Paola Simeone

Platelets and diabetes mellitus.

Platelet activation plays a key role in atherothrombosis in type 2 diabetes mellitus (T2DM) and increased in vivo platelet activation with enhanced thromboxane (TX) biosynthesis has been reported in patients with impairment of glucose metabolism even in the earlier stages of disease and in the preclinical phases. In this regards, platelets appear as addresses and players carrying and transducing metabolic derangement into vascular injury. The present review critically addresses key pathophysiological aspects including (i) hyperglycemia, glycemic variability and insulin resistance as determinants and predictors of platelet activation, (ii) inflammatory mediators derived from platelets, such as soluble CD40 ligand, soluble CD36, Dickkopf-1 and probably soluble receptor for advanced glycation-end-products (sRAGE), which expand the functional repertoire of platelets from players of hemostasis and thrombosis to powerful amplifiers of inflammation by promoting the release of cytokines and chemokines, cell activation, and cell-cell interactions; (iii) molecular mechanisms underpinning the less-than-expected antithrombotic protection by aspirin (ASA), despite regular antiplatelet prophylaxis at the standard dosing regimen, and (iv) stratification of patients deserving different antiplatelet strategies, based on the metabolic phenotype. Taken together, these pathophysiological aspects may contribute to the development of promising mechanism-based therapeutic strategies to reduce the progression of atherothrombosis in diabetic subjects.

Increased circulating resistin is associated with insulin resistance, oxidative stress and platelet activation in type 2 diabetes mellitus

Resistin is an adipokine that promotes inflammation and insulin resistance by targeting several cells including platelets. We hypothesised that in type 2 diabetes (T2DM), resistin may foster in vivo oxidative stress, thromboxane-dependent platelet activation and platelet-derived inflammatory proteins release, key determinants of atherothrombosis. A cross-sectional comparison of circulating resistin, sCD40L, as a marker of platelet-mediated inflammation, asymmetric dimethylarginine (ADMA), endothelial dysfunction marker, Dickkopf (DKK)-1, reflecting the inflammatory interaction between platelets and endothelial cells, and urinary 8-iso-PGF2α and 11-dehydro-TxB2, reflecting in vivo lipid peroxidation and platelet activation, respectively, was performed between 79 T2DM patients and 30 healthy subjects. Furthermore, we investigated the effects of the α-glucosidase inhibitor acarbose and the PPARγ agonist rosiglitazone, targeting hyperglycaemia or insulin resistance, versus placebo, in 28 and 18 T2DM subjects, respectively. Age- and gender-adjusted serum resistin levels were significantly higher in patients than in controls. HOMA (β=0.266, p=0.017) and 11-dehydro-TXB2 (β=0.354, p=0.002) independently predicted resistin levels. A 20-week treatment with acarbose was associated with significant reductions (p=0.001) in serum resistin, DKK-1, urinary 11-dehydro-TXB2 and 8-iso-PGF2α with direct correlations between the change in serum resistin and in other variables. A 24-week rosiglitazone treatment on top of metformin was associated with significant decreases in resistin, DKK-1, 11-dehydro-TXB2 and 8-iso-PGF2α, in parallel with HOMA decrease. In conclusion, resistin, antagonising insulin action in part through PPARγ activation, may favour insulin resistance and enhance oxidative stress, endothelial dysfunction and platelet activation. The adipokine-platelet interactions may be involved in platelet insulin resistance and their consequent pro-aggregatory phenotype in this setting.

The left atrial appendage: from embryology to prevention of thromboembolism

The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches.

Effects of Liraglutide on Weight Loss, Fat Distribution, and β-Cell Function in Obese Subjects With Prediabetes or Early Type 2 Diabetes

OBJECTIVE Obesity is associated with an increased risk of type 2 diabetes and cardiovascular complications. The risk depends significantly on adipose tissue distribution. Liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We determined whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese subjects with prediabetes or early type 2 diabetes. RESEARCH DESIGN AND METHODS Sixty-two metformin-treated obese subjects with prediabetes or newly diagnosed type 2 diabetes, were randomized to liraglutide (1.8 mg/day) or lifestyle counseling. Changes in SAT and VAT levels (determined by abdominal MRI), insulin sensitivity (according to the Matsuda index), and β-cell function (β-index) were assessed during a multiple-sampling oral glucose tolerance test; and circulating levels of IGF-I and IGF-II were assessed before and after a comparable weight loss (7% of initial body weight). RESULTS After comparable weight loss, achieved by 20 patients per arm, and superimposable glycemic control, as reflected by HbA1c level (P = 0.60), reduction in VAT was significantly higher in the liraglutide arm than in the lifestyle arm (P = 0.028), in parallel with a greater improvement in β-index (P = 0.021). No differences were observed in SAT reduction (P = 0.64). IGF-II serum levels were significantly increased (P = 0.024) only with liraglutide administration, and the increase in IGF-II levels correlated with both a decrease in VAT (ρ = −0.435, P = 0.056) and an increase in the β-index (ρ = 0.55, P = 0.012). CONCLUSIONS Liraglutide effects on visceral obesity and β-cell function might provide a rationale for using this molecule in obese subjects in an early phase of glucose metabolism dysregulation natural history.

Coagulation and infective endocarditis: sooner or later

Infective endocarditis (IE) is one of the best-characterized clinical paradigms, where inflammation, infection and coagulation are deeply intertwined in a bidirectional crosstalk [1]. Since, in normal circumstances, bacteremia is a daily, harmless event, and the endocardium is non-thrombogenic, a focal endocardial lining damage is believed to occur, leading to activation in situ of the haemostasis system, resulting in a sterile clot, with subsequent bacterial seeding. Thus, the interactions between pathogens, platelets and the coagulation system are critical to vegetation initiation and growth [2]. The triggering prothrombotic abnormality is amplified by ongoing inflammation, sepsis, and organ dysfunction, all contributing to further shifting the haemostatic system towards a thrombophilic state. The extent of the ensuing procoagulant imbalance is likely to be a predictor of a number of diverse outcomes related to IE, including vegetation size, embolic events and surgical complications [2]. Subjects with IE form a heterogeneous group, ranging from those who are successfully treated with no adverse events, to those with severe complications and a high mortality. An early diagnosis, prompt empiric antibiotic treatment and a careful selection of patients at risk of embolic complications remain the cornerstones of IE management [3]. In critically ill patients admitted to general Intensive Care Unit, multiple factors related both to the underlying conditions and to the performed procedures facilitate the occurrence of both infective and non-infective endocarditis, whose incidence is largely underestimated [4, 5]. In the manuscript of Durante-Mangoni et al. [6], published in this issue of IEM, the original choice of inherited thrombophilia as the candidate risk factor evaluated in a large group of IE patients, takes the opportunity to test different hypotheses: first, the role of inherited thrombophilia, as an underlying substrate favouring IE occurrence; second, to exploit a model of prothrombotic condition uninfluenced by the disease activity and pre-existing to the onset of endocarditis, in order to dissect out the relative contribution of a prothrombotic state in the initiation of an endocardial bacterial clot, regardless of subsequent amplifying loops [6] (Fig. 1). It should be emphasized that the chosen polymorphisms, the factor V Leiden and prothrombin G20201A mutations, are not significantly correlated with myocardial infarction [7], and, although associated with a substantial increase in the relative risk of venous thromboembolism, the absolute risk remains low, in view of the low prevalence of any thrombophilia [8]. Therefore, larger studies are warranted before the hypothesis of an involvement of initial prothrombotic abnormalities on the initiation or progression of IE and related outcomes may be ruled out. Nevertheless, the issue raised by the present paper is relevant in terms of the feasibility of testing the efficacy of antithrombotic prophylaxis before IE onset. Although it has been demonstrated that antiplatelet and anticoagulant strategies have an impact on in vitro and animal models of IE [9–11], results from the available clinical studies are conflicting [12, 13]. A post hoc analysis of observational data comparing patients taking long-term aspirin prior to & Francesca Santilli f.santilli@unich.it

Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs

Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease.Patients with diabetes mellitus have a prothrombotic status that increases the risk of cardiovascular events and worsens prognosis after these events. In this Consensus Statement, the Working Group on Thrombosis of the Italian Society of Cardiology proposes antithrombotic strategies for patients with diabetes in various cardiovascular settings.

Significance of urinary 11-dehydro-thromboxane B2 in age-related diseases: Focus on atherothrombosis

Platelet activation plays a key role in atherogenesis and atherothrombosis. Biochemical evidence of increased platelet activation in vivo can be reliably obtained through non-invasive measurement of thromboxane metabolite (TXM) excretion. Persistent biosynthesis of TXA2 has been associated with several ageing-related diseases, including acute and chronic cardio-cerebrovascular diseases and cardiovascular risk factors, such as cigarette smoking, type 1 and type 2 diabetes mellitus, obesity, hypercholesterolemia, hyperhomocysteinemia, hypertension, chronic kidney disease, chronic inflammatory diseases. Given the systemic nature of TX excretion, involving predominantly platelet but also extraplatelet sources, urinary TXM may reflect either platelet cyclooxygenase-1 (COX-1)-dependent TX generation or COX-2-dependent biosynthesis by inflammatory cells and/or platelets, or a combination of the two, especially in clinical settings characterized by low-grade inflammation or enhanced platelet turnover. Although urinary 11-dehydro-TXB2 levels are largely suppressed with low-dose aspirin, incomplete TXM suppression by aspirin predicts the future risk of vascular events and death in high-risk patients and may identify individuals who might benefit from treatments that more effectively block in vivo TX production or activity. Several disease-modifying agents, including lifestyle intervention, antidiabetic drugs and antiplatelet agents besides aspirin have been shown to reduce TX biosynthesis. Taken together, these aspects may contribute to the development of promising mechanism-based therapeutic strategies to reduce the progression of atherothrombosis. We intended to critically review current knowledge on both the pathophysiological significance of urinary TXM excretion in clinical settings related to ageing and atherothrombosis, as well as its prognostic value as a biomarker of vascular events.

Platelets and Diabetes

It is increasingly recognized that platelets are the culprit cells implicated in the propensity to atherothrombosis in the setting of both type 1 and type 2 diabetes mellitus, making the study of platelet pathophysiology and platelet activation/inhibition some of the most intriguing fields of research related to diabetes vascular complications. Indeed, a platelet hyperreactive phenotype with biochemical evidence of persistent in vivo platelet activation, with enhanced thromboxane (TX) biosynthesis, has been described in diabetic patients in different stages along the natural history of the impairment of glucose metabolism, even in the preclinical phases.

The deadly line linking sympathetic overdrive, dipping status and vascular risk: critical appraisal and therapeutic implications

The deadly line linking sympathetic overdrive, dipping status and vascular risk: critical appraisal and therapeutic implications