176 research outputs found
Platelet function tests
Traditionally developed for diagnosis of bleeding disorders, platelet function assays have
become increasingly used in basic research on platelet physiology, in phenotype-genotype
associations in bleeding disorders, in drug development as surrogate endpoints of efficacy for
new antiplatelet therapy, and to an extent, in monitoring of antiplatelet therapy in clinical
practice to predict thrombotic and bleeding risk. A multiplicity of platelet function assays is
available to measure the level of platelet activity in various settings. These include assays that
are restricted to a specialized laboratory as well as point-of-care instruments meant to
investigate platelet function at patient bedside. Unlike tests that determine a defined quantity
or measurement of a clinical biomarker (e.g. cholesterol or blood pressure), platelet function
testing assesses the dynamics of living cells, which immediately presents a series of unique
problems to any laboratory or clinic. This article presents currently used platelet function
assays and discusses important variables to take into account when performing these assays,
including pre-analytical issues and difficulties in interpreting platelet function test results
Platelet function in aging
Aging is associated with an increased incidence of cardiovascular disease and
thrombosis. Platelets play a major role in maintaining hemostasis and in thrombus
formation, making them a key player in thrombotic disorders. Whereas it is well-known
that platelet aggregability is increased in vascular diseases, the contribution of
age-related changes in platelet biology to cardiovascular risk is not well-understood.
Several lines of evidence support that platelets from older subjects differ in their function
and structure, making platelets more prone to activation and less sensitive to inhibition.
These age-related changes could lead to platelet hyperactivity and to the development
of a prothrombotic state in advanced age. This review will focus on platelet biochemical
modifications during aging and on the mechanisms by which these alterations could lead
to thrombotic disease
Étude de l’effet des médicaments antiplaquettaires sur la fonction plaquettaire : de la variabilité de réponse à l’effet rebond
En inhibant la formation de caillots dans le sang, les médicaments antiplaquettaires diminuent de façon importante le risque d’événements ischémiques aigus. Cependant, une sous-population de patients souffrant de maladie coronarienne présente une inhibition inadéquate de la fonction plaquettaire malgré la prise quotidienne d’acide acétylsalicylique (AAS). Le premier volet de cette thèse démontre qu’une régénération plaquettaire accélérée pourrait expliquer en partie la variabilité dans la persistance de l’effet antiplaquettaire de l’AAS chez certains sujets souffrant de maladie coronarienne. Ces données suggèrent qu’une augmentation de la fréquence d’administration d’AAS d’une à deux fois par jour pourrait être bénéfique chez ces sujets.
Des méta-analyses ont suggéré qu’une réponse plaquettaire inadéquate à l’AAS pourrait augmenter le risque d’événements ischémiques récurrents. La nature rétrospective de ces analyses ne permet pas d’établir la causalité. Dans le deuxième volet de cette thèse, les résultats d’une étude prospective visant à comparer la pertinence clinique de 6 tests de fonction plaquettaire fréquemment utilisés pour évaluer la réponse plaquettaire à l’AAS est présentée. Les résultats démontrent qu’aucun des tests de fonction plaquettaire couramment employés ne prédit la survenue d’événements ischémiques aigus chez des patients souffrant de maladie coronarienne stable. Toutefois, la cessation de la prise d’AAS est un prédicteur important d’événements thrombotiques.
La cessation de médicaments antiplaquettaires a souvent été associée à la survenue d’événements thrombotiques dans les jours suivant l’interruption. À savoir si la survenue de ces événements est attribuable uniquement au retrait d’un médicament protecteur ou plutôt à une sensibilisation plaquettaire, constitue un débat d’actualité. Dans le troisième volet de cette thèse, des données sont présentées démontrant que la cessation de clopidogrel après la période recommandée par les lignes directrices actuelles provoque une sensibilisation des plaquettes nouvellement formées aux stimuli plaquettaires physiologiques. Ces résultats encouragent la recherche sur différentes modalités pour atténuer le risque thrombotique accru chez ces patients souffrant de maladie coronarienne.
En conclusion, cet ouvrage présente des études visant à identifier les sous-populations de patients qui sont plus à risque de complications cardiovasculaires récurrentes. Dans ce contexte, la personnalisation de traitement est une avenue thérapeutique prometteuse, où chaque patient pourra recevoir un traitement ciblé en fonction de ses besoins et de ses contre-indications. Ce changement de paradigme d’une thérapie empirique issue d’études de grande envergure sur des données populationnelles à une thérapie ajustée aux besoins individuels représente un vaste champ de recherche, où la majorité des découvertes sont à faire.By inhibiting the formation of blood clots, antiplatelet drugs significantly reduce the risk of acute ischemic events. However, a subpopulation of patients suffering from coronary artery disease presents with an inadequate inhibition of platelet function despite taking acetylsalicylic acid (ASA) daily. The first part of this thesis demonstrates that accelerated platelet turnover could partly explain the variability in the persistence of the antiplatelet effect of ASA in some coronary artery disease patients. These results suggest that increasing the frequency of administration of ASA from once to twice daily may be beneficial in selected patients.
Meta-analyses have suggested that an inadequate platelet response to ASA may increase the risk of recurrent ischemic events. The retrospective nature of these analyses forbids the inference of causality. In the second part of this thesis, the results of a prospective study comparing the clinical relevance of 6 platelet function tests commonly used to assess platelet response to ASA are presented. The results show that none of the commonly used platelet function tests predict the occurrence of acute ischemic events in stable coronary artery disease patients. However, discontinuation of ASA is an important predictor of thrombotic events.
Discontinuation of antiplatelet drugs has often been associated with thrombotic events in the days following cessation. If the occurrence of these events is due solely to the withdrawal of a protective drug or rather platelet sensitization is a topic of some debate. In the third part of this thesis, data are presented demonstrating that clopidogrel discontinuation, after the period recommended by current guidelines, leads to sensitization of newly formed platelets to physiological platelet stimuli. These results encourage research on different ways to mitigate the increased risk of thrombosis in coronary artery disease patients scheduled to discontinue clopidogrel therapy.
In conclusion, this dissertation presents studies aiming to identify subpopulations of patients who are at increased risk of recurrent cardiovascular events. In this context, the personalization of treatment is a promising therapeutic avenue, where each patient can receive a targeted therapy according to his needs and contraindications. This shift in paradigm from empirical therapy based on population data retrieved from large clinical studies to therapy tailored to individual needs opens a vast field of research, where the majority of discoveries remain to be made
Dépistage de la résistance à l'aspirine chez les patients coronariens stables, suivis à la clinique externe de cardiologie de l'Hôpital du Sacré-Coeur de Montréal
Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal
Current and novel antiplatelet therapies for the treatment of cardiovascular diseases
Over the last decades, antiplatelet agents, mainly aspirin and P2Y12 receptor antagonists, have significantly reduced morbidity and mortality associated with arterial thrombosis. Their pharmacological characteristics, including pharmacokinetic/pharmacodynamics profiles, have been extensively studied, and a significant number of clinical trials assessing their efficacy and safety in various clinical settings have established antithrombotic efficacy. Notwithstanding, antiplatelet agents carry an inherent risk of bleeding. Given that bleeding is associated with adverse cardiovascular outcomes and mortality, there is an unmet clinical need to develop novel antiplatelet therapies that inhibit thrombosis while maintaining hemostasis. In this review, we present the currently available antiplatelet agents, with a particular focus on their targets, pharmacological characteristics, and patterns of use. We will further discuss the novel antiplatelet therapies in the pipeline, with the goal of improved clinical outcomes among patients with atherothrombotic diseases
Tissue-specificity of antibodies raised against TrkB and p75NTR receptors ; implications for platelets as models of neurodegenerative diseases
Platelets and neurons share many similarities including comparable secretory granule
types with homologous calcium-dependent secretory mechanisms as well as
internalization, sequestration and secretion of many neurotransmitters. Thus, platelets
present a high potential to be used as peripheral biomarkers to reflect neuronal
pathologies. The brain-derived neurotrophic factor (BDNF) acts as a neuronal growth
factor involved in learning and memory through the binding of two receptors, the
tropomyosin receptor kinase B (TrkB) and the 75 kDa pan-neurotrophic receptor
(p75NTR). In addition to its expression in the central nervous system, BDNF is found in
much greater quantities in blood circulation, where it is largely stored within platelets.
Levels 100- to 1,000-fold those of neurons make platelets the most important peripheral
reservoir of BDNF. This led us to hypothesize that platelets would express canonical
BDNF receptors, i.e., TrkB and p75NTR, and that the receptors on platelets would bear
significant resemblance to the ones found in the brain. However, herein we report
discrepancies regarding detection of these receptors using antibody-based assays,
with antibodies displaying important tissue-specificity. The currently available antibodies
raised against TrkB and p75NTR should therefore be used with caution to study platelets
as models for neurological disorders. Rigorous characterization of antibodies and
bioassays appears critical to understand the interplay between platelet and neuronal
biology of BDNF
Advances in platelet function testing—light transmission aggregometry and beyond
Platelet function testing is essential for the diagnosis of hemostasis disorders. While there
are many methods used to test platelet function for research purposes, standardization is often
lacking, limiting their use in clinical practice. Light transmission aggregometry has been the gold
standard for over 60 years, with inherent challenges of working with live dynamic cells in specialized
laboratories with independent protocols. In recent years, standardization efforts have brought
forward fully automated systems that could lead to more widespread use. Additionally, new technical
approaches appear promising for the future of specialized hematology laboratories. This review
presents developments in platelet function testing for clinical applications
Increased platelet reactivity and platelet–leukocyte aggregation after elective coronary bypass surgery
Inflammatory mechanisms are activated, and thrombotic complications occur during the initial
months after coronary artery bypass grafting (CABG). Therefore, changes over time of platelet
activation and platelet–leukocyte interactions after CABG are of interest. Whole-blood flow cytometry
was performed before, and 4–6 days, one month, and three months after elective CABG in 54 men
with stable coronary artery disease treated with acetylsalicylic acid (ASA). Single platelets and
platelet–leukocyte aggregates (PLAs) among monocytes (P-Mon), neutrophils (P-Neu), and lymphocytes (P-Lym) were studied without and with stimulation by submaximal concentrations of ADP,
thrombin, and the thromboxane analog U46619. White blood cell counts were increased during the
initial postoperative course, and platelet counts were increased after one month. Platelet P-selectin
expression was significantly enhanced at one month when stimulated by thrombin and U46619 and
at three months with ADP and thrombin. All PLAs subtypes were increased at one month without
stimulation in vitro. P-Mon and P-Neu stimulated by ADP, thrombin, or U46619 were significantly
increased one month after the operation but decreased compared to baseline at three months.
Agonist stimulated P-Lyms were increased at one month and remained increased at three months
after ADP stimulation. There was significant platelet activation and formation of PLAs unstimulated
and after agonist stimulation by ADP, thrombin, and a thromboxane analog after CABG in patients
with stable coronary artery disease irrespective of ASA treatment. Changes observed up to three
months after CABG support further studies of the clinical implications of protracted increases in
platelet activation and platelet–leukocyte interactions
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