-
Cancer Metastasis Reviews Mar 2014Human platelets arise as subcellular fragments of megakaryocytes in bone marrow. The physiologic demand, presence of disease such as cancer, or drug effects can regulate... (Review)
Review
Human platelets arise as subcellular fragments of megakaryocytes in bone marrow. The physiologic demand, presence of disease such as cancer, or drug effects can regulate the production circulating platelets. Platelet biology is essential to hemostasis, vascular integrity, angiogenesis, inflammation, innate immunity, wound healing, and cancer biology. The most critical biological platelet response is serving as "First Responders" during the wounding process. The exposure of extracellular matrix proteins and intracellular components occurs after wounding. Numerous platelet receptors recognize matrix proteins that trigger platelet activation, adhesion, aggregation, and stabilization. Once activated, platelets change shape and degranulate to release growth factors and bioactive lipids into the blood stream. This cyclic process recruits and aggregates platelets along with thrombogenesis. This process facilitates wound closure or can recognize circulating pathologic bodies. Cancer cell entry into the blood stream triggers platelet-mediated recognition and is amplified by cell surface receptors, cellular products, extracellular factors, and immune cells. In some cases, these interactions suppress immune recognition and elimination of cancer cells or promote arrest at the endothelium, or entrapment in the microvasculature, and survival. This supports survival and spread of cancer cells and the establishment of secondary lesions to serve as important targets for prevention and therapy.
Topics: Animals; Blood Platelets; Cell Communication; Hemostasis; Humans; Models, Biological; Neoplasms; Platelet Activation; Prognosis
PubMed: 24696047
DOI: 10.1007/s10555-014-9498-0 -
Clinical and Applied... Aug 2011Platelet activation is crucial for wound healing at sites of endothelial cell injury and involves multiple factors that mediate platelet recruitment, adherence, and... (Review)
Review
Platelet activation is crucial for wound healing at sites of endothelial cell injury and involves multiple factors that mediate platelet recruitment, adherence, and aggregation. Platelet activation in response to atherosclerotic plaque rupture or endothelial cell detachment can result in pathologic thrombus formation and acute ischemic events. Current oral antiplatelet agents, aspirin and adenosine diphosphate (ADP) receptor antagonists, are effective but associated with bleeding as they target activation pathways critical for protective hemostasis and pathologic thrombosis. Each inhibits a single platelet activation pathway and does not impact activation by thrombin. The lack of complete inhibition of platelet function allows continued thrombus formation and recurrent thrombotic events. Inhibition of the protease-activated receptor 1 (PAR-1) stimulated by thrombin offers a rational strategy to achieve more comprehensive platelet inhibition when used in combination with standard-of-care, dual antiplatelet therapy. We expect that this new approach may mitigate bleeding risk, because PAR-1 is not essential for hemostasis.
Topics: Blood Platelets; Hemostasis; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Receptor, PAR-1; Thrombosis
PubMed: 20566574
DOI: 10.1177/1076029610373366 -
PloS One 2015Patients with critical limb ischemia (CLI) have a high risk to develop cardiovascular events (CVE). We hypothesized that in CLI patients platelets would display... (Clinical Trial)
Clinical Trial
BACKGROUND
Patients with critical limb ischemia (CLI) have a high risk to develop cardiovascular events (CVE). We hypothesized that in CLI patients platelets would display increased baseline activation and reactivity.
OBJECTIVES
We investigated baseline platelet activation and platelet reactivity in patients with CLI.
PATIENTS/METHODS
In this study baseline platelet activation and platelet reactivity in response to stimulation of all major platelet activation pathways were determined in 20 CLI patients (11 using aspirin and 9 using vitamin K-antagonists) included in the Juventas-trial (clinicaltrials.gov NCT00371371) and in 17 healthy controls. Platelet activation was quantified with flow cytometric measurement of platelet P-selectin expression and fibrinogen binding.
RESULTS
CLI patients not using aspirin showed higher baseline platelet activation compared to healthy controls. Maximal reactivity to stimulation of the collagen and thrombin activation pathway was decreased in CLI patients compared to healthy controls. In line, attenuated platelet reactivity to stimulation of multiple activation pathways was associated with several traditional risk factors for cardiovascular disease.
CONCLUSIONS
Baseline platelet activation was increased in CLI patients, whereas the reactivity of circulating platelets to several stimulatory agents is decreased. Reactivity of platelets was inversely correlated with cardiovascular risk factors.
Topics: Aspirin; Blood Platelets; Cardiovascular Diseases; Case-Control Studies; Collagen; Female; Fibrinogen; Humans; Ischemia; Male; Middle Aged; Peripheral Arterial Disease; Platelet Activation; Risk Factors; Thrombin
PubMed: 26148006
DOI: 10.1371/journal.pone.0131356 -
PloS One 2022Activation of circulating platelets by receptor binding and subsequent coagulation events are defined by a well characterized physiological response. However, the...
Activation of circulating platelets by receptor binding and subsequent coagulation events are defined by a well characterized physiological response. However, the growing prevalence of chronic kidney disease (CKD) and implication of platelet-released factors in worsening cardiovascular outcomes with hemodialysis warrant further investigation into the mechanobiology of platelet degranulation. The significant drops in pressure caused by high friction across the hemodialysis flow circuit present an overlooked platelet stimulant not involving immobilization as a driver for cytoskeletal rearrangement. In this study, platelets from healthy and dialysis (pre- and post-treatment) donors were cyclically depressurized in static suspension to measure changes in physiology by integrin αIIbβ3 activation and surface P-selectin expression. The progressive increase in CD62P with no changes in PAC1 over pressure-cycling duration regardless of uremia signifies that hydrostatic depressurization involves a novel agonist-free mechanism leading to platelet degranulation as a unique case in which CD62P and PAC1 do not interchangeably indicate platelet activation. Subsequent stimulation using ADP further suggests that sustained depressurization regimens desensitize integrin αIIbβ3 activation. Variability in platelet response caused by uremia and CKD are observed by elevated baseline PAC1 in pre-dialysis samples, PAC1 retention after ADP exposure, and maximum CD62P with ADP independent of pressure. Theory for hydrostatic pressure-induced degranulation circumventing integrin-initiated signal transduction is here presented based on the Starling Equation.
Topics: Adenosine Diphosphate; Gonadal Steroid Hormones; Humans; P-Selectin; Platelet Activation; Platelet Glycoprotein GPIIb-IIIa Complex; Renal Insufficiency, Chronic; Uremia
PubMed: 36107866
DOI: 10.1371/journal.pone.0274178 -
Journal of Veterinary Internal Medicine Sep 2016Clopidogrel is commonly prescribed to cats with perceived increased risk of thromboembolic events, but little information exists regarding its antiplatelet effects.
BACKGROUND
Clopidogrel is commonly prescribed to cats with perceived increased risk of thromboembolic events, but little information exists regarding its antiplatelet effects.
OBJECTIVE
To determine effects of clopidogrel on platelet responsiveness in cats with or without the A31P mutation in the MYBPC3 gene. A secondary aim was to characterize variability in feline platelet responses to clopidogrel.
ANIMALS
Fourteen healthy cats from a Maine Coon/outbred mixed Domestic cat colony: 8 cats homozygous for A31P mutation in the MYPBC3 gene and 6 wild-type cats without the A31P mutation.
METHODS
Ex vivo study. All cats received clopidogrel (18.75 mg PO q24h) for 14 days. Before and after clopidogrel treatment, adenosine diphosphate (ADP)-induced P-selectin expression was evaluated. ADP- and thrombin-induced platelet aggregation was measured by optical aggregometry (OA). Platelet pVASP and ADP receptor response index (ARRI) were measured by Western blot analysis.
RESULTS
Platelet activation from cats with the A31P mutation was significantly (P = .0095) increased [35.55% (18.58-48.55) to 58.90% (24.85-69.90)], in response to ADP. Clopidogrel treatment attenuated ADP-induced P-selectin expression and platelet aggregation. ADP- and PGE -treated platelets had a similar level of pVASP as PGE -treated platelets after clopidogrel treatment. Clopidogrel administration resulted in significantly lower ARRI [24.13% (12.46-35.50) to 11.30% (-7.383 to 23.27)] (P = .017). Two of 13 cats were nonresponders based on OA and flow cytometry.
CONCLUSION AND CLINICAL IMPORTANCE
Clopidogrel is effective at attenuating platelet activation and aggregation in some cats. Cats with A31P mutation had increased platelet activation relative to the variable response seen in wild-type cats.
Topics: Adenosine Diphosphate; Animals; Carrier Proteins; Cat Diseases; Cats; Clopidogrel; Gene Expression Regulation; Genetic Predisposition to Disease; Genotype; Mutation; Platelet Activation; Platelet Aggregation Inhibitors; Thrombosis; Ticlopidine
PubMed: 27615120
DOI: 10.1111/jvim.14568 -
International Journal of Molecular... Mar 2021Pancreatic cancer patients have an elevated risk of suffering from venous thrombosis. Among several risk factors that contribute to hypercoagulability of this...
Pancreatic cancer patients have an elevated risk of suffering from venous thrombosis. Among several risk factors that contribute to hypercoagulability of this malignancy, platelets possess a key role in the initiation of clot formation. Although single mechanisms of platelet activation are well-known in principle, combinations thereof and their potential synergy to mediate platelet activation is, in the case of pancreatic cancer, far from being clear. Applying an inhibitor screening approach using light transmission aggregometry, dense granule release, and thrombin formation assays, we provide evidence that a combination of tissue factor-induced thrombin formation by cancer cells and their platelet P-selectin binding is responsible for AsPC-1 and Capan-2 pancreatic cancer cell-mediated platelet activation. While the blockade of one of these pathways leads to a pronounced inhibition of platelet aggregation and dense granule release, the simultaneous blockade of both pathways is inevitable to prevent platelet aggregation completely and minimize ATP release. In contrast, MIA PaCa-2 pancreatic cancer cells express reduced levels of tissue factor and P-selectin ligands and thus turn out to be poor platelet activators. Consequently, a simultaneous blockade of thrombin and P-selectin binding seems to be a powerful approach, as mediated by heparin to crucially reduce the hypercoagulable state of pancreatic cancer patients.
Topics: Blood Platelets; Cell Line, Tumor; Humans; Ligands; P-Selectin; Pancreatic Neoplasms; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Risk Factors; Thrombin; Thrombophilia; Thromboplastin; Venous Thrombosis
PubMed: 33805059
DOI: 10.3390/ijms22073323 -
Drug Discovery Today Aug 2014Pulmonary arterial hypertension (PAH) is a progressive disease that involves pathological remodeling, vasoconstriction and thrombosis. Alterations in hemostasis,... (Review)
Review
Pulmonary arterial hypertension (PAH) is a progressive disease that involves pathological remodeling, vasoconstriction and thrombosis. Alterations in hemostasis, coagulation and platelet activation are consistently observed in PAH patients. Microparticles derived from platelets, inflammatory cells and the endothelium are an increasingly well-recognized signal in a variety of cardiovascular diseases, including PAH. This review will focus on the roles of coagulation, thrombosis, platelet activation and microparticles in the pathology and progression of PAH.
Topics: Blood Coagulation; Blood Platelets; Cell-Derived Microparticles; Humans; Hypertension, Pulmonary; Platelet Activation; Thrombosis
PubMed: 24747560
DOI: 10.1016/j.drudis.2014.04.001 -
Critical Care (London, England) Oct 2015Sepsis is a common condition that is associated with significant morbidity, mortality and health-care cost. Pulmonary and non-pulmonary sepsis are common causes of the... (Review)
Review
Sepsis is a common condition that is associated with significant morbidity, mortality and health-care cost. Pulmonary and non-pulmonary sepsis are common causes of the acute respiratory distress syndrome (ARDS). The mortality from ARDS remains high despite protective lung ventilation, and currently there are no specific pharmacotherapies to treat sepsis or ARDS. Sepsis and ARDS are characterised by activation of the inflammatory cascade. Although there is much focus on the study of the dysregulated inflammation and its suppression, the associated activation of the haemostatic system has been largely ignored until recently. There has been extensive interest in the role that platelet activation can have in the inflammatory response through induction, aggregation and activation of leucocytes and other platelets. Aspirin can modulate multiple pathogenic mechanisms implicated in the development of multiple organ dysfunction in sepsis and ARDS. This review will discuss the role of the platelet, the mechanisms of action of aspirin in sepsis and ARDS, and aspirin as a potential therapy in treating sepsis and ARDS.
Topics: Aspirin; Humans; Lung; Platelet Activation; Respiratory Distress Syndrome; Sepsis
PubMed: 26494395
DOI: 10.1186/s13054-015-1091-6 -
European Journal of Vascular and... Mar 2002to evaluate platelet and leukocyte activation during aortoiliac angiography and percutaneous transluminal angioplasty (PTA).
OBJECTIVE
to evaluate platelet and leukocyte activation during aortoiliac angiography and percutaneous transluminal angioplasty (PTA).
METHODS
an observational study of 14 patients with aortoiliac atherosclerotic disease, nine of whom underwent PTA. The proportion of fibrinogen-, and P-selectin positive platelets, P-selectin expression on platelets, intraplatelet cGMP and cAMP, CD18 positive granulocytes, CD18 expression on granulocytes, plasma (p)-neopterin, p-TNF alpha and p- interleukin-6 were repeatedly measured in arterial blood during angiography and in venous blood before and after.
RESULTS
compared to a previous venous sample, arterial intraplatelet cAMP was increased proximal to the atherosclerotic lesion before contrast infusion and PTA (median 18 [range: 14-22] vs 16 [15-21] pmol/10(9) platelets p<0.05), and intraplatelet cGMP was increased proximal to the lesion after contrast infusion and PTA (1.2 [0.8-3.9] vs 0.9 [0.6-2.5] pmol/10(9) platelets p<0.05). Four hours after angiography, both the proportion of P-selectin positive platelets (28[11-55]%) and platelet P-selectin expression (9[6-40]) had decreased (p<0.05), from arterial values distal to the lesion before contrast infusion and PTA (57 [24-78]% and 26 [10-83]). Granulocyte CD18 expression was lower during angiography than in a previous venous sample.
CONCLUSIONS
the results are compatible with platelet but not leukocyte activation during peripheral angiography.
Topics: Aged; Aged, 80 and over; Angiography; Angioplasty, Balloon; Aorta; Aortography; Arteriosclerosis; Contrast Media; Female; Humans; Iliac Artery; Leukocytes; Male; Middle Aged; Platelet Activation
PubMed: 11914008
DOI: 10.1053/ejvs.2001.1594 -
PloS One 2018Sepsis is characterized by an intense systemic inflammatory response activating a cascade of proinflammatory events resulting in leukocyte dysregulation and host tissue...
Sepsis is characterized by an intense systemic inflammatory response activating a cascade of proinflammatory events resulting in leukocyte dysregulation and host tissue damage. The lung is particularly susceptible to systemic inflammation, leading to acute lung injury. Key to inflammation-induced lung damage is the excessive migration of neutrophils across the vascular endothelium. The mechanisms which regulate neutrophil activation and migration in sepsis are not well defined but there is growing evidence that platelets are actively involved and play a key role in microvascular permeability and neutrophil-mediated organ damage. We previously identified PKC-delta (PKCδ) as a critical regulator of the inflammatory response in sepsis and demonstrated PKCδ inhibition was lung protective. However, the role of PKCδ in sepsis-induced platelet activation and platelet-leukocyte interactions is not known. In this study, rats underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. Following surgeries, a PKCδ inhibitor (200μg/kg) or vehicle (PBS) was administered intra-tracheally. At 24 hours post-surgeries, lung tissue, BAL fluid, and blood samples were collected. While sepsis caused thrombocytopenia, the remaining circulating platelets were activated as demonstrated by increased p-selectin expression, elevated plasma PF4, and enhanced platelet-leukocyte aggregate formation compared to Sham animals. Platelet activation was associated with increased platelet PKCδ activity. Inhibition of PKCδ attenuated sepsis-induced platelet activation, secretion and aggregate formation. Sepsis-induced thrombocytopenia was also significantly reduced and circulating platelet numbers were similar to sham animals. In the lung, sepsis induced significant influx of platelets and neutrophils and the development of lung injury. Administration of the PKCδ inhibitor decreased platelet and neutrophil influx, and was lung protective. Thus, PKCδ inhibition modulated platelet activity both locally and systemically, decreased neutrophil influx into the lung, and was lung protective. We demonstrate for the first time that PKCδ plays an important role in platelet activation and platelet-neutrophil interaction during sepsis.
Topics: Animals; Blood Platelets; Disease Models, Animal; Leukocytes; Lung; Male; Neutrophil Infiltration; Platelet Activation; Platelet Aggregation; Protein Kinase C-delta; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Sepsis; Thrombocytopenia
PubMed: 29617417
DOI: 10.1371/journal.pone.0195379