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It is currently unknown whether thrombin generation is associated with venous thromboembolism (VTE) recurrence, major bleeding, or mortality in the elderly. Therefore, our aim was to prospectively study the association between thrombin generation and VTE recurrence, major bleeding, and mortality in elderly patients with acute VTE. Consecutive patients aged ≥65 years with acute VTE were followed for 2 years, starting from 1 year after the index VTE. Primary outcomes were VTE recurrence, major bleeding, and mortality. Thrombin generation was assessed in 551 patients 1 year after the index VTE. At this time, 59% of the patients were still anticoagulated. Thrombin generation was discriminatory for VTE recurrence, but not for major bleeding and mortality in non-anticoagulated patients. Moreover, peak ratio (adjusted subhazard ratio 4.09, 95% CI, 1.12–14.92) and normalized peak ratio (adjusted subhazard ratio 2.18, 95% CI, 1.28–3.73) in the presence/absence of thrombomodulin were associated with VTE recurrence, but not with major bleeding and mortality after adjustment for potential confounding factors. In elderly patients, thrombin generation was associated with VTE recurrence, but not with major bleeding and/or mortality. Therefore, our study suggests the potential usefulness of thrombin generation measurement after anticoagulation completion for VTE to help identify among elderly patients those at higher risk of VTE recurrence. [ABSTRACT FROM AUTHOR]

Background and purpose: Vascular brain lesions, such as ischemic infarcts, are common among patients with atrial fibrillation (AF) and are associated with impaired cognitive function. The role of physical activity (PA) in the prevalence of brain lesions and cognition in AF has not been investigated. Methods: Patients from the multicenter Swiss‐AF cohort study were included in this cross‐sectional analysis. We assessed regular exercise (RE; at least once weekly) and minutes of weekly PA using a validated questionnaire. We studied associations with ischemic infarcts, white matter hyperintensities, cerebral microbleeds, and brain volume on brain magnetic resonance imaging and with global cognition measured with a cognitive construct (CoCo) score. Results: Among 1490 participants (mean age = 72 ± 9 years), 730 (49%) engaged in RE. In adjusted regression analyses, RE was associated with a lower prevalence of ischemic infarcts (odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.63–0.98, p = 0.03) and of moderate to severe white matter hyperintensities (OR = 0.78, 95% CI = 0.62–0.99, p = 0.04), higher brain volume (β‐coefficient = 10.73, 95% CI = 2.37–19.09, p = 0.01), and higher CoCo score (β‐coefficient = 0.08, 95% CI = 0.03–0.12, p < 0.001). Increasing weekly PA was associated with higher brain volume (β‐coefficient = 1.40, 95% CI = 0.65–2.15, p < 0.001). Conclusions: In AF patients, RE was associated with a lower prevalence of ischemic infarcts and of moderate to severe white matter disease, with larger brain volume, and with better cognitive performance. Prospective studies are needed to investigate whether these associations are causal. Until then, our findings suggest that patients with AF should be encouraged to remain physically active. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is considered as risk factor for the development of mild cognitive impairment (MCI) and dementia. However, dynamics of cognitive functions are subtle, and neurocognitive assessments largely differ in detecting these changes. We aimed to develop and evaluate a score which represents the common aspects of the cognitive functions measured by validated tests (i.e., "general cognitive construct"), while reducing overlap between tests and be more sensitive to identify changes in overall cognitive functioning. Methods: We developed the CoCo (cognitive construct) score to reflect the cognitive performance obtained by all items of four neurocognitive assessments (Montreal Cognitive Assessment (MoCA); Trail Making Test; Semantic Fluency, animals; Digital Symbol Substitution Test). The sample comprised 2,415 AF patients from the Swiss Atrial Fibrillation Cohort Study (Swiss-AF), 87% aged at least 65 years. Psychometric statistics were calculated for two cognitive measures based on (i) the full set of items from the neurocognitive test battery administered in the Swiss-AF study (i.e., CoCo item set) and (ii) the items from the widely used MoCA test. For the CoCo item set, a factor score was derived based on a principal component analysis, and its measurement properties were analyzed. Results: Both the MoCA item set and the full neurocognitive test battery revealed good psychometric properties, especially the full battery. A one-factor model with good model fit and performance across time and groups was identified and used to generate the CoCo score, reflecting for each patient the common cognitive skill performance measured across the full neurocognitive test battery. The CoCo score showed larger effect sizes compared to the MoCA score in relation to relevant clinical variables. Conclusion: The derived factor score allows summarizing AF patients' cognitive performance as a single score. Using this score in the Swiss-AF project increases measurement sensitivity and decreases the number of statistical tests needed, which will be helpful in future studies addressing how AF affects the risk of developing cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Patients with atrial fibrillation (AF) have an increased risk of cognitive decline, potentially resulting from clinically unrecognized vascular brain lesions.Objectives: This study sought to assess the relationships between cognitive function and vascular brain lesions in patients with AF.Methods: Patients with known AF were enrolled in a multicenter study in Switzerland. Brain magnetic resonance imaging (MRI) and cognitive testing using the Montreal Cognitive Assessment (MoCA) were performed in all participants. Large noncortical or cortical infarcts (LNCCIs), small noncortical infarcts (SNCIs), microbleeds, and white matter lesions were quantified by a central core laboratory. Clinically silent infarcts were defined as infarcts on brain MRI in patients without a clinical history of stroke or transient ischemic attack.Results: The study included 1,737 patients with a mean age of 73 ± 8 years (28% women, 90% taking oral anticoagulant agents). On MRI, LNCCIs were found in 387 patients (22%), SNCIs in 368 (21%), microbleeds in 372 (22%), and white matter lesions in 1715 (99%). Clinically silent infarcts among the 1,390 patients without a history of stroke or transient ischemic attack were found in 201 patients with LNCCIs (15%) and 245 patients with SNCIs (18%). The MoCA score was 24.7 ± 3.3 in patients with and 25.8 ± 2.9 in those without LNCCIs on brain MRI (p < 0.001). The difference in MoCA score remained similar when only clinically silent LNCCIs were considered (24.9 ± 3.1 vs. 25.8 ± 2.9; p < 0.001). In a multivariable regression model including all vascular brain lesion parameters, LNCCI volume was the strongest predictor of a reduced MoCA (β = -0.26; 95% confidence interval: -0.40 to -0.13; p < 0.001).Conclusions: Patients with AF have a high burden of LNCCIs and other brain lesions on systematic brain MRI screening, and most of these lesions are clinically silent. LNCCIs were associated with worse cognitive function, even among patients with clinically silent infarcts. Our findings raise the question of MRI screening in patients with AF. [ABSTRACT FROM AUTHOR]

Aims: The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated. Methods and results: Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-α); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibitor (TFPI) and the underlying mechanisms were determined. Further, arterial thrombosis by photochemical injury of the common carotid artery, and TF expression in the murine endothelium were examined in C57BL/6 mice treated with ticagrelor or clopidogrel. Ticagrelor, but not CAM, reduced TNF-ainduced TF expression via proteasomal degradation and TF activity, independently of the P2Y12 receptor and the equilibrative nucleoside transporter 1 (ENT1), an additional target of ticagrelor. In C57BL/6 mice, ticagrelor prolonged time to arterial occlusion, compared with clopidogrel, despite comparable antiplatelet effects. In line with our in vitro results, ticagrelor, but not clopidogrel, reduced TF expression in the endothelium of murine arteries. Conclusion: Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants (DOACs) have a favourable risk-benefit profile compared to vitamin K-antagonists (VKAs) in atrial fibrillation (AF). Dosing is based on age, weight and renal function, without need of routine monitoring. In two prospective, multicentre AF cohorts (Swiss-AF, BEAT-AF) patients were stratified as receiving VKAs or adequately-, under- or overdosed DOACs, according to label. Primary outcome was a composite of major adverse clinical events (MACE), defined as cardiovascular death, myocardial infarction (MI), ischaemic stroke and systemic embolism. Secondary outcomes included major bleeding. Adjustment for confounding was performed. Median follow-up was 4 years. Of 3236 patients, 1875 (58%) were on VKAs and 1361 (42%) were on DOACs, of which 1137 (83%) were adequately-, 134 (10%) over- and 90 (7%) under-dosed. Compared to adequately dosed individuals, overdosed patients were more likely to be older and female. Underdosing correlated with concomitant aspirin therapy and coronary artery disease. Both groups had higher CHA 2 DS 2 -VASc scores. Patients on overdosed DOACs had higher incidence of MACE (HR 1.75; CI 1.10–2.79; adjusted-HR: 1.22) and major bleeding (HR 1.99; CI 1.14–3.48; adjusted-HR: 1.51). Underdosing was not associated with a higher incidence of MACE (HR 0.94; CI 0.46–1.92; adjusted-HR 0.61) or major bleeding (HR 1.07; CI 0.46–2.46; adjusted-HR 0.82). After adjustment, all CIs crossed 1.0. Inappropriate DOAC-dosing was more prevalent in multimorbid patients, but did not correlate with higher risks of adverse events after adjusting for confounders. DOAC prescription should follow label. [ABSTRACT FROM AUTHOR]

Previously we reported that dietary intake of alpha-linolenic acid (ALA) reduces ath-erogenesis and inhibits arterial thrombosis. Here, we analyze the substantial increase in platelet count induced by ALA and the mechanisms of reduced platelet clearance. Eight-week-old male apolipoprotein E knockout (ApoE)-/- mice were fed a 0.21 g% cholesterol diet complemented by either a high- (7.3g%) or low-ALA (0.03g%) content. Platelet counts doubled after 16 weeks of ALA feeding, whereas the bleeding time remained similar. Plasma glycocalicin and glycocalicin index were reduced, while reticulated platelets, thrombopoietin, and bone marrow megakaryocyte colony-forming units remained unchanged. Platelet contents of liver and spleen were substantially reduced, without affecting macrophage function and number. Glycoprotein lb (GPIb) shedding, exposure of P-selectin, and activated integrin αllbβ3 upon activation with thrombin were reduced. Dietary ALA increased the platelet count by reducing platelet clearance in the reticulo-endothelial system. The latter appears to be mediated by reduced cleavage of GPIb by tumor necrosis factor-a-converting enzyme and reduced platelet activation/ expression of procoagulant signaling. Ex vivo, there was less adhesion of human platelets to von Willebrand factor under high shear conditions after ALA treatment. Thus, ALA may be a promising tool in transfusion medicine and in high turnover/high activation platelet disorders. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Air pollution with fine particulates (PM10 and PM2.5) is associated with an increased incidence of cardiovascular events. The proposed mechanisms include indirect proinflammatory and procoagulant reactions involving activation of pulmonary macrophages, endothelial cells and the TNF/TF pathway, or direct procoagulant effects. Our laboratory has observed a reduction of the platelet responsiveness to collagen after exposure to diesel exhaust particles (DEP). Hypothesis: DEP directly interfere with platelet–collagen interactions by selectively inducing the shedding of platelet signaling receptors via metalloproteinases, which would represent a novel mechanism for DEP action on platelets. Methods: Citrated blood from healthy volunteers was exposed to highly standardized DEP at concentrations of 0.1, 2.5 and 5.0μg/ml or ultrafine carbon black (ufCB, 0.1μg/ml) and the plasmatic and platelet response was analysed. The closure times with the PFA-100 device and the platelet aggregation in response to a variety of agonists were monitored. Interleukins (IL)-1β and IL-8 levels were determined by ELISA and soluble P-selectin by the Luminex bead assay. Thrombin activity was measured as the endogenous thrombin potential (ETP) by fluorescence spectrometry. Soluble GPVI and GPIbα (glycocalicin) ectodomain fragments were measured by ELISA. ADAMTS13 activity was determined by a FRETS based assay and plasmin activity with Spectrozyme PL. Results: Aggregation assays where platelets were treated with low dose DEP or ultrafine carbon black (ufCB) revealed a significantly increased response to low doses of collagen (p <0.05, n =5). At higher doses, however, collagen induced aggregation was suppressed by DEP treatment: at 2.5μg/ml, the inhibition was 34±12% (p <0.01, n =10). Aggregations with cross-linked collagen related peptide (CRPxl), convulxin and with the monoclonal antibody 9O12.2 (all known to specifically bind to and activate GPVI) were also diminished. Ristocetin, arachidonic acid and ADP responses were normal at all DEP concentrations. No cleavage of GPVI ectodomain was detected (soluble GPVI 27.8±3 vs. 28±4μg/ml mean±SEM, n =10); however increased plasma glycocalicin (GPIbα ectodomain) was detected upon diesel exposure (2.58±0.11 vs. 2.28±0.03μg/ml p <0.01, n =10). ADAMTS13 and plasmin activity remained unaffected by DEP under the conditions tested. Platelets were not activated by either DEP or ufCB as soluble P-selectin was insensitive to these. Conclusions: DEP specifically and directly interferes with platelet–collagen interactions. The functional consequences are biphasic and include enhance platelet aggregation at lower DEP concentrations and inhibition at a higher dose. Our data indicate that this interaction does not involve P-selectin or GPVI shedding. It is however associated with an increase in GPIb cleavage. [Copyright &y& Elsevier]

Background: Combining high‐sensitivity cardiac Troponin T (hs‐cTnT), NT‐pro‐B‐type natriuretic peptide (NT‐proBNP) and high‐sensitivity C‐reactive protein (hs‐CRP) may improve risk stratification of patients with pulmonary embolism (PE) beyond the PESI risk score. Methods: In the prospective multicentre SWITCO65+ study, we analysed 214 patients ≥ 65 years with a new submassive PE. Biomarkers and clinical information for the PESI risk score were ascertained within 1 day after diagnosis. Associations of hs‐TnT, NT‐proBNP, hs‐CRP and the PESI risk score with the primary endpoint defined as 6‐month mortality were assessed. The discriminative power of the PESI risk score and its combination with hs‐cTnT, NT‐proBNP and hs‐CRP for 6‐month mortality was compared using integrated discrimination improvement (IDI) index and net reclassification improvement (NRI). Results: Compared with the lowest quartile, patients in the highest quartile had a higher risk of death during the first 6 months for hs‐cTnT (adjusted HR 10.22; 95% CI 1.79‐58.34; P = 0.009) and a trend for NT‐proBNP (adjusted HR 4.3; 95% CI 0.9‐20.41; P = 0.067) unlike hs‐CRP (adjusted HR 1.97; 95% CI 0.48‐8.05; P = 0.344). The PESI risk score (c‐statistic 0.77 (95% CI 0.69‐0.84) had the highest prognostic accuracy for 6‐month mortality, outperforming hs‐cTnT, NT‐proBNP and hs‐CRP (c‐statistics of 0.72, 0.72, and 0.54), respectively. Combining all three biomarkers had no clinically relevant impact on risk stratification when added to the PESI risk score (IDI = 0.067; 95% CI 0.012‐0.123; P = 0.018; NRI = 0.101 95% CI −0.099‐0.302; P = 0.321). Conclusions: In elderly patients with PE, 6‐month mortality can adequately be predicted by the PESI risk score alone. [ABSTRACT FROM AUTHOR]