundance of pseudopods with a 100- to 200-nm diameter. We conclude there is platelet activation in the bloodstream in cases of DCS.
Topics: Animals; Blood Platelets; Cell Shape; Decompression Sickness; Platelet Activation; Platelet Count; Platelet-Rich Plasma; Pressure; Rabbits; Time Factors
PubMed: 33227836
DOI: 10.22462/10.12.2020.9 -
PloS One 2016Regulators of G protein signaling (RGS) proteins act as GTPase activating proteins to negatively regulate G protein-coupled receptor (GPCR) signaling. Although several...
Regulators of G protein signaling (RGS) proteins act as GTPase activating proteins to negatively regulate G protein-coupled receptor (GPCR) signaling. Although several RGS proteins including RGS2, RGS16, RGS10, and RGS18 are expressed in human and mouse platelets, the respective unique function(s) of each have not been fully delineated. RGS10 is a member of the D/R12 subfamily of RGS proteins and is expressed in microglia, macrophages, megakaryocytes, and platelets. We used a genetic approach to examine the role(s) of RGS10 in platelet activation in vitro and hemostasis and thrombosis in vivo. GPCR-induced aggregation, secretion, and integrin activation was much more pronounced in platelets from Rgs10-/- mice relative to wild type (WT). Accordingly, these mice had markedly reduced bleeding times and were more susceptible to vascular injury-associated thrombus formation than control mice. These findings suggest a unique, non-redundant role of RGS10 in modulating the hemostatic and thrombotic functions of platelets in mice. RGS10 thus represents a potential therapeutic target to control platelet activity and/or hypercoagulable states.
Topics: Adenosine Diphosphate; Animals; Bleeding Time; Blood Platelets; Blotting, Western; Flow Cytometry; Hemostasis; Mice, Knockout; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; RGS Proteins; Receptors, G-Protein-Coupled; Signal Transduction; Thrombosis
PubMed: 27829061
DOI: 10.1371/journal.pone.0165984