Platelets and Their Role in Hemostasis and Thrombosis—From Physiology to Pathophysiology and Therapeutic Implications

Hemostasis is a physiological process critical for survival. Meanwhile, thrombosis is amongst the leading causes of death worldwide, making antithrombotic therapy one of the most crucial aspects of modern medicine. Although antithrombotic therapy has progressed tremendously over the years, it remains far from ideal, and this is mainly due to the incomplete understanding of the exceptionally complex structural and functional properties of platelets. However, advances in biochemistry, molecular biology, and the advent of ‘omics’ continue to provide crucial information for our understanding of the complex structure and function of platelets, their interactions with the coagulation system, and their role in hemostasis and thrombosis. In this review, we provide a comprehensive view of the complex role that platelets play in hemostasis and thrombosis, and we discuss the major clinical implications of these fundamental blood components, with a focus on hemostatic platelet-related disorders and existing and emerging antithrombotic therapies. We also emphasize a number of questions that remain to be answered, and we identify hotspots for future research

La fibrillation atriale : Aperçus concernant le substrat arythmogène

Atrial fibrillation is the most prevalent form of cardiac arrhythmia. Studies in animal modelshave provided important insights into arrhythmia mechanisms. However, to date, we do not dispose ofanimal models of spontaneous atrial arrhythmia.Thus, we aimed to develop a model of spontaneous atrial arrhythmia in rats and to assesspathophysiological mechanisms of these arrhythmias by using a multidisciplinary approach. We alsoaimed to assess the presence and the extent of inflammation and endothelial dysfunction, incriminatedin atrial fibrillation-related complications such as stroke, in atrial fibrillation patients.The animal study describes the first animal model of spontaneous atrial arrhythmias. We alsoprovide evidence that multiple mechanisms participate in arrhythmia occurrence in this model,particularly autonomic imbalance with relative vagal hyperactivity, left atrial endocardial fibrosis, anddecreased left atrial expression of the Pitx2 gene. In our clinical study, we found high levels ofvascular endothelial growth factor and von Willebrand factor in atrial fibrillation patients compared tosinus rhythm controls. These results suggest specific thromboembolic risk patterns according to theclinical form of arrhythmia and highlight a parallel evolution of atrial fibrillation and endothelialdysfunction. These results add new insights into the understanding of atrial arrhythmias. This new animalmodel could facilitate studies of pathophysiological mechanisms involved in atrial arrhythmias andallow assessment of efficacy and toxicity of therapeutic agents in a setting that faithfully reproducesthe clinical presentation of the arrhythmiaLa fibrillation atriale est l'arythmie cardiaquela plus fréquente. Les études sur les modèles animaux ont fourni beaucoup de renseignements sur les mécanismes de cette arythmie, mais, à ce jour, nous ne disposons pas de modèle animal d'arythmie atriale spontanée.Nous avons cherché à développer un modèle d'arythmie atriale spontanée chez le rat et àidentifier les mécanismes physiopathologiques de ces arythmies. Nous avons également cherché àévaluer la présence et la sévérité de l'inflammation et de la dysfonction endothéliale, impliquées dansla survenue des complications de la fibrillation atriale comme les accidents vasculaires cérébraux, chezles patients avec fibrillation atriale. Nous avons également constaté des niveauxélevés de facteur de croissance endothélial vasculaire et de facteur von Willebrand chez les patientsavec fibrillation atriale par rapport aux contrôles. Ces résultats suggèrent un profil spécifique du risquethromboembolique en fonction de la forme clinique de l'arythmie et mettent en évidence une évolutionparallèle de la fibrillation atriale et de la dysfonction endothéliale.Ce nouveau modèle animal permettra d'étudier les mécanismes physiopathologiques desarythmies atriales et d'évaluer de nouveaux agents thérapeutiques dans un cadre qui reproduitfidèlement la présentation clinique de l'arythmi

Challenges of Anticoagulant Therapy in Atrial Fibrillation—Focus on Gastrointestinal Bleeding

The rising prevalence and the complexity of atrial fibrillation (AF) pose major clinical challenges. Stroke prevention is accompanied by non-negligible risks, making anticoagulant treatment an ongoing challenge for the clinician. Current guidelines recommend direct oral anticoagulants (DOACs) over warfarin for stroke prevention in most AF patients, mainly due to the ease of their use. However, assessing the bleeding risk in patients receiving oral anticoagulants remains—particularly in the case of DOACs—highly challenging. Using dose-adjusted warfarin increases threefold the risk of gastrointestinal bleeding (GIB). Although the overall bleeding risk appears to be lower, the use of DOACs has been associated with an increased risk of GIB compared to warfarin. Accurate bleeding (including GIB-specific) risk scores specific for DOACs remain to be developed. Until then, the assessment of bleeding risk factors remains the only available tool, although the extent to which each of these factors contributes to the risk of bleeding is unknown. In this paper, we aim to provide a comprehensive review of the bleeding risk associated with oral anticoagulant therapy in AF patients, with a highlight on the latest insights into GIB associated with oral anticoagulation; we emphasize questions that remain to be answered; and we identify hotspots for future research

Targeting Myocardial Fibrosis—A Magic Pill in Cardiovascular Medicine?

Fibrosis, characterized by an excessive accumulation of extracellular matrix, has long been seen as an adaptive process that contributes to tissue healing and regeneration. More recently, however, cardiac fibrosis has been shown to be a central element in many cardiovascular diseases (CVDs), contributing to the alteration of cardiac electrical and mechanical functions in a wide range of clinical settings. This paper aims to provide a comprehensive review of cardiac fibrosis, with a focus on the main pathophysiological pathways involved in its onset and progression, its role in various cardiovascular conditions, and on the potential of currently available and emerging therapeutic strategies to counteract the development and/or progression of fibrosis in CVDs. We also emphasize a number of questions that remain to be answered, and we identify hotspots for future research

Atrial Fibrillation – An Orchestra of Classic and Modern Risk Factors

Over the past years, prevention and control of risk factors has begun to play an important role in the management of patients prone to develop atrial fibrillation (AF). A considerable number of risk factors that contribute to the creation of a predisposing substrate for AF has been identified over the years. Although certain AF risk factors such as age, gender, genetic predisposition, or race are unmodifiable, controlling modifiable risk factors may represent an invaluable tool in the management of AF patients. In the recent decades, numerous studies have evaluated the mechanisms linking different risk factors to AF, but the exact degree of atrial remodeling induced by each factor remains unknown. Elucidating these mechanisms is essential for initiating personalized therapies in patients prone to develop AF. The present review aims to provide an overview of the most relevant modifiable risk factors involved in AF occurrence, with a focus on the mechanisms by which these factors lead to AF initiation and perpetuation

Anti-platelet Therapy Resistance – Concept, Mechanisms and Platelet Function Tests in Intensive Care Facilities

It is well known that critically ill patients require special attention and additional consideration during their treatment and management. The multiple systems and organ dysfunctions, typical of the critical patient, often results in different patterns of enteral absorption in these patients. Anti-platelet drugs are the cornerstone in treating patients with coronary and cerebrovascular disease. Dual anti-platelet therapy with aspirin and clopidogrel is the treatment of choice in patients undergoing elective percutaneous coronary interventions and is still widely used in patients with acute coronary syndromes. However, despite the use of dual anti-platelet therapy, some patients continue to experience cardiovascular ischemic events. Recurrence of ischemic events is partly attributed to the fact that some patients have poor inhibition of platelet reactivity despite treatment. These patients are considered low- or nonresponders to therapy. The underlying mechanisms leading to resistance are not yet fully elucidated and are probably multifactorial, cellular, genetic and clinical factors being implicated. Several methods have been developed to asses platelet function and can be used to identify patients with persistent platelet reactivity, which have an increased risk of thrombosis. In this paper, the concept of anti-platelet therapy resistance, the underlying mechanisms and the methods used to identify patients with low responsiveness to anti-platelet therapy will be highlighted with a focus on aspirin and clopidogrel therapy and addressing especially critically ill patients