Hospitalisation and morbidity due to adverse drug reactions in elderly patients: a single-centre study.

BACKGROUND: Adverse drug reaction (ADR) is a leading but under-recognised cause of illness, particularly in frail subjects with multiple comorbidities. AIM: To investigate the frequency, patterns and outcomes of ADR as a cause of hospitalisation in elderly patients admitted to an internal medicine ward. METHODS: We performed a retrospective observational study including every patient aged over 65 years who was admitted to our department during a 12-month period. Patients admitted to short-stay (<24 h) observation unit were excluded. RESULTS: ADR accounted for 106 of total 1750 recorded admissions, which constituted a proportion of 6.1% (95% confidence interval 5.0-7.3%). The median age of patients was 83.5 (78.0-87.0) years and 56.6% were on polypharmacy. A total of 170 ADR was recorded with 45.3% of subjects experiencing concomitantly more than one ADR from a single molecule. Diuretics were the most commonly imputed molecules (30 events, 17.6%), followed by antithrombotics (25 events, 14.7%) and central nervous system-active drugs (16 events, 9.4%). Interactions were judged responsible for 39 cases of ADR (36.8%). An unfavourable outcome was observed in about one-third of patients (37.7%). Among those subjects, 11 (10.4%) died and 29 (27.4%) had residual disability. CONCLUSION: ADR are a common cause of hospital admission in elderly patients and are often associated with adverse outcomes. Our data underline the need of appropriate strategies aimed at identifying high-risk patients and avoiding potentially preventable drug toxicities.

Pentraxin 3 and Platelet Activation in Obese Patients After Gastric Banding.

BACKGROUND: Circulating pentraxin 3 (PTX3), the main regulator of the inflammatory response, rapidly increases following cardiovascular events, and low PTX3 is associated with high body mass index. METHODS AND RESULTS: We conducted a 12-month longitudinal study, to test the hypothesis that laparoscopic adjustable gastric banding (LAGB)-induced weight loss was associated with changes in platelet activation markers and PTX3. Twelve obese patients, scheduled to undergo LAGB, were enrolled at the University Obesity Center. Urinary 11-dehydro-thromboxane (Tx)B2excretion rate was measured on radioimmunoassay, and PTX3 and CD40L were determined on immunoassay. Plasma PTX3 increased by 178.8 and 214.9% (P<0.0001), respectively, 6 and 12 months after LAGB. High-sensitivity CRP decreased by 24 and 29.7% (P<0.0001), whereas CD40L decreased by 64.3 and 58.6% (P=0.002), respectively. Urinary 11-dehydro-TxB2decreased from 1,443 to 715 and 564 pg/mg creatinine, respectively 6 months and 12 months after LAGB (P<0.0001). PTX3 was inversely related to platelet activation markers, 11-dehydro-TxB2and CD40L. Moreover, multiple regression analysis on pooled data showed that plasma PTX3 was an independent predictor of urinary 11-dehydro-TxB2. CONCLUSIONS: There is an association between inflammation, platelet activation and metabolic dysfunction in obesity, and PTX3 is a key player within these circuits.

Variability in the response to antiplatelet treatment in diabetes mellitus.

Atherothrombosis is a leading cause of death in patients with diabetes mellitus. Among factors contributing to the diabetic prothrombotic state, platelet activation plays a pivotal role. Numerous studies have investigated the benefits of antiplatelet therapy for primary and secondary cardiovascular prevention in diabetic patients. However, there are limited evidences that low-dose aspirin may be effective in this clinical setting. Several disease-specific factors have been identified as potential determinants of aspirin treatment failure. In this review, the main determinants of interindividual variability in response to antiplatelet agents are discussed, with particular emphasis on the pharmacokinetic and pharmacodynamic mechanisms of clinical efficacy and safety of antiplatelet drugs in patients with diabetes mellitus.

Thromboxane receptors antagonists and/or synthase inhibitors.

Atherothrombosis is the major cause of mortality and morbidity in Western countries. Several clinical conditions are characterized by increased incidence of cardiovascular events and enhanced thromboxane (TX)-dependent platelet activation. Enhanced TX generation may be explained by mechanisms relatively insensitive to aspirin. More potent drugs possibly overcoming aspirin efficacy may be desirable. Thromboxane synthase inhibitors (TXSI) and thromboxane receptor antagonists (TXRA) have the potential to prove more effective than aspirin due to their different mechanism of action along the pathway of TXA(2). TXSI prevent the conversion of PGH(2) to TXA(2), reducing TXA(2) synthesis mainly in platelets, whereas TXRA block the downstream consequences of TXA(2) receptors (TP) activation.TXA(2) is a potent inducer of platelet activation through its interaction with TP on platelets. TP are activated not only by TXA(2), but also by prostaglandin (PG) D(2), PGE(2), PGF(2α), PGH(2), PG endoperoxides (i.e., 20-HETE), and isoprostanes, all representing aspirin-insensitive mechanisms of TP activation. Moreover, TP are also expressed on several cell types such as macrophages or monocytes, and vascular endothelial cells, and exert antiatherosclerotic, antivasoconstrictive, and antithrombotic effects, depending on the cellular target.Thus, targeting TP receptor, a common downstream pathway for both platelet and extraplatelet TXA(2) as well as for endoperoxides and isoprostanes, may be a useful antiatherosclerotic and a more powerful antithrombotic intervention in clinical settings, such as diabetes mellitus, characterized by persistently enhanced thromboxane (TX)-dependent platelet activation through isoprostane formation and low-grade inflammation, leading to extraplatelet sources of TXA(2). Among TXRA, terutroban is an orally active drug in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. Despite great expectations on this drug supported by a large body of preclinical and clinical evidence and pathophysiological rationale, the PERFORM trial failed to demonstrate the superiority of terutroban over aspirin in secondary prevention of cerebrovascular and cardiovascular events among ~20,000 patients with stroke. However, the clinical setting and the design of the study in which the drug has been challenged may explain, at least in part, this unexpected finding.Drugs with dual action, such as dual TXS inhibitors/TP antagonist and dual COXIB/TP antagonists are currently in clinical development. The theoretical rationale for their benefit and the ongoing clinical studies are herein discussed.

Procalcitonin and secondary bacterial infections in COVID-19: association with disease severity and outcomes.

INTRODUCTION: Procalcitonin (PCT) is an emerging prognostic marker in coronavirus disease 2019 (COVID-19). Whether PCT can detect secondary bacterial infections or reflect target tissue injury in this setting is still unclear. Here we performed a meta-analysis to review the prognostic value of PCT for severe disease and adverse outcome events in COVID-19. METHODS: We searched relevant publications in online databases. Studies were included if they reported categorical data according to disease severity and/or outcomes. We analysed extracted data using fixed or random-effects meta-analysis models, as appropriate, depending on the presence of significant heterogeneity. RESULTS: Data from 14 studies (3492 patients) were included in the analysis. Overall, 163 of 256 patients with elevated PCT had severe disease (63.7%) compared with 553 of 2047 with negative PCT (27.0%) (OR: 5.92; 95% CI: 3.20 to 10.94). Elevated PCT was also associated with adverse outcomes (OR: 13.1; 95% CI: 7.37 to 23.1). PCT was increased in 22.8% and 30.6% of patients with the severe course and adverse outcome, respectively. Rates of secondary bacterial infections ranged from 4.7% to 19.5% and were associated with increased risk of severe course or fatal outcomes (OR: 20.8; 95% CI: 11.6 to 37.4). CONCLUSIONS: Elevated PCT levels could identify a subset of COVID-19 patients at increased risk of severe disease and adverse outcome. Its limitations include low sensitivity and undefined cost-utility ratio. Whether PCT may be used for detecting secondary bacterial infections and guiding antibiotic therapy in COVID-19 is still undefined.

Pneumomediastinum and subcutaneous emphysema after noninvasive ventilation in a COVID-19 patient.

Pneumomediastinum is an uncommon but well recognized complication of both invasive and non-invasive mechanical ventilation. Spontaneous pneumomediastinum has been observed in association with a variety of structural lung diseases including severe interstitial disorders. More recently it has been reported complicating the course of COVID-19 pneumonia. In the present report we describe a case of pneumomediastinum associated with subcutaneous emphysema in a patient with severe respiratory failure due to extensive interstitial pneumoniae correlated to SARS-CoV-2 infection which necessitated non-invasive ventilatory support. Prompt recognition is required during ventilatory support as it may promote its progression. Further data are needed in order to identify the mechanisms, frequency, risk factors and prognostic role of this rare complication of the clinical course of COVID-19.

Soluble forms of RAGE in human diseases: clinical and therapeutical implications.

The ligand - receptor for advanced glycation end-products (RAGE) axis has emerged as a novel pathway involved in a wide spectrum of diseases, including diabetes mellitus, atherothrombosis, chronic renal failure, rheumatoid arthritis, neurodegeneration, cancer and aging. Circulating soluble forms of RAGE (sRAGE), arising from receptor ectodomain shedding and splice variant [endogenous secretory (es) RAGE] secretion, may counteract RAGE-mediated pathogenesis, by acting as a decoy. Several studies suggest that decreased levels of sRAGE and/or esRAGE may be useful as a biomarker of ligand-RAGE pathway hyperactivity and inadequate endogenous protective response, thus providing a powerful complement to cardiovascular risk stratification and an interesting target of therapeutic interventions. This review will focus on the pathophysiological determinants of soluble forms of RAGE in different clinical settings, with particular reference to the mechanisms involved in their generation and clearance, the association with cardiovascular risk factors, the interplay with low-grade inflammation, oxidative stress and endothelial dysfunction, and the possible pharmacological modulation of their plasma levels.

Determinants of thromboxane biosynthesis in patients with moderate to severe chronic kidney disease.

BACKGROUND: Mechanisms of accelerated atherothrombosis in patients with chronic kidney disease (CKD) are only partly characterized. The aims of this study were to evaluate the extent of thromboxane (TX)-dependent platelet activation in patients with CKD, and to characterize the determinants of altered TX biosynthesis in this setting, with particular reference to enhanced lipid peroxidation, low grade inflammation and CKD-related anemia. PATIENTS AND METHODS: A cross sectional comparison between urinary 8-iso-PGF2α and 11-dehydro-TXB2, in vivo markers of oxidative stress and platelet activation, respectively, was performed in 115 patients with stage 1-4 CKD. RESULTS: Levels of both urinary 11-dehydro-TXB2 and 8-iso-PGF2α increased sequentially across the four CKD stages (P<0.0001, Kruskal-Wallis test). Both urinary prostanoids were inversely associated with either estimated glomerular filtration rate (eGFR, P<0.0001) or hemoglobin levels (P<0.0001). A significant direct correlation was also observed between urinary 11-dehydro-TXB2 and 8-iso-PGF2α (Rho=0.620, P<0.0001). On multivariate analysis, urinary 8-iso-PGF2α (ß=0.459, P<0.0001), hemoglobin levels (ß=- 0.261, P=0.002) and eGFR (ß=-0.172, P=0.032) were independent predictors of urinary 11-dehydro-TXB2 (adjusted R(2)=0.488). CONCLUSIONS: This study provides biochemical evidence of persistent platelet activation in patients with CKD. This condition occurs early in the natural history of the disease and is related to kidney function and oxidative stress. Moreover, we found an independent inverse relationship between hemoglobin levels and TX-dependent platelet activation. This finding may provide a mechanistic link between CKD-related anemia and increased cardiovascular risk.

Acquired Factor XI Inhibitor Presenting as Spontaneous Bilateral Subdural Hematoma in an Elderly Patient.

Development of autoantibodies against coagulation factors is an uncommon bleeding disorder associated with cancer, autoimmune conditions, pregnancy, or no apparent disease. Spontaneous FVIII inhibitors are the most frequently encountered; those against FXI have been only anecdotally reported. We report a case of acquired FXI inhibitor presenting as fatal intracranial spontaneous bleeding in an elderly patient with history of cancer and previous transfusions. Few cases of acquired FXI inhibitor have been reported in association with connective tissue disease, cancer, or surgery. Bleeding includes mucocutaneous bleeding, postsurgical hemorrhage, or life-threatening events. Treatment consists of arresting the bleeding and inhibitor eradication. High degree of suspicion is essential to promptly diagnose and treat this uncommon condition.

Circulating dickkopf-1 in diabetes mellitus: association with platelet activation and effects of improved metabolic control and low-dose aspirin.

BACKGROUND: Dickkopf-1 (DKK-1) is a major regulator of the Wnt signaling pathway, involved in inflammation, atherogenesis, and the regulation of glucose metabolism. Because platelets are major contributors to circulating levels of DKK-1 in other clinical settings, we aimed at characterizing the platelet contribution to DKK-1 in type 2 diabetes mellitus (T2DM) and evaluating associations of DKK-1 with glucose metabolism, platelet activation, and endothelial dysfunction. METHODS AND RESULTS: A cross-sectional comparison of DKK-1, soluble CD40L (sCD40L; reflecting platelet-mediated inflammation), asymmetric dimethylarginine (ADMA; marker of endothelial dysfunction), and urinary 11-dehydro-thromboxane B2 (in vivo marker of platelet activation) was performed among 214 diabetic patients (90 receiving aspirin at 100 mg/day) and 30 healthy controls. Plasma DKK-1 levels were markedly higher in patients with T2DM than in healthy patients (P<0.0001). DKK-1 levels were significantly lower in diabetic patients receiving compared with those not on aspirin treatment (P=0.008); in the latter, DKK-1 was significantly correlated with 11-dehydro-thromboxane B2, ADMA, and CD40L (ρ=0.303. P<0.0001, ρ=0.45. P<0.0001, and ρ=0.37, P<0.0001, respectively) but not with glycemic control or DM duration. Among patients not receiving aspirin, improvement of metabolic control in a subgroup of newly diagnosed patients treated with acarbose for 20 weeks and in a group treated with rosiglitazone for 24 weeks was associated with concurrent significant reductions in DKK-1 (P=0.005 and P=0.004) and 11-dehydro-thromboxane B2 (P=0.005 and P=0.004). CONCLUSIONS: Circulating DKK-1 is increased in T2DM and associated with endothelial dysfunction and platelet activation. Plasma DKK-1 levels are reduced with improvement of glycemic control and low-dose aspirin treatment.

Enhanced lipid peroxidation and platelet activation as potential contributors to increased cardiovascular risk in the low-HDL phenotype.

BACKGROUND: Low high-density lipoprotein (HDL) levels are major predictors of cardiovascular (CV) events, even in patients on statin treatment with low-density lipoprotein (LDL) at target. In animal models HDLs protect LDL from oxidation and blunt platelet activation. Our study aimed to examine whether HDL levels are related to in vivo oxidative stress and platelet activation, as determinants of atherothrombosis. METHODS AND RESULTS: Urinary 8-iso-PGF2α and 11-dehydro-TXB2, in vivo markers of oxidative stress and platelet activation, respectively, were measured in 65 coronary heart disease (CHD) normocholesterolemic patients with HDL ≤35 mg/dL, and in 47 CHD patients with HDL >35 mg/dL. The 2 eicosanoids were also measured before and after an intensive exercise program in sedentary people (n=18) and before and after fenofibrate treatment in otherwise healthy subjects with low HDL (n=10). Patients with HDL ≤35 mg/dL showed significantly higher urinary 8-iso-PGF2α (median [25th to 75th percentiles]: 289 [189 to 380] versus 216 [171 to 321] pg/mg creatinine, P=0.019) and 11-dehydro-TXB2 (563 [421 to 767] versus 372 [249 to 465] pg/mg creatinine, P=0.0001) than patients with higher HDL. A direct correlation was found between urinary 8-iso-PGF2α and 11-dehydro-TXB2 in the entire group of patients (ρ=0.77, P<0.0001). HDL levels were inversely related to both 8-iso-PGF2α (ρ=-0.32, P=0.001) and 11-dehydro-TXB2 (ρ=-0.52, P<0.0001). On multiple regression, only 8-iso-PGF2α (ß=0.68, P<0.0001) and HDL level (ß=-0.29, P<0.0001) were associated with urinary 11-dehydro-TXB2 excretion, independent of sex, age, smoking, hypertension, diabetes, previous myocardial infarction, total cholesterol, LDL, and triglycerides. Both intensive exercise and fenofibrate treatment significantly reduced the 2 eicosanoids in healthy subjects, in parallel with an HDL increase. CONCLUSIONS: A low HDL phenotype, both in CHD patients and in healthy subjects, is associated with increased lipid peroxidation and platelet activation. These data provide novel insight into the mechanisms linking low HDL with increased CV risk.

Effects of high-amount-high-intensity exercise on in vivo platelet activation: modulation by lipid peroxidation and AGE/RAGE axis.

Physical activity is associated with cardiovascular risk reduction, but the effects of exercise on platelet activation remain controversial. We investigated the effects of regular high-amount, high intensity aerobic exercise on in vivo thromboxane (TX)-dependent platelet activation and plasma levels of platelet-derived proteins, CD40L and P-selectin, and whether platelet variables changes may be related to changes in high-density lipoprotein (HDL) and in the extent of oxidative stress and oxidative stress-related inflammation, as reflected by urinary isoprostane excretion and endogenous soluble receptor for advanced glycation end-products (esRAGE), respectively. Urinary excretion of 11-dehydro-TXB2 and 8-iso-prostaglandin (PG)F(2α) and plasma levels of P-selectin, CD40L and esRAGE were measured before and after a eight-week standardised aerobic high-amount-high-intensity training program in 22 sedentary subjects with low-to-intermediate risk. Exercise training had a clear beneficial effect on HDL cholesterol (+10%, p=0.027) and triglyceride (-27%, p=0.008) concentration. In addition, a significant (p<0.0001) decrease in urinary 11-dehydro-TXB2 (26%), 8-iso-PGF(2α) (21%), plasma P-selectin (27%), CD40L (35%) and a 61% increase in esRAGE were observed. Multiple regression analysis revealed that urinary 8-iso-PGF(2α) [beta=0.33, SEM=0.116, p=0.027] and esRAGE (beta=-0.30, SEM=31.3, p=0.046) were the only significant predictors of urinary 11-dehydro-TXB2 excretion rate over the training period. In conclusion, regular high-amount-high-intensity exercise training has broad beneficial effects on platelet activation markers, paralleled and possibly associated with changes in the lipoprotein profile and in markers of lipid peroxidation and AGE/RAGE axis. Our findings may help explaining why a similar amount of exercise exerts significant benefits in preventing cardiovascular events.

Diabetes mellitus and thrombosis.

Atherothrombosis is the leading cause of morbidity and mortality in patients with diabetes mellitus. Several mechanisms contribute to the diabetic prothrombotic state, including endothelial dysfunction, coagulative activation and platelet hyper-reactivity. In particular, diabetic platelets are characterised by dysregulation of several signaling pathways leading to enhanced adhesion, activation and aggregation. These alterations result from the interaction among hyperglycemia, insulin resistance, inflammation and oxidative stress. This review will provide an overview of the current status of knowledge on mechanisms of accelerated atherothrombosis in patients with diabetes mellitus.

Biomarkers of platelet activation in acute coronary syndromes.

The most convincing evidence for the participation of platelets in arterial thrombosis in humans comes from studies of platelet activation in patients with acute coronary syndromes (ACS) and from trials of antiplatelet drugs. Both strongly support the concept that repeated episodes of platelet activation over the thrombogenic surface of a vulnerable plaque may contribute to the risk of death from coronary causes. However, the relation of in vivo platelet activation and adverse clinical events to results of platelet function tests remains largely unknown. A valuable marker of in vivo platelet activation should be specific, unaltered by pre-analytical artefacts and reproducibly measured by easily performed methods. This article describes current biomarkers of platelet activation in ACS, reviews their advantages and disadvantages, discusses their potential pitfalls, and demonstrates emerging data supporting the positive clinical implications of monitoring in vivo platelet activation in the setting of ACS.

Platelet function in health and disease: from molecular mechanisms, redox considerations to novel therapeutic opportunities.

Increased oxidative stress appears to be of fundamental importance in the pathogenesis and development of several disease processes. Indeed, it is well known that reactive oxygen species (ROS) exert critical regulatory functions within the vascular wall, and it is, therefore, plausible that platelets represent a relevant target for their action. Platelet activation cascade (including receptor-mediated tethering to the endothelium, rolling, firm adhesion, aggregation, and thrombus formation) is tightly regulated. In addition to already well-defined platelet regulatory factors, ROS may participate in the regulation of platelet activation. It is already established that enhanced ROS release from the vascular wall can indirectly affect platelet activity by scavenging nitric oxide (NO), thereby decreasing the antiplatelet properties of endothelium. On the other hand, recent data suggest that platelets themselves generate ROS, which may evoke pro-thrombotic responses, triggering many biological processes participating in atherosclerosis initiation, progression, and complication. That oxidative stress may alter platelet function is conceivable when considering that antioxidants play a role in the prevention of cardiovascular disease, although the precise mechanism accounting for changes attributable to antioxidants in atherosclerosis remains unknown. It is possible that the effects of antioxidants may be a consequence of their enhancing or promoting the antiplatelet effects of NO derived from both endothelial cells and platelets. This review focuses on current knowledge regarding ROS-dependent regulation of platelet function in health and disease, and summarizes in vitro and in vivo evidence for their physiological and potential therapeutic relevance.

Plasma levels of soluble CD36, platelet activation, inflammation, and oxidative stress are increased in type 2 diabetic patients.

Inflammation, oxidative stress, and platelet activation are involved in type 2 diabetes and its complications. Soluble CD36 (sCD36) has been proposed to early identify diabetics at risk of accelerated atherothrombosis. We aimed at characterizing the platelet contribution to sCD36 in diabetes, by correlating its concentration with the extent of platelet-mediated inflammation and in vivo lipid peroxidation and investigating the effects of low-dose aspirin on these processes. A cross-sectional comparison of sCD36, soluble CD40L (sCD40L) reflecting platelet-mediated inflammation, urinary 11-dehydro-TxB(2), and 8-iso-PGF(2α), in vivo markers of platelet activation and lipid peroxidation, was performed among 200 diabetic patients (94 of them on aspirin 100mg/day) and 47 healthy controls. sCD36 levels (median [IQR]: 0.72 [0.31-1.47] vs 0.26 [0.2-0.37], P=0.003) and urinary 11-dehydro-TxB(2) levels (666 [293-1336] vs 279 [160-396], P≤0.0001) were significantly higher in diabetic patients not on aspirin (n=106) than in healthy subjects. These variables were significantly lower in aspirin-treated diabetics than untreated patients (P<0.0001). Among patients not on aspirin, those with long-standing diabetes (>1 year) had significantly higher sCD36 levels in comparison to patients with diabetes duration <1 year (1.01 [0.62-1.86] vs 0.44 [0.22-1.21], P=0.001). sCD36 linearly correlated with sCD40L (rho=0.447; P=0.0001). On multiple regression analysis, 11-dehydro-TxB(2) (ß=0.360; SEM=0.0001, P=0.001), 8-iso-PGF(2α) (ß=0.469; SEM=0.0001, P<0.0001), and diabetes duration (ß=0.244; SEM=0.207, P=0.017) independently predicted sCD36 levels. sCD36, platelet activation, inflammation, and oxidative stress are increased in type 2 diabetes. Future studies are needed to elucidate if the incomplete down-regulation of sCD36 by low-dose aspirin implies that sCD36 may be derived from tissues other than platelets or if additional antiplatelet strategies in diabetes are necessary to interrupt CD36-dependent platelet activation.

Endogenous secretory RAGE in obese women: association with platelet activation and oxidative stress.

CONTEXT: The receptor for advanced glycation end-products (RAGE) has been implicated in obesity-related metabolic disease and accelerated atherothrombosis. OBJECTIVE: We tested the hypothesis that changes in endogenous secretory (es)RAGE levels as a result of excess adiposity and oxidative stress may contribute to enhancing platelet activation in obese women, thus increasing the cardiovascular risk. PATIENTS: Eighty otherwise healthy obese women and 20 nonobese women were studied. RESULTS: esRAGE and plasma adiponectin were reduced in obese women [median (interquartile range), 0.18 (0.13-0.26) vs. 0.38 (0.20-0.48) ng/ml, P = 0.003; and 4.4 (2.8-6.4) vs. 10.0 (6.9-12.5) µg/ml, P < 0.0001, respectively] who also displayed higher urinary 11-dehydro-thromboxane B(2) (11-dehydro-TXB(2)) [795 (572-1089) vs. 211 (135-301) pg/mg creatinine; P < 0.0001] and 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)) [544 (402-698) vs. 149 (98-219) pg/mg creatinine; P < 0.0001] compared to nonobese women. Direct correlations between plasma adiponectin and esRAGE (Rho = 0.43; P < 0.0001) and between urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2) (Rho = 0.36; P = 0.001) were observed in obese women. Moreover, plasma esRAGE and urinary 11-dehdro-TXB(2) were inversely related (Rho = -0.29; P = 0.008). On multiple linear regression analysis, urinary 8-iso-PGF(2α) and plasma esRAGE were independent predictors of urinary 11-dehydro-TXB(2). In five obese women, a short-term weight loss program gave a significant increase in esRAGE and decrease in urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2). CONCLUSION: In otherwise healthy obese women, low plasma esRAGE levels are associated with reduced circulating adiponectin and enhanced thromboxane biosynthesis, which is in part mediated by increased lipid peroxidation. Thus, excess adiposity may be implicated in RAGE hyperactivation and thromboxane-dependent platelet activation, contributing to obesity-related metabolic and vascular disease.

Inflammation, oxidative stress and platelet activation in aspirin-treated critical limb ischaemia: beneficial effects of iloprost.

Platelets critically contribute to atherothrombosis and worsening ischaemia in patients with peripheral arterial disease (PAD), eventually leading to critical limb ischaemia (CLI). Furthermore, persistent platelet activation despite antiplatelet therapy has been reported in this setting. The prostacyclin analogue iloprost is currently recommended in CLI patients for its effects in relieving symptoms by promoting local perfusion. In this study, we investigated the effects of iloprost infusion on urinary 11-dehydro-TXB2 and 8-iso-PGF(2α) excretion rate, as in vivo indexes of thromboxane-dependent platelet activation and lipid peroxidation, respectively, and on platelet-derived proinflammatory sCD40L and nitric oxide bioavailability in 44 patients with CLI while on chronic treatment with low-dose aspirin. Daily iloprost infusion for one-week significantly decreased urinary 11-dehydro-TXB2 [499 (277-807) vs. 380 (189-560) pg/mg creatinine, p < 0.0001] and 8-iso-PGF(2α) [533 (316-842) vs. 334 (196-540) pg/mg creatinine, p < 0.0001] as well as plasma sCD40L [1540 (1005-3015) vs. 948 (845-2030) pg/ml, p < 0.0001]. Furthermore, a significant increase in plasma nitrate plus nitrite levels has been observed [26.8 (18.8-35.9) vs. 43.7 (33.0-75.5) µM, p < 0.0001]. A significant direct correlation was also found between urinary 8-iso-PGF(2α) and 11-dehydro-TXB2 before and after iloprost treatment (Rho = 0.695, p < 0.0001). In conclusion, we report that a short-term course of iloprost is able to significantly reduce residual thromboxane biosynthesis, oxidative stress, endothelial dysfunction and platelet-derived inflammation in low-dose aspirin treated patients with CLI.