Mechanisms of platelet activation: Need for new strategies to protect against platelet-mediated atherothrombosis

2009 ◽  
Vol 102 (08) ◽  
pp. 248-257 ◽  
Author(s):  
Lisa Jennings
Keyword(s):  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Antiplatelet Agents ◽  
Bleeding Risk ◽  
Adenosine Diphosphate ◽  
Adp Receptor ◽  
Activation Pathways ◽  
New Strategies

SummaryPlatelets are central mediators of haemostasis at sites of vascular injury, but they also mediate pathologic thrombosis. Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. They also interact with endothelial cells and leukocytes to promote inflammation, which contributes to atherosclerosis. Multiple pathways contribute to platelet activation, and current oral antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate (ADP) receptor antagonist target the thromboxane A2 and ADP pathways, respectively. Both can diminish activation by other factors, but the extent of their effects depends upon the agonist, agonist strength, and platelet reactivity status. Although these agents have demonstrated significant clinical benefit, residual morbidity and mortality remain high. Neither agent is effective in inhibiting thrombin, the most potent platelet activator. This lack of comprehensive inhibition of platelet function allows continued thrombus formation and exposes patients to risk for recurrent thrombotic events. Moreover, bleeding risk is a substantial limitation of antiplatelet therapy, because these agents target platelet activation pathways critical for both protective haemostasis and pathologic thrombosis. Novel antiplatelet therapies that provide more complete inhibition of platelet activation without increasing bleeding risk could considerably decrease residual risk for ischemic events. Inhibition of the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin is a novel, emerging approach to achieve more comprehensive inhibition of platelet activation when used in combination with current oral antiplatelet agents. PAR-1 inhibition is not expected to increase bleeding risk, as this pathway does not interfere with haemostasis.

Novel Antiplatelet Agents in Cardiovascular Disease

2020 ◽  
Vol 25 (3) ◽  
pp. 191-200 ◽  
Author(s):  
Maximilian Tscharre ◽  
Alan D. Michelson ◽  
Thomas Gremmel
Keyword(s):  
Cardiovascular Disease ◽  
Antiplatelet Therapy ◽  
Animal Studies ◽  
Randomized Clinical Trials ◽  
Thrombus Formation ◽  
Antiplatelet Agents ◽  
Adenosine Diphosphate ◽  
Clinical Routine ◽  
New Agents ◽  
Antithrombotic Efficacy

Antiplatelet therapy reduces atherothrombotic risk and has therefore become a cornerstone in the treatment of cardiovascular disease. Aspirin, adenosine diphosphate P2Y12 receptor antagonists, glycoprotein IIb/IIIa inhibitors, and the thrombin receptor blocker vorapaxar are effective antiplatelet agents but significantly increase the risk of bleeding. Moreover, atherothrombotic events still impair the prognosis of many patients with cardiovascular disease despite established antiplatelet therapy. Over the last years, advances in the understanding of thrombus formation and hemostasis led to the discovery of various new receptors and signaling pathways of platelet activation. As a consequence, many new antiplatelet agents with high antithrombotic efficacy and supposedly only moderate effects on regular hemostasis have been developed and yielded promising results in preclinical and early clinical studies. Although their long journey from animal studies to randomized clinical trials and finally administration in daily clinical routine has just begun, some of the new agents may in the future become meaningful additions to the pharmacological armamentarium in cardiovascular disease.

scholarly journals Current Concepts in the Clinical Utility of Platelet Reactivity Testing

2013 ◽  
Vol 8 (2) ◽  
pp. 100 ◽  
Author(s):  
Collet Jean-Philippe ◽  
Keyword(s):  
Risk Factors ◽  
Clinical Utility ◽  
Platelet Reactivity ◽  
Antiplatelet Agents ◽  
Bleeding Risk ◽  
Adenosine Diphosphate ◽  
Coronary Intervention ◽  
Therapeutic Window ◽  
Cardiac Events ◽  
Coronary Syndrome

The pharmacodynamic effect of clopidogrel varies among individuals; approximately a third will have high on-treatment platelet reactivity (HTPR) to adenosine diphosphate and may benefit from more intensive antiplatelet therapy. Platelet reactivity testing has an important role in monitoring the therapeutic efficiency of clopidogrel and the safety of more potent drugs that confer an increased bleeding risk, because it provides a direct measure of the biological effect of these drugs. Numerous studies have demonstrated an association between HTPR and the risk of cardiac events in acute coronary syndrome (ACS) or after percutaneous coronary intervention (PCI). While the prognostic value of platelet reactivity testing following PCI has been demonstrated repeatedly in cohort studies and meta-analyses, randomised controlled studies investigating the clinical utility of the technique to guide treatment decisions failed to improve clinical outcomes of clopidogrel-treated patients undergoing stent implantation. Available data suggest that platelet function monitoring may be carried out in clopidogrel-treated patients with a higher risk of thrombotic events. These include patient risk factors such as body mass index (BMI), type 2 diabetes, and those prior unexpected ischemic events such as stent thrombosis, as well as procedural risk factors. As we move towards conclusively defining a therapeutic window associated with both cardiovascular (upper threshold) and bleeding risk (lower threshold) for antiplatelet agents, platelet reactivity testing will become a central tool in the practice of personalised strategies.

Monitoring of antiplatelet therapy

2011 ◽  
Vol 31 (01) ◽  
pp. 41-51 ◽  
Author(s):  
H. Seidel ◽  
M. M. Rahman ◽  
R. E. Scharf
Keyword(s):  
Antiplatelet Therapy ◽  
Platelet Function ◽  
Platelet Reactivity ◽  
Point Of Care ◽  
High Sensitivity ◽  
Antiplatelet Agents ◽  
Daily Practice ◽  
Adenosine Diphosphate ◽  
Poor Responders ◽  
Platelet Aggregometry

SummaryScreening of platelet function can be performed by point-of-care testing followed by platelet aggregometry in response to agonists such as collagen, adenosine diphosphate, epinephrine, and arachidonic acid. Despite in use for decades, this technique is not well standardized. Monitoring of antiplatelet therapy is increasingly applied in patients at high risk for re-thrombosis or bleeding. To assess pharmacological inhibition of platelet function, agonist-induced platelet aggregation, thromboxane B2 (TxB2) and vasodilator-stimulated protein phosphorylation (VASP) are being measured. While serum TxB2 levels of < 2 ng/ml reflect aspirin-induced inhibition of cyclo-oxygenase-1 activity with high sensitivity, VASP exhibits a wide variability upon treatment with clopidogrel or prasugrel. Multiple studies reveal an association between high residual platelet reactivity and adverse cardiovascular events in patients on antiplatelet therapy. However, despite the plethora of platelet function assays currently under investigation, their use in daily practice cannot be recommended. This is due to several reasons: (i) there is no consensus on the method and a respective cut-off value associated with clinical adverse outcome, and (ii) data demonstrating any benefit of tailored antiplatelet therapy and its monitoring (based on assessment of platelet functions) are still limited. Thus, appropriate identification of ‘resistant’ or ‘poor responders’ to antiplatelet agents remains challenging in clinical practice.

scholarly journals Multifactorial Background for a Low Biological Response to Antiplatelet Agents Used in Stroke Prevention

Medicina ◽  
2021 ◽  
Vol 57 (1) ◽  
pp. 59
Author(s):  
Adam Wiśniewski
Keyword(s):  
Ischemic Stroke ◽  
Secondary Prevention ◽  
Antiplatelet Therapy ◽  
Negative Impact ◽  
Platelet Reactivity ◽  
Antiplatelet Agent ◽  
Biological Response ◽  
Antiplatelet Agents ◽  
Platelet Inhibition ◽  
High Risk Group

Effective platelet inhibition is the main goal of the antiplatelet therapy recommended as a standard treatment in the secondary prevention of non-embolic ischemic stroke. Acetylsalicylic acid (aspirin) and clopidogrel are commonly used for this purpose worldwide. A low biological response to antiplatelet agents is a phenomenon that significantly reduces the therapeutic and protective properties of the therapy. The mechanisms leading to high on-treatment platelet reactivity are still unclear and remain multifactorial. The aim of the current review is to establish the background of resistance to antiplatelet agents commonly used in the secondary prevention of ischemic stroke and to explain the possible mechanisms. The most important factors influencing the incidence of a low biological response were demonstrated. The similarities and the differences in resistance to both drugs are emphasized, which may facilitate the selection of the appropriate antiplatelet agent in relation to specific clinical conditions and comorbidities. Despite the lack of indications for the routine assessment of platelet reactivity in stroke subjects, this should be performed in selected patients from the high-risk group. Increasing the detectability of low antiaggregant responders, in light of its negative impact on the prognosis and clinical outcomes, can contribute to a more individualized approach and modification of the antiplatelet therapy to maximize the therapeutic effect in the secondary prevention of stroke.

scholarly journals Clopidogrel Resistance: Current Issues

2016 ◽  
Vol 6 (1) ◽  
pp. 38-46
Author(s):  
NS Neki
Keyword(s):  
Antiplatelet Therapy ◽  
Dual Antiplatelet Therapy ◽  
Ex Vivo ◽  
Platelet Reactivity ◽  
Antiplatelet Agents ◽  
Clinical Problem ◽  
Coronary Intervention ◽  
Platelet Activity ◽  
Clopidogrel Resistance ◽  
Underlying Mechanisms

Antiplatelet agents are mainly used in the prevention and management of atherothrombotic complications. Dual antiplatelet therapy, combining aspirin and clopidogrel, is the standard care for patients having acute coronary syndromes or undergoing percutaneous coronary intervention according to the current ACC/AHA and ESC guidelines. But in spite of administration of dual antiplatelet therapy, some patients develop recurrent cardiovascular ischemic events especially stent thrombosis which is a serious clinical problem. Antiplatelet response to clopidogrel varies widely among patients based on ex vivo platelet function measurements. Clopidogrel is an effective inhibitor of platelet activation and aggregation due to its selective and irreversible blockade of the P2Y12 receptor. Patients who display little attenuation of platelet reactivity with clopidogrel therapy are labeled as low or nonresponders or clopidogrel resistant. The mechanism of clopidogrel resistance remains incompletely defined but there are certain clinical, cellular and genetic factors including polymorphisms responsible for therapeutic failure. Currently there is no standardized or widely accepted definition of clopidogrel resistance. The future may soon be realised in the routine measurement of platelet activity in the same way that blood pressure, cholesterol and blood sugar are followed to help guide the therapy, thus improving the care for millions of people. This review focuses on the methods used to identify patients with clopidogrel resistance, the underlying mechanisms, metabolism, clinical significance and current therapeutic strategies to overcome clopidogrel resistance.J Enam Med Col 2016; 6(1): 38-46

Abstract 3472: The Prediction of Ischemic Events After Percutaneous Coronary Intervention by Platelet Reactivity to Adenosine Diphosphate: First Evidence for an Oral Antiplatelet Therapeutic Target Determined by an Ex Vivo Test of Platelet Function.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Paul Gurbel ◽  
Kevin P Bliden ◽  
Joseph Dichiara ◽  
Mark J Antonino ◽  
Thomas A Suarez ◽  
...  
Keyword(s):  
Percutaneous Coronary Intervention ◽  
Risk Factor ◽  
Antiplatelet Therapy ◽  
Therapeutic Target ◽  
Ex Vivo ◽  
Platelet Reactivity ◽  
Adenosine Diphosphate ◽  
Coronary Intervention ◽  
Percutaneous Coronary ◽  
Ischemic Events

Background: High on-treatment platelet reactivity to adenosine diphosphate (HPR-ADP) may be a risk factor for ischemic events after percutaneous coronary intervention (PCI). We determined whether a cutpoint of HPR-ADP, similar to the INR used to guide anticoagulant therapy, could predict ischemic event occurrence after PCI. Methods : Post-procedural platelet reactivity to ADP was measured by conventional aggregometry in 352 consecutive patients undergoing non-emergent PCI followed for up to 2 years for post-discharge ischemic events. All patients had received clopidogrel and aspirin therapy at the time of aggregation measurements. Results: Eighty-two patients (23%) suffered ischemic events and had higher 5 and 20 μM ADP-induced aggregation compared to patients without ischemic events (46 ± 14% and 60 ± 13% versus 30 ± 17% and 43 ± 19%, respectively, p<0.0001 for both measurements). Using a combined receiver operator curve analysis, HPR-ADP cutpoints of 46% aggregation following 5μM ADP stimulation and 59% aggregation following 20μM ADP stimulation were associated with 63% and 74% of ischemic events, respectively. Multivariate Cox regression demonstrated significance between events and post-procedural HPR-ADP cutpoints (20μM ADP, OR=8.6, p<0.0001; and 5μM ADP, OR=2.9, p=0.01). Conclusions: High on-treatment platelet reactivity to ADP is an independent risk factor for ischemic events within 2 years of non-emergent PCI. These data are the first to support a therapeutic target for antiplatelet therapy based on an ex vivo platelet function test, similar to the INR used for anticoagulant therapy. The study is a step towards a personalized medicine approach to guide the intensity of antiplatelet therapy.

scholarly journals microRNAs as Promising Biomarkers of Platelet Activity in Antiplatelet Therapy Monitoring

2020 ◽  
Vol 21 (10) ◽  
pp. 3477
Author(s):  
Teresa L. Krammer ◽  
Manuel Mayr ◽  
Matthias Hackl
Keyword(s):  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Platelet Function ◽  
Platelet Reactivity ◽  
Therapy Monitoring ◽  
Platelet Inhibition ◽  
High Morbidity ◽  
Platelet Function Tests ◽  
Function Tests ◽  
Plasma Mirna

Given the high morbidity and mortality of cardiovascular diseases (CVDs), novel biomarkers for platelet reactivity are urgently needed. Ischemic events in CVDs are causally linked to platelets, small anucleate cells important for hemostasis. The major side-effect of antiplatelet therapy are life-threatening bleeding events. Current platelet function tests are not sufficient in guiding treatment decisions. Platelets host a broad spectrum of microRNAs (miRNAs) and are a major source of cell-free miRNAs in the blood stream. Platelet-related miRNAs have been suggested as biomarkers of platelet activation and assessment of antiplatelet therapy responsiveness. Platelets release miRNAs upon activation, possibly leading to alterations of plasma miRNA levels in conjunction with CVD or inadequate platelet inhibition. Unlike current platelet function tests, which measure platelet activation ex vivo, signatures of platelet-related miRNAs potentially enable the assessment of in vivo platelet reactivity. Evidence suggests that some miRNAs are responsive to platelet inhibition, making them promising biomarker candidates. In this review, we explain the secretion of miRNAs upon platelet activation and discuss the potential use of platelet-related miRNAs as biomarkers for CVD and antiplatelet therapy monitoring, but also highlight remaining gaps in our knowledge and uncertainties regarding clinical utility. We also elaborate on technical issues and limitations concerning plasma miRNA quantification.

Supplemental Fibrinogen Restores Platelet Inhibitor-Induced Reduction in Thrombus Formation without Altering Platelet Function: An In Vitro Study

2020 ◽  
Vol 120 (11) ◽  
pp. 1548-1556
Author(s):  
Thomas Bärnthaler ◽  
Elisabeth Mahla ◽  
Gabor G. Toth ◽  
Rufina Schuligoi ◽  
Florian Prüller ◽  
...  
Keyword(s):  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Platelet Function ◽  
Dual Antiplatelet Therapy ◽  
Thrombus Formation ◽  
In Vitro Study ◽  
Coronary Intervention ◽  
Calcium Flux ◽  
Major Surgery

Abstract Background For patients treated with dual antiplatelet therapy, standardized drug-specific 3-to-7 day cessation is recommended prior to major surgery to reach sufficient platelet function recovery. Here we investigated the hypothesis that supplemental fibrinogen might mitigate the inhibitory effects of antiplatelet therapy. Methods and Results To this end blood from healthy donors was treated in vitro with platelet inhibitors, and in vitro thrombus formation and platelet activation were assessed. Ticagrelor, acetylsalicylic acid, the combination of both, and tirofiban all markedly attenuated the formation of adherent thrombi, when whole blood was perfused through collagen-coated microchannels at physiological shear rates. Addition of fibrinogen restored in vitro thrombus formation in the presence of antiplatelet drugs and heparin. However, platelet activation, as investigated in assays of P-selectin expression and calcium flux, was not altered by fibrinogen supplementation. Most importantly, fibrinogen was able to restore in vitro thrombogenesis in patients on maintenance dual antiplatelet therapy after percutaneous coronary intervention. Conclusion Thus, our in vitro data support the notion that supplementation of fibrinogen influences the perioperative hemostasis in patients undergoing surgery during antiplatelet therapy by promoting thrombogenesis without significantly interfering with platelet activation.

scholarly journals Black Sorghum Phenolic Extract Modulates Platelet Activation and Platelet Microparticle Release

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1760 ◽  
Author(s):  
Borkwei Ed Nignpense ◽  
Kenneth A Chinkwo ◽  
Christopher L Blanchard ◽  
Abishek B Santhakumar
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Conformational Changes ◽  
Thrombus Formation ◽  
Antiplatelet Agents ◽  
Limited Information ◽  
Platelet Activity ◽  
Dietary Polyphenols ◽  
High Antioxidant Activity ◽  
Phenolic Extract

Platelet hyper-activation and platelet microparticles (PMPs) play a key role in the pathogenesis of cardiovascular diseases. Dietary polyphenols are believed to mimic antiplatelet agents by blunting platelet activation receptors via its antioxidant phenomenon. However, there is limited information on the anti-platelet activity of grain-derived polyphenols. The aim of the study is to evaluate the effects of sorghum extract (Shawaya short black 1 variety), an extract previously characterised for its high antioxidant activity and reduction of oxidative stress-related endothelial dysfunction, on platelet aggregation, platelet activation and PMP release. Whole blood samples collected from 18 healthy volunteers were treated with varying non-cytotoxic concentrations of polyphenol-rich black sorghum extract (BSE). Platelet aggregation study utilised 5 µg/mL collagen to target the GPVI pathway of thrombus formation whereas adenine phosphate (ADP) was used to stimulate the P2Y1/P2Y12 pathway of platelet activation assessed by flow cytometry. Procaspase-activating compound 1 (PAC-1) and P-selectin/CD62P were used to evaluate platelet activation- related conformational changes and degranulation respectively. PMPs were isolated from unstimulated platelets and quantified by size distribution and binding to CD42b. BSE treatment significantly reduced both collagen-induced platelet aggregation and circulatory PMP release at 40 µg/mL (p < 0.001) when compared to control. However, there was no significant impact of BSE on ADP-induced activation-dependent conformational change and degranulation of platelets. Results of this study suggest that phenolic rich BSE may confer cardio-protection by modulating specific signalling pathways involved in platelet activation and PMP release.

scholarly journals Omega-6 DPA and its 12-lipoxygenase–oxidized lipids regulate platelet reactivity in a nongenomic PPARα-dependent manner

2020 ◽  
Vol 4 (18) ◽  
pp. 4522-4537
Author(s):  
Jennifer Yeung ◽  
Reheman Adili ◽  
Adriana Yamaguchi ◽  
Cody J. Freedman ◽  
Angela Chen ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Docosapentaenoic Acid ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Cardiovascular Protection ◽  
Omega 6 ◽  
12 Lipoxygenase

Abstract Arterial thrombosis is the underlying cause for a number of cardiovascular-related events. Although dietary supplementation that includes polyunsaturated fatty acids (PUFAs) has been proposed to elicit cardiovascular protection, a mechanism for antithrombotic protection has not been well established. The current study sought to investigate whether an omega-6 essential fatty acid, docosapentaenoic acid (DPAn-6), and its oxidized lipid metabolites (oxylipins) provide direct cardiovascular protection through inhibition of platelet reactivity. Human and mouse blood and isolated platelets were treated with DPAn-6 and its 12-lipoxygenase (12-LOX)–derived oxylipins, 11-hydroxy-docosapentaenoic acid and 14-hydroxy-docosapentaenoic acid, to assess their ability to inhibit platelet activation. Pharmacological and genetic approaches were used to elucidate a role for DPA and its oxylipins in preventing platelet activation. DPAn-6 was found to be significantly increased in platelets following fatty acid supplementation, and it potently inhibited platelet activation through its 12-LOX–derived oxylipins. The inhibitory effects were selectively reversed through inhibition of the nuclear receptor peroxisome proliferator activator receptor-α (PPARα). PPARα binding was confirmed using a PPARα transcription reporter assay, as well as PPARα−/− mice. These approaches confirmed that selectivity of platelet inhibition was due to effects of DPA oxylipins acting through PPARα. Mice administered DPAn-6 or its oxylipins exhibited reduced thrombus formation following vessel injury, which was prevented in PPARα−/− mice. Hence, the current study demonstrates that DPAn-6 and its oxylipins potently and effectively inhibit platelet activation and thrombosis following a vascular injury. Platelet function is regulated, in part, through an oxylipin-induced PPARα-dependent manner, suggesting that targeting PPARα may represent an alternative strategy to treat thrombotic-related diseases.

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