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Seminars in Thrombosis and Hemostasis Jul 2024This article represents a republication of an article originally published in STH in 2005. This republication is to help celebrate 50 years of publishing for STH. The... (Review)
Review
This article represents a republication of an article originally published in STH in 2005. This republication is to help celebrate 50 years of publishing for STH. The original abstract follows.Platelets are specialized blood cells that play central roles in physiologic and pathologic processes of hemostasis, inflammation, tumor metastasis, wound healing, and host defense. Activation of platelets is crucial for platelet function that includes a complex interplay of adhesion and signaling molecules. This article gives an overview of the activation processes involved in primary and secondary hemostasis, for example, platelet adhesion, platelet secretion, platelet aggregation, microvesicle formation, and clot retraction/stabilization. In addition, activated platelets are predominantly involved in cross-talk to other blood and vascular cells. Stimulated "sticky" platelets enable recruitment of leukocytes at sites of vascular injury under high shear conditions. Platelet-derived microparticles as well as soluble adhesion molecules, sP-selectin and sCD40L, shed from the surface of activated platelets, are capable of activating, in turn, leukocytes and endothelial cells. This article focuses further on the new view of receptor-mediated thrombin generation of human platelets, necessary for the formation of a stable platelet-fibrin clot during secondary hemostasis. Finally, special emphasis is placed on important stimulatory and inhibitory signaling pathways that modulate platelet function.
Topics: Humans; Blood Platelets; Hemostasis; Platelet Activation; Platelet Adhesiveness; Signal Transduction; Platelet Aggregation
PubMed: 38086407
DOI: 10.1055/s-0043-1777305 -
European Heart Journal Jan 2024The leading cause of heart disease in developed countries is coronary atherosclerosis, which is not simply a result of ageing but a chronic inflammatory process that can... (Review)
Review
The leading cause of heart disease in developed countries is coronary atherosclerosis, which is not simply a result of ageing but a chronic inflammatory process that can lead to acute clinical events upon atherosclerotic plaque rupture or erosion and arterial thrombus formation. The composition and location of atherosclerotic plaques determine the phenotype of the lesion and whether it is more likely to rupture or to erode. Although plaque rupture and erosion both initiate platelet activation on the exposed vascular surface, the contribution of platelets to thrombus formation differs between the two phenotypes. In this review, plaque phenotype is discussed in relation to thrombus composition, and an overview of important mediators (haemodynamics, matrix components, and soluble factors) in plaque-induced platelet activation is given. As thrombus formation on disrupted plaques does not necessarily result in complete vessel occlusion, plaque healing can occur. Therefore, the latest findings on plaque healing and the potential role of platelets in this process are summarized. Finally, the clinical need for more effective antithrombotic agents is highlighted.
Topics: Humans; Plaque, Atherosclerotic; Coronary Artery Disease; Blood Platelets; Rupture, Spontaneous; Thrombosis; Biology
PubMed: 37940193
DOI: 10.1093/eurheartj/ehad720 -
International Immunopharmacology Jul 2023Dimethyl fumarate (DMF) is a methyl ester of fumaric acid and has been approved for treating multiple sclerosis (MS) and psoriasis due to anti-inflammatory effect. There...
BACKGROUND
Dimethyl fumarate (DMF) is a methyl ester of fumaric acid and has been approved for treating multiple sclerosis (MS) and psoriasis due to anti-inflammatory effect. There is a close association between platelets and the pathogenesis of MS. Whether DMF affects platelet function remains unclear. Our study intends to evaluate DMF's effect on platelet function.
METHODS
Washed human platelets were treated with different concentrations of DMF (0, 50, 100 and 200 μM) at 37 °C for 1 h followed by analysis of platelet aggregation, granules release, receptors expression, spreading and clot retraction. In addition, mice received intraperitoneal injection of DMF (15 mg/kg) to assess tail bleeding time, arterial and venous thrombosis.
RESULTS
DMF significantly inhibited platelet aggregation and the release of dense/alpha granules in response to collagen-related peptide (CRP) or thrombin stimulation dose-dependently without altering the expression of platelet receptors α, GPIbα, and GPVI. In addition, DMF-treated platelets presented significantly reduced spreading on collagen or fibrinogen and thrombin-mediated clot retraction along with the decreased phosphorylation of c-Src and PLCγ2. Moreover, administration of DMF into mice significantly prolonged the tail bleeding time and impaired arterial and venous thrombus formation. Furthermore, DMF reduced the generation of intracellular reactive oxygen species and calcium mobilization, and inhibited NF-κB activation and the phosphorylation of ERK1/2, p38 and AKT.
CONCLUSION
DMF inhibits platelet function and arterial/venous thrombus formation. Considering the presence of thrombotic events in MS, our study indicates that DMF treatment for patients with MS might obtain both anti-inflammatory and anti-thrombotic benefits.
Topics: Humans; Mice; Animals; Platelet Activation; Fibrinolytic Agents; Dimethyl Fumarate; Thrombin; Platelet Aggregation; Blood Platelets; Thrombosis
PubMed: 37245302
DOI: 10.1016/j.intimp.2023.110381 -
Journal of Thrombosis and Haemostasis :... Nov 2023Aspirin and platelet P2Y inhibitors, such as ticagrelor, suboptimally inhibit microvascular thrombosis during ST-elevation myocardial infarction. Glycoprotein (GP)...
BACKGROUND
Aspirin and platelet P2Y inhibitors, such as ticagrelor, suboptimally inhibit microvascular thrombosis during ST-elevation myocardial infarction. Glycoprotein (GP) IIb/IIIa inhibitors may further inhibit this but cause excessive bleeding.
OBJECTIVES
We investigated whether combination of glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor provides additional antithrombotic effects, as GPVI has a critical role in atherothrombosis but minimal involvement in hemostasis.
METHODS
We investigated the effects of glenzocimab (monoclonal antibody Fab fragment) using blood from healthy donors and patients with acute coronary syndrome treated with aspirin and ticagrelor. Platelets were stimulated with multiple agonists, including atherosclerotic plaque, from patients undergoing carotid endarterectomy.
RESULTS
Aspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation by 48% compared with control (34 ± 3 vs 65 ± 4 U; P < .001). Plaque-induced platelet aggregation, adhesion, secretion, and activation were critically dependent on GPVI activation. Glenzocimab alone reduced plaque-induced aggregation by 75% compared with control (16 ± 4 vs 65 ± 4 U; P < .001) and by >95% when combined with aspirin and ticagrelor (3 ± 1 vs 65 ± 4 U; P < .001). Glenzocimab reduced platelet aggregation, adhesion, and thrombin generation when added to blood of aspirin- and ticagrelor-treated patients with acute coronary syndrome. Glenzocimab shared several antithrombotic effects with the GPIIb/IIIa inhibitor eptifibatide with less effect on general hemostasis assessed by rotational thromboelastometry. In a murine intravital model of ST-elevation myocardial infarction, genetic depletion of GPVI reduced microvascular thrombosis.
CONCLUSION
Addition of glenzocimab to aspirin and ticagrelor enhances platelet inhibition via multiple mechanisms of atherothrombosis. Compared with a GPIIb/IIIa inhibitor, glenzocimab shares multiple antithrombotic effects, with less inhibition of mechanisms involved in general hemostasis.
Topics: Humans; Animals; Mice; Platelet Aggregation Inhibitors; Ticagrelor; Plaque, Atherosclerotic; Fibrinolytic Agents; Acute Coronary Syndrome; ST Elevation Myocardial Infarction; Platelet Activation; Aspirin; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombosis
PubMed: 37541591
DOI: 10.1016/j.jtha.2023.07.018 -
Angiology Jul 2023Hypertension (HT) is a common chronic disease that often causes target-organ damage and severe complications, contributing to cardiovascular morbidity and mortality...
Hypertension (HT) is a common chronic disease that often causes target-organ damage and severe complications, contributing to cardiovascular morbidity and mortality worldwide. Accumulating evidence suggests that inflammation plays a prominent role in the initiation and progression of HT. Multiple inflammatory biomarkers have been proposed to predict HT. Several new hematological parameters can reflect the inflammatory response and platelet activation. The major advantage of hematological parameters over conventional inflammatory markers is that they are relatively inexpensive and easily obtained from routine blood tests. Numerous studies have investigated several hematological parameters for their utility as predictive biomarkers for the diagnosis and prognosis of HT. Among them, the neutrophil to lymphocyte ratio (NLR), monocyte to high density lipoprotein cholesterol ratio (MHR), red cell distribution width (RDW), platelet to lymphocyte ratio (PLR), mean platelet volume (MPV), platelet distribution width (PDW), and systemic immune-inflammation index (SII) have recently received attention. We searched PubMed and Embase databases (up to September 18, 2022) to assess the relationships between hematological parameters and HT. This review discusses the diagnostic and prognostic value of these hematological parameters in HT, providing an important basis for early screening, risk stratification, and optimal management of hypertensive patients.
PubMed: 37459606
DOI: 10.1177/00033197231190423 -
Prostaglandins & Other Lipid Mediators Dec 2023Platelets are one of the key mediators in thrombosis as well as in the progression of many diseases. An increase in platelet activation and a decrease in platelet count... (Review)
Review
Platelets are one of the key mediators in thrombosis as well as in the progression of many diseases. An increase in platelet activation and a decrease in platelet count is associated with a plethora of liver diseases. In non-alcoholic fatty liver disease (NAFLD), platelets are highly activated and participate in the disease progression by enhancing the pro-thrombotic and pro-inflammatory state. Some altered platelet parameters such as mean platelet volume, plateletcrits, and platelet distribution width, aspartate transaminase to platelet ratio index, liver stiffness to platelet ratio and red cell distribution width to platelet ratio were found to be associated with NAFLD disease. Further, platelet contributes to the progression of cardiovascular complications in NAFLD is gaining the researcher's attention. An elevated mean platelet volume is known to enhance the risk of stroke, atherosclerosis, thrombosis, and myocardial infarction in NAFLD. Evidence also suggested that modulation in platelet function using aspirin, ticlopidine, and cilostazol help in controlling the NAFLD progression. Future research should focus on antiplatelet therapy as a treatment strategy that can control platelet activation in NAFLD as well as its cardiovascular risk. In the present review, we have detailed the role of platelets in NAFLD and its cardiovascular complications. We further aimed to highlight the growing need for antiplatelet therapy in NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Platelet Aggregation Inhibitors; Blood Platelets; Platelet Activation; Thrombosis; Liver
PubMed: 37479133
DOI: 10.1016/j.prostaglandins.2023.106766 -
Journal of Thrombosis and Haemostasis :... Dec 2023Upon vessel injury, platelets adhere to exposed matrix constituents via specific membrane receptors, including the von Willebrand factor receptor glycoprotein...
BACKGROUND
Upon vessel injury, platelets adhere to exposed matrix constituents via specific membrane receptors, including the von Willebrand factor receptor glycoprotein (GP)Ib-IX-V complex and integrins β1 and β3. In platelets, the Fes/CIP4-homology Bin-Amphiphysin-Rvs protein PACSIN2 associates with the cytoskeletal and scaffolding protein filamin A (FlnA), linking GPIbα and integrins to the cytoskeleton.
OBJECTIVES
Here we investigated the role of PACSIN2 in platelet function.
METHODS
Platelet parameters were evaluated in mice lacking PACSIN2 and platelet integrin β1.
RESULTS
Pacsin2 mice displayed mild thrombocytopenia, prolonged bleeding time, and delayed thrombus formation in a ferric chloride-mediated carotid artery injury model, which was normalized by injection of control platelets. Pacsin2 platelets formed unstable thrombi that embolized abruptly in a laser-induced cremaster muscle injury model. Pacsin2 platelets had hyperactive integrin β1, as evidenced by increased spreading onto surfaces coated with the collagen receptor α2β1-specific peptide GFOGER and increased binding of the antibody 9EG7 directed against active integrin β1. By contrast, Pacsin2 platelets had normal integrin αIIbβ3 function and expressed P-selectin normally following stimulation through the collagen receptor GPVI or with thrombin. Deletion of platelet integrin β1 in Pacsin2 mice normalized platelet count, hemostasis, and thrombus formation. A PACSIN2 peptide mimicking the FlnA-binding site mediated the pull-down of a FlnA rod 2 construct by integrin β7, a model for integrin β-subunits.
CONCLUSIONS
Pacsin2 mice displayed severe thrombus formation defects due to hyperactive platelet integrin β1. The data suggest that PACSIN2 binding to FlnA negatively regulates platelet integrin β1 hemostatic function.
Topics: Animals; Mice; Blood Platelets; Hemostasis; Hemostatics; Integrin beta1; Peptides; Platelet Activation; Platelet Adhesiveness; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Membrane Glycoproteins; Receptors, Collagen; Thrombosis
PubMed: 37678551
DOI: 10.1016/j.jtha.2023.08.026 -
Platelets Dec 2023Platelets play many roles in the vasculature ensuring proper hemostasis and maintaining integrity. These roles are facilitated, in part, by cargo molecules released from...
Platelets play many roles in the vasculature ensuring proper hemostasis and maintaining integrity. These roles are facilitated, in part, by cargo molecules released from platelet granules via oluble SF ttachment rotein eceptor (SNARE) mediated membrane fusion, which is controlled by several protein-protein interactions. Chaperones have been characterized for t-SNAREs (. Munc18b for Syntaxin-11), but none have been clearly identified for v-SNAREs. α-Synuclein has been proposed as a v-SNARE chaperone which may affect SNARE-complex assembly, fusion pore opening, and thus secretion. Despite its abundance and that it is the only isoform present, α-synuclein's role in platelet secretion is uncharacterized. In this study, immunofluorescence showed that α-synuclein was present on punctate structures that co-stained with markers for α-granules and lysosomes and in a cytoplasmic pool. We analyzed the phenotype of α-synuclein mice and their platelets. Platelets from knockout mice had a mild, agonist-dependent secretion defect but aggregation and spreading were unaffected. Consistently, thrombosis/hemostasis were unaffected in the tail-bleeding, FeCl carotid injury and jugular vein puncture models. None of the platelet secretory machinery examined, . the v-SNAREs, were affected by α-synuclein's loss. The results indicate that, despite its abundance, α-synuclein has only a limited role in platelet function and thrombosis.
Topics: Animals; Mice; alpha-Synuclein; Blood Platelets; Cytoplasmic Granules; Exocytosis; Mice, Knockout; Platelet Activation; Protein Isoforms; SNARE Proteins; Thrombosis
PubMed: 37927048
DOI: 10.1080/09537104.2023.2267147 -
Cell Reports Methods Jul 2023A characteristic clinical complication in cancer patients is the frequent incidence of thrombotic events. Numerous studies have shown hyperactive/activated platelets to...
A characteristic clinical complication in cancer patients is the frequent incidence of thrombotic events. Numerous studies have shown hyperactive/activated platelets to be a critical earlier trigger for cancer-associated thrombus formation. However, there currently is no viable approach to monitor specific changes in tumor-associated platelet activity. Here, we describe a chromatograph-like microfluidic device that is highly sensitive to the activity status of peripheral circulating platelets in both tumor-bearing mice and clinical cancer patients. Our results show a strongly positive correlation between platelet activation status and tumor progression. Six-month follow-up data from advanced cancer patients reveal positive links between platelet activity level and thrombus occurrence rate, with a high predictive capacity of thrombotic events (AUC = 0.842). Our findings suggest that circulating platelet activity status determined by this microfluidic device exhibits sensitive, predictive potential for thrombotic events in cancer patients for directing well-timed antithrombosis treatment.
Topics: Mice; Animals; Blood Platelets; Platelet Activation; Thrombosis; Neoplasms
PubMed: 37533637
DOI: 10.1016/j.crmeth.2023.100513 -
Gas plasma-induced platelet activation corresponds to reactive species profiles and lipid oxidation.Free Radical Biology & Medicine Oct 2023Surgical-induced hemostasis is a critical step in the closure of incisions, which is frequently achieved via electrocauterization and subsequent tissue necrotization....
Surgical-induced hemostasis is a critical step in the closure of incisions, which is frequently achieved via electrocauterization and subsequent tissue necrotization. The latter is associated with postoperative complications. Recent in vivo work suggested reactive species-producing gas plasma technology as a pro-homeostatic agent acting via platelet activation. However, it remained elusive how platelet activation is linked to lipid and protein oxidation and the reactive species compositions. A direct relation between the reactive species composition and platelet activation was revealed by assessing the production of several reactive species and by using antioxidants. In addition, platelet lipidome and proteome analysis identified significantly regulated key lipids in the platelet activation pathway, such as diacylglycerols and phosphatidylinositol as well as oxylipins like thromboxanes. Lipid oxidation products mainly derived from phosphatidylethanolamine and phosphatidylserine species were observed at modest levels. In addition, oxidative post-translational modifications were identified on key proteins of the hemostasis machinery. This study provides new insights into oxidation-induced platelet activation in general and suggests a potential role of those processes in gas plasma-mediated hemostasis in particular.
Topics: Platelet Activation; Blood Platelets; Oxidation-Reduction; Antioxidants; Lipids
PubMed: 37490986
DOI: 10.1016/j.freeradbiomed.2023.07.024