Isabella Russo

Introduction: Immune thrombocytopenia (ITP) and antiphospholipid syndrome (APS) are distinct autoimmune disorders with clinical intersections. While APS is marked by thrombosis and pregnancy complications, ITP typically presents as isolated low platelet counts with bleeding risk. Thrombocytopenia can also occur in APS, and a subset of ITP patients test positive for antiphospholipid antibodies (aPL). Discussion: This study examined aPL in 90 ITP patients and compared them to 132 APS patients. Among the ITP group, 18.3% were aPL‐positive, with lupus anticoagulant most common; 12% had anti‐phosphatidylserine/prothrombin (aPS/PT) antibodies. In the APS cohort, 16% exhibited thrombocytopenia (< 100,000/µL), with a mean platelet count of 44,000/µL, and 71% of these were positive for aPS/PT. Platelet levels varied significantly among ITP aPL‐negative, ITP aPL‐positive and APS‐ITP groups ( p < 0.001). aPL positivity was linked to less severe thrombocytopenia but affected treatment approaches, showing differences in first‐line ( p = 0.034) and second‐line ( p = 0.025) therapies. Patients with ITP secondary to APS had a higher mean platelet count compared to aPL‐positive ITP patients and aPL‐negative ITP patients. Conclusion: Screening for aPL and aPS/PT is vital to identify an ITP subset with milder thrombocytopenia and increased thrombotic risk, and may guide therapeutic decisions such as between thrombopoietin receptor agonists and SYK inhibitor. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Beyond the regulation of cholesterol metabolism, a number of extrahepatic functions of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been increasingly identified. The main purpose of this study was to verify whether PCSK9 expression in vascular smooth muscle cells (VSMC) is influenced by insulin resistance and high glucose (HG). In cultured rat aortic VSMC from lean insulin-sensitive Zucker rats (LZRs) and obese insulin-resistant Zucker rats (OZRs), a classical animal model of insulin resistance, we evaluated PCSK9 expression with or without the monoclonal antibodies against PCSK9 Alirocumab and Evolocumab or the synthetic PCSK9-binding peptide PEP 2-8. Effects and molecular mechanisms underlying altered PCSK9 expression were evaluated by proliferation and migration assay, reactive oxygen species (ROS) production, and involvement of PKC, NADPH-oxidase, MAPK/ERK-1/2 pathway activation. As a result, we found that, in comparison with LZR, VSMC from OZR showed basal PCSK9 overexpression mitigated by Alirocumab, Evolocumab, PEP 2-8, and the inhibitors of PKC, NADPH-oxidase, and MAPK. The finding of PCSK9 upregulation in VSMC from OZR paralleled with increased ROS production, proliferation, and migration. HG increased PCSK9 expression in VSMC from LZR, but not in OZR, via oxidative stress and with effects reduced by PCSK9 inhibitors. These findings suggest that a dysregulation of PCSK9 in VSMC could be involved in vascular damage in metabolic disorders, such as obesity and diabetes.

The role of antiplatelet therapy in patients with acute coronary syndromes is a moving target with considerable novelty in the last few years. The pathophysiological basis of the treatment depends on platelet biology and physiology, and the interplay between these aspects and clinical practice must guide the physician in determining the best therapeutic options for patients with acute coronary syndromes. In the present narrative review, we discuss the latest novelties in the antiplatelet therapy of patients with acute coronary syndromes. We start with a description of platelet biology and the role of the main platelet signal pathways involved in platelet aggregation during an acute coronary syndrome. Then, we present the latest evidence on the evaluation of platelet function, focusing on the strengths and weaknesses of each platelet’s function test. We continue our review by describing the role of aspirin and P2Y12 inhibitors in the treatment of acute coronary syndromes, critically appraising the available evidence from clinical trials, and providing current international guidelines and recommendations. Finally, we describe alternative therapeutic regimens to standard dual antiplatelet therapy, in particular for patients at high bleeding risk. The aim of our review is to give a comprehensive representation of current data on antiplatelet therapy in patients with acute coronary syndromes that could be useful both for clinicians and basic science researchers to be up-to-date on this complex topic.

Machine-learning models can rank molecules, estimate molecular properties, and predict compound–target relations with increasing computational accuracy. Nevertheless, an accurate prediction does not necessarily reveal why a molecule behaves as predicted, whether the model has learned pharmacologically relevant information, or whether its explanation can support an experimental decision. This conceptual gap is especially consequential in early drug discovery, where model outputs are frequently in

Essential thrombocythemia (ET) is a myeloproliferative neoplasm variant characterized by excessive production of platelets. Since the most common cause of mortality and morbidity in ET patients is thrombosis, the excessive production of platelets may cause thrombotic events. However, little is known about the function of platelets in ET. We report a female patient who presented as asymptomatic, without a remarkable medical history, and ET was diagnosed after an incidental finding of moderate thrombocytosis. Notably, together with thrombocytosis, an abnormal platelet phenotype was found for the presence of a massive, rapid and spontaneous formation of aggregates and platelet hypersensitivity to subthreshold concentrations of aggregating agonists. Bone marrow histopathological examination and genetic analysis with the JAK2 (V617F) gene mutation findings confirmed the initial suspicion of ET. Although the ET patient was placed on aspirin, the persistence of the platelet hyperactivation and hyperaggregability prompted a switch in antiplatelet medication from entero-coated (EC) to plain aspirin. As result, platelet hypersensitivity to agonists and spontaneous aggregation were no longer found. Collectively, our study demonstrates that platelet function analysis could be a reliable predictor of ET and that plain aspirin should be preferred over EC aspirin to attenuate platelet hyperreactivity.

Chronic disorders are strongly linked to cardiovascular (CV) diseases, and it is unanimously accepted that regular exercise training is a key tool to improving CV risk factors, including diabetes, dyslipidemia, and obesity. Increased oxidative stress due to an imbalance between reactive oxygen species production and their scavenging by endogenous antioxidant capacity is the common ground among these metabolic disorders, and each of them affects platelet function. However, the correction of hyperglycemia in diabetes and lipid profile in dyslipidemia as well as the lowering of body weight in obesity all correlate with amelioration of platelet function. Habitual physical exercise triggers important mechanisms related to the exercise benefits for health improvement and protects against CV events. Platelets play an important role in many physiological and pathophysiological processes, including the development of arterial thrombosis, and physical (in)activity has been shown to interfere with platelet function. Although data reported by studies carried out on this topic show discrepancies, the current knowledge on platelet function affected by exercise mainly depends on the type of applied exercise intensity and whether acute or habitual, strenuous or moderate, thus suggesting that physical activity and exercise intensity may interfere with platelet function differently. Thus, this review is designed to cover the aspects of the relationship between physical exercise and vascular benefits, with an emphasis on the modulation of platelet function, especially in some metabolic diseases.

Nitric oxide (NO) and carbon monoxide (CO) represent a pair of biologically active gases with an increasingly well-defined range of effects on circulating platelets. These gases interact with platelets and cells in the vessels and heart and exert fundamentally similar biological effects, albeit through different mechanisms and with some peculiarity. Within the cardiovascular system, for example, the gases are predominantly vasodilators and exert antiaggregatory effects, and are protective against damage in myocardial ischemia-reperfusion injury. Indeed, NO is an important vasodilator acting on vascular smooth muscle and is able to inhibit platelet activation. NO reacts with superoxide anion (O₂(⁻•)) to form peroxynitrite (ONOO(⁻)), a nitrosating agent capable of inducing oxidative/nitrative signaling and stress both at cardiovascular, platelet, and plasma levels. CO reduces platelet reactivity, therefore it is an anticoagulant, but it also has some cardioprotective and procoagulant properties. This review article summarizes current knowledge on the platelets and roles of gas mediators (NO, and CO) in cardioprotection. In particular, we aim to examine the link and interactions between platelets, NO, and CO and cardioprotective pathways.

Splanchnic vein thrombosis is a rare but potentially life-threatening manifestation of venous thromboembolism, with challenging implications both at the pathological and therapeutic level. It is frequently associated with liver cirrhosis, but it could also be provoked by myeloproliferative disorders, cancer of various gastroenterological origin, abdominal infections and thrombophilia. A portion of splanchnic vein thrombosis is still classified as idiopathic. Here, we review the mechanisms of splanchnic vein thrombosis, including new insights on the role of clonal hematopoiesis in idiopathic SVT pathogenesis, with important implications from the therapeutic standpoint.

The imbalance between reactive oxygen species (ROS) synthesis and their scavenging by anti-oxidant defences is the common soil of many disorders, including hypercholesterolemia. Platelets, the smallest blood cells, are deeply involved in the pathophysiology of occlusive arterial thrombi associated with myocardial infarction and stroke. A great deal of evidence shows that both increased intraplatelet ROS synthesis and impaired ROS neutralization are implicated in the thrombotic process. Hypercholesterolemia is recognized as cause of atherosclerosis, cerebro- and cardiovascular disease, and, closely related to this, is the widespread acceptance that it strongly contributes to platelet hyperreactivity via direct oxidized LDL (oxLDL)-platelet membrane interaction via scavenger receptors such as CD36 and signaling pathways including Src family kinases (SFK), mitogen-activated protein kinases (MAPK), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In turn, activated platelets contribute to oxLDL generation, which ends up propagating platelet activation and thrombus formation through a mechanism mediated by oxidative stress. When evaluating the effect of lipid-lowering therapies on thrombogenesis, a large body of evidence shows that the effects of statins and proprotein convertase subtilisin/kexin type 9 inhibitors are not limited to the reduction of LDL-C but also to the down-regulation of platelet reactivity mainly by mechanisms sensitive to intracellular redox balance. In this review, we will focus on the role of oxidative stress-related mechanisms as a cause of platelet hyperreactivity and the pathophysiological link of the pleiotropism of lipid-lowering agents to the beneficial effects on platelet function.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly secreted in the liver, is a key regulator of cholesterol homeostasis inducing LDL receptors’ degradation. Beyond lipid metabolism, PCSK9 is involved in the development of atherosclerosis, promoting plaque formation in mice and human, impairing the integrity of endothelial monolayer and promoting the events that induce atherosclerosis disease progression. In addition, the PCSK9 ancillary role in the atherothrombosis process is widely debated. Indeed, recent evidence showed a regulatory effect of PCSK9 on redox system and platelet activation. In particular, the role of PCSK9 in the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2) system, of MAP-kinase cascades and of CD36 and LOX-1 downstream pathways, suggests that PCSK9 may be a significant cofactor in atherothrombosis development. This evidence suggests that the serum levels of PCSK9 could represent a new biomarker for the occurrence of cardiovascular events. Finally, other evidence showed that PCSK9 inhibitors, a novel pharmacological tool introduced in clinical practice in recent years, counteracted these phenomena. In this review, we summarize the evidence concerning the role of PCSK9 in promoting oxidative-stress-related atherothrombotic process.