Behçet syndrome is a systemic inflammatory condition characterized by muco-cutaneous and ocular manifestations, with central nervous system, vascular and/or gastro-intestinal involvement. The association of microbiota with Behçet syndrome has not been shown yet. Our work was aimed to compare the gut microbiota structure and the profiles of short-chain fatty acids production in Behçet syndrome patients and healthy control relatives. Here, we compared the fecal microbiota of 22 patients with Behçet syndrome and that of 16 healthy co-habiting controls, sharing the same diet and lifestyle by pyrosequencing of the V3-V4 hypervariable regions of the 16 rDNA gene and biochemical analyses. Our analyses showed significant differences in gut microbiota between Behçet patients and healthy cohabitants. In particular we found that Behçet's patients were significantly depleted in the genera Roseburia and Subdoligranulum. Roseburia showed a relative abundance value of 10.45±6.01% in healthy relatives and 4.97±5.09% in Behçet's patients, and Subdoligranulum, which reached a relative abundance of 3.28±2.20% in healthy controls, was only at 1.93±1.75% of abundance in Behçet's patients. Here we report, for the first time, that a peculiar dysbiosis of the gut microbiota is present in patients with Behçet syndrome and this corresponds to specific changes in microbiome profile. A significant decrease of butyrate production (P=0.0033) in Behçet's patients was demonstrated. Butyrate is able to promote differentiation of T-regulatory cells, and consequently the results obtained prompt us to speculate that a defect of butyrate production might lead to both reduced T-reg responses and activation of immuno-pathological T-effector responses. Altogether, our results indicate that both a peculiar dysbiosis of the gut microbiota and a significant decrease of butyrate production are present in patients with Behçet syndrome.

In recent years, the relationship between inflammation and thrombosis has been deeply investigated and it is now clear that immune and coagulation systems are functionally interconnected. Inflammation-induced thrombosis is by now considered a feature not only of autoimmune rheumatic diseases, but also of systemic vasculitides such as Behçet’s syndrome, ANCA-associated vasculitis or giant cells arteritis, especially during active disease. These findings have important consequences in terms of management and treatment. Indeed, Behçet’syndrome requires immunosuppressive agents for vascular involvement rather than anticoagulation or antiplatelet therapy, and it is conceivable that also in ANCA-associated vasculitis or large vessel-vasculitis an aggressive anti-inflammatory treatment during active disease could reduce the risk of thrombotic events in early stages. In this review we discuss thrombosis in vasculitides, especially in Behçet’s syndrome, ANCA-associated vasculitis and large-vessel vasculitis, and provide pathogenetic and clinical clues for the different specialists involved in the care of these patients.

Summary. Background: Two point-of-care (POC) systems have been recently proposed as rapid tools with which to evaluate residual platelet reactivity (RPR) in coronary artery disease (CAD) patients. Objectives and Methods: We compared Platelet Function Analyzer-100 (PFA-100) closure times (CTs) by collagen/adenosine 5´-diphosphate (ADP) (C/ADP CT) cartridge and the VerifyNow P2Y12 Assay (VerifyNow) with light transmission aggregation (LTA) induced by 2 and 10 μmol L^–1 ADP in 1267 CAD patients on dual antiplatelet therapy who underwent percutaneous coronary intervention. We also performed the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay by cytofluorimetric analysis in a subgroup of 115 patients. Results: Cut-off values for identifying RPR were: ≥ 54% and ≥ 66% for LTA induced by 2 and 10 μmol L^–1 ADP respectively, and ≥ 264 P2Y12 Reaction Units (PRU) for VerifyNow. The cut-off for PFA-100 C/ADP CT was ≥ 68 s. RPR was detected in 25.1% of patients by 2 μmol L^–1 ADP-induced LTA (ADP-LTA), in 23.2% by 10 μmol L^–1 ADP-LTA, in 24.4% by PFA-100, and in 24.7% by VerifyNow. PFA-100 results did not parallel those obtained with LTA. VerifyNow showed a significant correlation (ρ = 0.62, P < 0.001) and significant agreement (k = 0.34, P < 0.001) with LTA induced by 2 μmol L^–1 ADP. The correlation was similar but the agreement was better between VerifyNow and 10 μmol L^–1 ADP-LTA (ρ = 0.64, P < 0.0001; k = 0.43, P < 0.001). Significant relationships were found between VASP platelet reactivity index and both ADP-LTA and VerifyNow. PFA-100 C/ADP CT did not significantly correlate with any of the other assays. Conclusions: Our results show a significant correlation between LTA and VerifyNow but not the PFA-100 C/ADP assay. Clinical validation studies for POC systems are necessary.

Background Recent studies suggest a role for inflammation in the pathophysiology of unstable angina. This study was designed to investigate whether circulating lymphocytes are involved in the inflammatory reaction associated with the episodes of unstable angina. Methods and Results Twenty-nine patients with proven unstable angina, 36 with stable angina, and 30 healthy subjects were studied. Both early and short-lived (interleukin-2 receptor [IL-2R], α-chain CD25, and transferrin receptor CD71) and late antigen (HLA-DR) expression were investigated by flow cytometric analysis. Soluble IL-2R (sIL-2R) was also measured in plasma by ELISA. Lymphocyte activation was studied at day 1 of hospital admission and after 7, 15, 30, 60, and 90 days. In patients with unstable angina, the number of HLA-DR+ CD3 lymphocytes and levels of sIL-2R were higher ( P <.001) than in patients with stable angina and control subjects. Both CD4+ and CD8+ lymphocytes expressed HLA-DR antigens. No differences were found among the different groups of subjects in regard to the expression of CD25 and CD71. Lymphocyte activation was more marked in patients with urgent revascularization. No relationships were found between the number of HLA-DR+ lymphocytes and either the severity of coronary angiographic lesions or the number of ischemic episodes. Observations over time showed a gradual decrease in the number of HLA-DR+ lymphocytes and sIL-2R levels from weeks 3 through 8 to 12. Conclusions The present results indicate that (1) CD4+ and CD8+ circulating lymphocytes are activated in patients with unstable angina, and their activation state lasts 6 to 8 weeks; and (2) activation of lymphocytes is not a consequence of myocardial ischemia. These results support the immune system–mediated inflammatory nature of unstable angina.

The PROLONG randomized trial showed that a normal D-dimer (D-d) 1 month after anticoagulation suspension for unprovoked venous thromboembolism (VTE) was associated with a low risk of late recurrences (4.4% patient years). However, it is unknown whether D-d changes subsequently. The aim of this prospective multicenter study was to assess D-d time course and its relation with late recurrences in patients with normal D-d 1 month after anticoagulation suspension for a first episode of unprovoked VTE. D-d was measured with a qualitative method (Clearview Simplify D-dimer; Inverness Medical Professional Diagnostics). Patients with a normal D-d 1 month after stopping anticoagulation repeated D-d testing every 2 months for 1 year. D-d was normal in 68% (243/355) of patients 1 month after anticoagulation suspension. Patients in whom D-d became abnormal at the third month and remained abnormal afterward had a higher risk of recurrence (7/31; 27% patient years; 95% confidence interval [CI]: 12-48) than patients in whom D-d remained normal at the third month and afterward (4/149; 2.9% patient years; 95% CI: 1-7; adjusted hazard ratio: 7.9; 95% CI: 2.1-30; P = .002). Repeated D-d testing after anticoagulation suspension for a first episode of unprovoked VTE could help tailor the duration of treatment. This trial is registered at http://clinicaltrials.gov as NCT00266045.

Background— Bridging therapy with low–molecular-weight heparin is usually recommended in patients who must stop oral anticoagulants before surgical or invasive procedures. To date, there is no universally accepted bridging regimen tailored to the patient’s thromboembolic risk. This prospective inception cohort management study was designed to assess the efficacy and safety of an individualized bridging protocol applied to outpatients. Methods and Results— Oral anticoagulants were stopped 5 days before the procedure. Low–molecular-weight heparin was started 3 to 4 days before surgery and continued for 6 days after surgery at 70 anti–factor Xa U/kg twice daily in high-thromboembolic-risk patients and prophylactic once-daily doses in moderate- to low-risk patients. Oral anticoagulation was resumed the day after the procedure with a boost dose of 50% for 2 days and maintenance doses afterward. The patients were followed up for 30 days. Of the 1262 patients included in the study (only 15% had mechanical valves), 295 (23.4%) were high-thromboembolic-risk patients and 967 (76.6%) were moderate- to low-risk patients. In the intention-to-treat analysis, there were 5 thromboembolic events (0.4%; 95% confidence interval, 0.1 to 0.9), all in high-thromboembolic-risk patients. There were 15 major (1.2%; 95% confidence interval, 0.7 to 2.0) and 53 minor (4.2%; 95% confidence interval, 3.2 to 5.5) bleeding episodes. Major bleeding was associated with twice-daily low–molecular-weight heparin administration (high-risk patients) but not with the bleeding risk of the procedure. Conclusions— This management bridging protocol, tailored to patients’ thromboembolic risk, appears to be feasible, effective, and safe for many patients, but safety in patients with mechanical prosthetic valves has not been conclusively established.