SARS-CoV-2 infection and thrombotic complications: a narrative review.

The current, global situation regarding the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic and its potentially devastating clinical manifestations, i.e. coronavirus disease 2019 (COVID-19), took the world by storm, as millions of people have been infected worldwide and more than 1,600,000 patients have succumbed. Infection induced by various respiratory viruses may lead to thrombotic complications. Infection-elicited thrombosis may involve a repertoire of distinct, yet interconnected pathophysiological mechanisms, implicating a hyperinflammatory response, platelet activation and triggering of the coagulation cascade. In the present review, we present current knowledge on the pathophysiological mechanisms that may underlie thrombotic complications in SARS-CoV-2 infection. Furthermore, we provide clinical data regarding the incidence rate of thrombotic events in several viral respiratory infections that cause acute respiratory distress syndrome, including SARS-CoV-2 infection and finally we summarize current recommendations concerning thromboprophylaxis and antithrombotic therapy in patients with thrombotic complications related to SARS-CoV-2 infection.

Factor Xa and thrombin induce endothelial progenitor cell activation. The effect of direct oral anticoagulants.

Factor Xa (FXa) and thrombin exert non-hemostatic cellular actions primarily mediated through protease-activated receptors (PARs). We investigated the effect of FXa and thrombin on human late-outgrowth endothelial cells (OECs), a type of endothelial progenitor cells (EPCs), and on human umbilical vein endothelial cells (HUVECs). The effect of direct oral anticoagulants (DOACs), rivaroxaban and dabigatran, was also studied. The membrane expression of intercellular adhesion molecule-1 (ICAM-1) and the secretion of monocyte chemoattractant protein-1 (MCP-1) were used as cell activation markers. FXa and thrombin increase the ICAM-1 expression and the MCP-1 secretion on both cells, being higher on OECs. Vorapaxar, a specific PAR-1 antagonist, completely inhibits FXa-induced activation of both cells and thrombin-induced HUVEC activation, but only partially thrombin-induced OEC activation. Furthermore, thrombin-receptor activating peptide; TRAP-6, only partially activates OECs. OECs do not membrane-express PAR-4, therefore it may not be involved on thrombin-induced OEC activation. Rivaroxaban and dabigatran inhibit OEC and HUVEC activation by FXa and thrombin, respectively. Rivaroxaban enhances thrombin-induced OEC and HUVEC activation, which is completely inhibited by vorapaxar. The inhibition of OEC and HUVEC activation by vorapaxar and DOACs may represent a new pleiotropic effect of these drugs. The pathophysiological and clinical significance of our findings need to be established.

Neutrophil Extracellular Traps (NETs) and Atherosclerosis: Does Hypolipidemic Treatment Have an Effect?

Neutrophil extracellular traps (NETs) have attracted much attention recently, beyond elemental host immunity, due to their fundamental implication in a variety of pathologic conditions and widespread impactful diseases. Atherosclerotic cardiovascular disease (ASCVD) is one of them, and a major cause of mortality and disability worldwide. Consequently, years of basic and clinical research were dedicated to shedding light on every possible pathophysiologic mechanism that could be used as an effective prevention and treatment tool to ameliorate its burden. This led to the development of complex and prevention protocols and regimens that are now widely used, with lipid-lowering treatment being the current cornerstone; however, this is not adequate to alleviate the residual cardiovascular risk, which remains prominent. Despite the demonstrated pathogenic role of NETs in the progression and complications of ASCVD, little is known about their potential as a therapeutic target and the effects hypolipidemics exert on them.

Inflammation, Oxidative Stress, Vascular Aging and Atherosclerotic Ischemic Stroke.

Vascular aging is a crucial risk factor for atherosclerotic ischemic stroke. Vascular aging is characterized by oxidative stress, endothelial dysfunction, inflammation, intimal and media thickening, as well as the gradual development of arterial stiffness, among other pathophysiological features. Regarding oxidative stress, increased concentration of reactive oxygen and nitrogen species is linked to atherosclerotic ischemic stroke in vascular aging. Additionally, oxidative stress is associated with an inflammatory response. Inflammation is related to aging through the "inflammaging" theory, which is characterized by decreased ability to cope with a variety of stressors, in combination with an increased pro-inflammatory state. Vascular aging is correlated with changes in cerebral arteries that are considered predictors of the risk for atherosclerotic ischemic stroke. The aim of the present review is to present the role of oxidative stress and inflammation in vascular aging, as well as their involvement in atherosclerotic ischemic stroke.

The pathway of neutrophil extracellular traps towards atherosclerosis and thrombosis.

Neutrophil extracellular traps (NETs) are web-like extrusions of genetic material, which are released upon neutrophil activation. NETs consist of a chromatin substructure, onto which a vast array of proteins with various properties is dispersed. NETs production was initially described as an unrecognized defense mechanism of neutrophils, due to their ability to entrap and possibly eliminate a wide range of pathogens. Nevertheless, growing evidence suggests that NETs are implicated in a multitude of pathophysiological conditions, such as autoimmunity, cancer, diabetes mellitus and Alzheimer's disease. Importantly, NETs may also play a decisive role in atherosclerosis and thrombosis. In this context, it has been demonstrated that NETs are present in atherosclerotic lesions of both humans and animal models and are implicated in various mechanisms leading to atherogenesis. Among others, NETs induce oxidative stress and oxidize high-density lipoprotein particles, thus reducing their beneficial cholesterol efflux capacity. NETs also induce endothelial cell dysfunction and apoptosis and promote the generation of anti-double-stranded-DNA autoantibodies. NETs may also play a prothrombotic role, since they form a fibrin-like base for platelet adhesion, activation and aggregation. Furthermore, NETs promote the accumulation of prothrombotic molecules, like von Willebrand factor and fibrinogen, thus significantly contributing to thrombus formation. Notably, there is vast data linking NETs to arterial and venous thrombosis in animal models, as well as in humans. Future large-scale studies should incorporate NETs and their individual components as disease markers, as well as potential therapeutic targets, to reduce atherosclerosis and to prevent thrombosis.

Increased Benefit With Vorapaxar Use in Patients With a History of Myocardial Infarction and Diabetes Mellitus: What the Data Show Us.

Type 2 diabetes mellitus (T2DM) is a progressive and multifactorial metabolic disease mainly characterized by hyperglycemia and insulin resistance. Abnormal platelet reactivity associated with an increased risk of cardiovascular disease (CVD) is also a feature characteristic of patients with T2DM. Dual antiplatelet therapy consisting of aspirin and an adenosine diphosphate platelet P2Y12 receptor antagonist, such as clopidogrel, represents the standard antithrombotic regimen for the secondary prevention of CVD risk in T2DM. However, a high proportion of patients with T2DM exhibit high on-treatment platelet reactivity to aspirin and/or clopidogrel, associated with a greater risk of adverse cardiovascular events compared with nondiabetic patients. Consequently, novel antiplatelet therapeutic approaches may be required in order to avoid such events. Vorapaxar is a novel antiplatelet agent that targets the platelet protease-activated receptor 1 and inhibits thrombin-induced platelet activation. Vorapaxar has been studied in 2 phase III clinical trials and has been approved for use in the secondary prevention of atherothrombotic events in patients with a previous myocardial infarction (MI) or peripheral arterial disease. New data from the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial MI cohort demonstrate that the subgroup of patients with T2DM exhibits increased benefit from vorapaxar use compared with non-T2DM patients. The aim of the present work is to critically review the current knowledge concerning vorapaxar use in patients with T2DM as well as to discuss the possible mechanism(s) underlying vorapaxar's beneficial effect in T2DM.

High on treatment platelet reactivity to aspirin and clopidogrel in ischemic stroke: A systematic review and meta-analysis.

Emerging studies highlight high on-treatment of platelet reactivity (HTPR) as a major hindrance to the secondary prevention of cardiovascular ischemic events. The aim of this systematic review and meta-analysis is to assess the prevalence of HTPR in patients with ischemic stroke (IS) or transient ischemic attack (TIA) and reveal a possible relation with a higher risk of cerebrovascular event recurrence. Studies were selected if they reported absolute numbers or percentages of HTPR with ASA or clopidogrel in IS/TIA patients at any time point after the cerebrovascular event onset and assessed with any type of platelet function tests. We included 52 full-text studies with a total of 8364 patients. Overall, the pooled prevalence of HTPR was 24% (95%CI: 20-27%). In subgroup analyses, the prevalence of HTPR on ASA was 23% (95%CI: 20-28%), on clopidogrel 27% (95%CI: 22-32%) and on dual antiplatelet treatment (DAPT) 7% (95%CI: 5-10%). The overall analysis of all studies providing data on the risk of IS/TIA recurrence, indicates that the patients with HTPR had a significantly higher risk for IS/TIA recurrence (RR=1.81, 95%CI: 1.30-2.52; p<0.001). In conclusion the present study shows a significant lower prevalence of HTPR in DAPT and an increased rate of recurrent cerebrovascular ischemic events in patients presenting HTPR.