-
BioMed Research International 2022Evodia rutaecarpa has multiple pharmacological effects and is widely used in the prevention and treatment of migraine, diabetes, cardiovascular disease, cancer, and...
Evodia rutaecarpa has multiple pharmacological effects and is widely used in the prevention and treatment of migraine, diabetes, cardiovascular disease, cancer, and other chronic diseases; however, the pharmacological effects of its active compound evodiamine (Evo) have not been thoroughly investigated. The purpose of this study was to investigate the effects of Evo on antiplatelet activation and thrombosis. We discovered that Evo effectively inhibited collagen-induced platelet activation but had no effect on platelet aggregation caused by activators such as thrombin, ADP, and U46619. Second, we found that Evo effectively inhibited the release of platelet granules induced by collagen. Finally, evodiamine inhibits the transduction of the SFKs/Syk/Akt/PLC2 activation pathway in platelets. According to in vivo studies, Evo significantly prolonged the mesenteric thromboembolism induced by ferric chloride and had no discernible effect on the coagulation function of mice. In conclusion, the antiplatelet and thrombotic effects of Evo discovered in this study provide an experimental basis for the investigation of the pharmacological mechanisms of Evo and the development of antiplatelet drugs.
Topics: Animals; Blood Platelets; Collagen; Mice; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Quinazolines; Thrombosis
PubMed: 35937403
DOI: 10.1155/2022/4893859 -
Journal of Biomechanical Engineering Apr 2022Shear-induced platelet activation is one of the critical outcomes when blood is exposed to elevated shear stress. Excessively activated platelets in the circulation can...
Shear-induced platelet activation is one of the critical outcomes when blood is exposed to elevated shear stress. Excessively activated platelets in the circulation can lead to thrombus formation and platelet consumption, resulting in serious adverse events such as thromboembolism and bleeding. While experimental observations reveal that it is related to the shear stress level and exposure time, the underlying mechanism of shear-induced platelet activation is not fully understood. Various models have been proposed to relate shear stress levels to platelet activation, yet most are modified from the empirically calibrated power-law model. Newly developed multiscale platelet models are tested as a promising approach to capture a single platelet's dynamic shape during activation, but it would be computationally expensive to employ it for a large-scale analysis. This paper summarizes the current numerical models used to study the shear-induced platelet activation and their computational applications in the risk assessment of a particular flow pattern and clot formation prediction.
Topics: Blood Platelets; Humans; Hydrodynamics; Platelet Activation; Stress, Mechanical; Thrombosis
PubMed: 34529037
DOI: 10.1115/1.4052460 -
Interventional Cardiology Clinics Jan 2017Hemostasis requires tightly regulated interaction of the coagulation system, platelets, blood cells, and vessel wall components at a site of vascular injury.... (Review)
Review
Hemostasis requires tightly regulated interaction of the coagulation system, platelets, blood cells, and vessel wall components at a site of vascular injury. Dysregulation of this response may result in excessive bleeding if the response is impaired, and pathologic thrombosis with vessel occlusion and tissue ischemia if the response is robust. Studies have elucidated the major molecular signaling pathways responsible for platelet activation and aggregation. Antithrombotic agents targeting these pathways are in clinical use. This review summarizes research examining mechanisms by which these multiple platelet signaling pathways are integrated at a site of vascular injury to produce an optimal hemostatic response.
Topics: Animals; Blood Coagulation; Blood Platelets; Humans; Platelet Activation; Platelet Aggregation; Thrombosis; Vascular System Injuries
PubMed: 27886814
DOI: 10.1016/j.iccl.2016.08.001 -
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 -
Pannexin-1 Activation by Phosphorylation Is Crucial for Platelet Aggregation and Thrombus Formation.International Journal of Molecular... May 2022Pannexin-1 (PANX1) is a transmembrane protein that forms ion channels as hexamers on the plasma membrane. Electrophysiological studies prove that PANX1 has a high...
Pannexin-1 (PANX1) is a transmembrane protein that forms ion channels as hexamers on the plasma membrane. Electrophysiological studies prove that PANX1 has a high conductance for adenosine triphosphate (ATP), which plays an important role as a signal molecule in platelet activation. Recently, it was shown that PANX1 channels modulate platelet functions. To date, it remains unclear how PANX1 channels are activated and which signaling mechanisms are responsible for impaired hemostasis and thrombosis. Analysis of PANX1 phosphorylation at Tyr and Tyr, and the impact on platelet activation and thrombus formation using genetically modified platelets or pharmacological inhibitors. Platelet activation via immunoreceptor tyrosine-based activation motif (ITAM) coupled, G Protein-Coupled Receptors (GPCR) and thromboxane receptor (TP)-mediated signaling pathways led to increased PANX1 phosphorylation at Tyr and Tyr. We identified the Src-GPVI signaling axes as the main pathway inducing PANX1 activation, while PKC and Akt play a minor role. PANX1 channels function as ATP release channels in platelets to support arterial thrombus formation. PANX1 activation is regulated by phosphorylation at Tyr and Tyr following platelet activation. These results suggest an important role of PANX1 in hemostasis and thrombosis by releasing extracellular ATP to support thrombus formation.
Topics: Adenosine Triphosphate; Animals; Blood Platelets; Connexins; Humans; Mice; Nerve Tissue Proteins; Phosphorylation; Platelet Activation; Platelet Aggregation; Thrombosis
PubMed: 35563450
DOI: 10.3390/ijms23095059 -
Current Medicinal Chemistry 2016Nanomaterials can get into the blood circulation after injection or by release from implants but also by permeation of the epithelium after oral, respiratory or dermal... (Review)
Review
Nanomaterials can get into the blood circulation after injection or by release from implants but also by permeation of the epithelium after oral, respiratory or dermal exposure. Once in the blood, they can affect hemostasis, which is usually not intended. This review addresses effects of biological particles and engineered nanomaterials on hemostasis. The role of platelets and coagulation in normal clotting and the interaction with the immune system are described. Methods to identify effects of nanomaterials on clotting and results from in vitro and in vivo studies are summarized and the role of particle size and surface properties discussed. The literature overview showed that mainly pro-coagulative effects of nanomaterials have been described. In vitro studies suggested stronger effects of smaller than of larger NPs on coagulation and a greater importance of material than of surface charge. For instance, carbon nanotubes, polystyrene particles, and dendrimers inferred with clotting independent from their surface charge. Coating of particles with polyethylene glycol was able to prevent interaction with clotting by some particles, while it had no effect on others and the more recently developed bio-inspired surfaces might help to design coatings for more biocompatible particles. The mainly pro-coagulative action of nanoparticles could present a particular risk for individuals affected by common diseases such as diabetes, cancer, and cardiovascular diseases. Under standardized conditions, in vitro assays using human blood appear to be a suitable tool to study mechanisms of interference with hemostasis and to optimize hemocompatibility of nanomaterials.
Topics: Biocompatible Materials; Blood Coagulation; Hemostasis; Humans; Nanoparticles; Platelet Activation
PubMed: 26063498
DOI: 10.2174/0929867323666160106151428 -
Cellular Physiology and Biochemistry :... 2017The retinoid X receptor (RXRs) stimulator Bexarotene ((4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl] benzoic acid) is used for the treatment of...
BACKGROUND/AIMS
The retinoid X receptor (RXRs) stimulator Bexarotene ((4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl] benzoic acid) is used for the treatment of several malignancies. Bexarotene is at least in part effective by stimulation of apoptosis of tumor cells. Moreover, Bexarotene triggers eryptosis, the suicidal death of erythrocytes. Similar to erythrocytes, blood platelets lack nuclei but are nevertheless able to enter an apoptosis-like phenotype, characterized by caspase activation, cell shrinkage and cell membrane scrambling with phospha-tidylserine translocation to the cell surface. Platelet apoptosis is triggered by increase of cytosolic Ca2+-activity ([Ca2+]i), which further leads to degranulation and integrin activation. Platelet activation and apoptosis could be elicited by thrombin or collagen related peptide (CRP). The present study explored whether treatment of platelets with bexarotene modifies platelet activation and apoptosis following exposure to thrombin or CRP.
METHODS
Platelets isolated from wild-type mice were exposed for 30 minutes to bexarotene (6 µg/ml) without or with an additional treatment with thrombin (0.01 U/ml) or CRP (2 µg/ml or 5 µg/ml). Flow cytometry was employed to estimate cytosolic Ca2+-activity ([Ca2+]i) from Fluo-3 fluorescence, platelet degranulation from P-selectin abundance, integrin activation from αIIbβ3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, and relative platelet volume from forward scatter.
RESULTS
In the absence of thrombin or CRP, the administration of bexarotene slightly but significantly increased [Ca2+]i, but did not significantly modify P-selectin abundance, activated αIIbβ3 integrin, annexin-V-binding, cell volume, or caspase activity. Exposure of platelets to thrombin or CRP was followed by significant increase of [Ca2+]i, P-selectin abundance, active αIIbβ3 integrin, annexin-V-binding, and caspase activity. The effects of thrombin on [Ca2+]i, annexin-V-binding, cell volume, and caspase activity as well as the effects of CRP on [Ca2+]i, P-selectin abundance, activated αIIbβ3 integrin, annexin-V-binding, cell volume, and caspase activity were significantly augmented in the presence of bexarotene.
CONCLUSIONS
Bexarotene sensitizes blood platelets for thrombin and/or CRP induced activation and apoptosis.
Topics: Animals; Apoptosis; Bexarotene; Blood Platelets; Calcium; Collagen; Erythrocytes; Flow Cytometry; Hemolysis; Humans; Mice; Platelet Activation; Platelet Glycoprotein GPIIb-IIIa Complex; Reactive Oxygen Species; Tetrahydronaphthalenes; Thrombin
PubMed: 28641286
DOI: 10.1159/000478627 -
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 -
Blood Advances Oct 2023Blood platelets undergo several successive motor-driven reorganizations of the cytoskeleton when they are recruited to an injured part of a vessel. These reorganizations...
Blood platelets undergo several successive motor-driven reorganizations of the cytoskeleton when they are recruited to an injured part of a vessel. These reorganizations take place during the platelet activation phase, the spreading process on the injured vessel or between fibrin fibers of the forming clot, and during clot retraction. All these steps require a lot of energy, especially the retraction of the clot when platelets develop strong forces similar to those of muscle cells. Platelets can produce energy through glycolysis and mitochondrial respiration. However, although resting platelets have only 5 to 8 individual mitochondria, they produce adenosine triphosphate predominantly via oxidative phosphorylation. Activated, spread platelets show an increase in size compared with resting platelets, and the question arises as to where the few mitochondria are located in these larger platelets. Using expansion microscopy, we show that the number of mitochondria per platelet is increased in spread platelets. Live imaging and focused ion beam-scanning electron microscopy suggest that a mitochondrial fission event takes place during platelet activation. Fission is Drp1 dependent because Drp1-deficient platelets have fused mitochondria. In nucleated cells, mitochondrial fission is associated with a shift to a glycolytic phenotype, and using clot retraction assays, we show that platelets have a more glycolytic energy production during clot retraction and that Drp1-deficient platelets show a defect in clot retraction.
Topics: Platelet Activation; Blood Platelets; Clot Retraction; Oxidative Phosphorylation; Mitochondria
PubMed: 37624769
DOI: 10.1182/bloodadvances.2023010423 -
Cirugia Y Cirujanos 2020Platelets, in addition to participating in atherosclerosis, play a very active role in the immune response of this disease since they have the ability to interact with... (Review)
Review
Platelets, in addition to participating in atherosclerosis, play a very active role in the immune response of this disease since they have the ability to interact with various inflammatory cells, in addition to secreting cytokines, chemokines, growth factors, etc. The functions of platelets go beyond their interaction with the endothelium, as they participate in creating an inflammatory environment, which contributes to the loss of homeostasis. On the other hand, platelet-derived microparticles induce the activation of other platelets, of endothelial cells and in recruiting leukocytes. For all the above, platelets and the inflammatory environment can be considered as possible therapeutic targets to prevent the development of atherosclerosis and the events associated with it.
Topics: Atherosclerosis; Cell-Derived Microparticles; Endothelium, Vascular; Humans; Inflammation; Platelet Activation
PubMed: 32116325
DOI: 10.24875/CIRU.19000725