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We examined whether resting levels and exercise-induced changes during exercise ECG stress test (EST) of cardiac Troponin T (cTnT), NT-proBNP and prothrombotic markers were affected by revascularization in patients with coronary artery disease (CAD).EST1 was performed before coronary angiography and revascularization, and patients (n  =  20) with confirmed CAD, performed another EST (EST2) 9 weeks later. Blood samples were drawn at rest and within five min after termination of ESTs.cTnT and NT-proBNP increased during exercise at both ESTs (p < 0.001, all). Resting cTnT levels at EST2 versus EST1 were significantly higher (p  =  0.02) whereas NT-proBNP did not differ. At both visits, increased D-dimer (p  =  0.008 and <0.001), pro-thrombin fragment 1  +  2 (p  =  0.009 and 0.001) and tissue factor pathway inhibitor (TFPI) (p < 0.001 and 0.001) during exercise were demonstrated. Resting levels of endogenous thrombin potential (ETP) and TFPI were reduced at EST2 versus EST1 (p < 0.01).Revascularization did not affect exercise-induced release of cardiac and prothrombotic biomarkers and did not reduce resting levels of cTnT or NT-proBNP, suggesting revascularization per se not to prevent secretion of biomarkers. The lower resting levels of ETP and TFPI after revascularization may however, be indicative of reduced thrombin generation and endothelial activation.Clinicaltrials.gov, CADENCE, NCT01495091 https://clinicaltrials.gov/ct2/show/NCT01495091?term = 01495091&draw = 2&rank = 1.

Objective: Circulating microvesicles, released from activated/apoptotic cells, are involved in vascular complications and may be looked upon as biomarkers. Albuminuria is characteristic of disease progression in type 2 diabetes mellitus. We aimed to investigate quantitative and qualitative differences of circulating microvesicles in type 2 diabetes mellitus with and without albuminuria and whether 12-month exercise training influenced expression of circulating microvesicles., Methods: Coronary artery disease patients with type 2 diabetes mellitus (n = 75), of which 25 had albuminuria, were included. Annexin V + (AV + ) circulating microvesicles were analysed by flow cytometry in citrated plasma. The exercise volume was 150 min per week., Results: In albuminuria patients, circulating microvesicles from endothelial-(CD146 + /CD62E + /AV + ) and endothelial-progenitor-(CD309 + /CD34 + /AV + ) cells were significantly higher compared to those without ( p  ⩽ 0.01, both). Receiver operating characteristic curve analysis of the endothelial circulating microvesicles shows an area under the curve of 0.704 (95% confidence interval: 0.57-0.84; p  = 0.004). Albuminuria patients had more circulating microvesicles derived from activated leukocytes and monocytes and monocytes carrying tissue factor (CD11b + /AV + , CD11b + /CD14 + /AV + , CD142 + /CD14 + /AV + , respectively, p  ⩽ 0.05, all) and higher number of circulating microvesicles from activated platelets (CD62P + /AV + ). Within exercising patients, circulating microvesicles from progenitor cells increased ( p  = 0.023), however, not significantly different from controls., Conclusion: Coronary artery disease patients with type 2 diabetes mellitus and albuminuria had elevated number of circulating microvesicles from activated blood and vascular cells, rendering them as potential predictors of disease severity. The circulating microvesicles were limitedly affected by long-term exercise training in our population.

Background Neutrophil extracellular traps, comprising chromatin and granule proteins, have been implicated in atherothrombosis. Design and methods We investigated whether the circulating neutrophil extracellular traps markers, double-stranded DNA and myeloperoxidase-DNA were associated with clinical outcome and hypercoagulability in patients with stable coronary artery disease. Patients with angiographically verified stable coronary artery disease ( n = 1001) were included. Follow-up was 2 years, recording 106 clinical endpoints (unstable angina, non-haemorrhagic stroke, myocardial infarction or death). Serum collected at baseline was used to determine double-stranded DNA and myeloperoxidase-DNA levels. Results The neutrophil extracellular traps markers were weakly intercorrelated ( r = 0.103, P = 0.001). Patients with the highest quartile of double-stranded DNA had weakly but significantly elevated hypercoagulability markers (prothrombin fragment 1+2, D-dimer, free and total tissue factor pathway inhibitor ( P < 0.001 for all)). Men, smokers, patients with metabolic syndrome and patients with a previous myocardial infarction had significantly elevated double-stranded DNA levels ( P ≤ 0.002 for all). Significantly higher double-stranded DNA levels were observed in the group experiencing a clinical endpoint compared to the group without ( P = 0.019). When categorising double-stranded DNA into quartiles, a distinct cut-off between the lowest and upper three quartiles was observed. Adjusting for relevant covariates, patients in the upper three quartiles had an odds ratio of 2.01 (95% confidence interval 1.12, 3.58, P = 0.019) for experiencing a clinical endpoint. Myeloperoxidase-DNA was not significantly associated with clinical outcome or hypercoagulability. Conclusions Double-stranded DNA levels were significantly related to adverse clinical outcome after 2 years, but only weakly associated with hypercoagulability. These observations suggest that the detrimental effects of neutrophil extracellular traps in coronary artery disease might extend beyond those related to hypercoagulability.

We investigated the effects of 12-month exercise training on hypercoagulability in patients with combined type 2 diabetes mellitus and coronary artery disease. Associations with severity of disease were further explored. Patients ( n = 131) were randomized to exercise training or a control group. Blood was collected at inclusion and after 12 months. Tissue factor, free and total tissue factor pathway inhibitor, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer were determined by enzyme-linked immunosorbent assay and ex vivo thrombin generation by the calibrated automated thrombogram assay. Tissue factor and ex vivo thrombin generation increased from baseline to 12 months ( p < 0.01, all), with no significant differences in changes between groups. At baseline, free and total tissue factor pathway inhibitor significantly correlated to fasting glucose ( p < 0.01, both) and HbA1c ( p < 0.05, both). In patients with albuminuria ( n = 34), these correlations were strengthened, and elevated levels of D-dimer, free and total tissue factor pathway inhibitor ( p < 0.01, all) and decreased ex vivo thrombin generation ( p < 0.05, all) were observed. These results show no effects of exercise training on markers of hypercoagulability in our population with combined type 2 diabetes mellitus and coronary artery disease. The association between poor glycaemic control and tissue factor pathway inhibitor might indicate increased endothelial activation. More pronounced hypercoagulability and increased tissue factor pathway inhibitor were demonstrated in patients with albuminuria.

Introduction: Aspirin inhibits the cyclooxygenase-1 (COX-1) mediated thromboxane A2 synthesis. Despite COX-1 inhibition, in patients with coronary artery disease (CAD), platelets can be activated through other mechanisms, like activation by thrombin., Materials and Methods: At baseline in this cross-sectional substudy of the ASCET trial, 1001 stable CAD patients, all on single aspirin treatment, were classified by the PFA100® method, as having high on-aspirin residual platelet reactivity (RPR) or not. Markers of hypercoagulability, endothelial and platelet activation as related to RPR, were evaluated to explore the potential mechanisms behind high on-aspirin RPR., Results: Altogether, 25.9% (n=259) of the patients were found to have high on-aspirin RPR. S-thromboxane B(2) levels were very low and did not differ between patients having high on-aspirin RPR or not. Patients with high on-aspirin RPR had significantly higher levels of von Willebrand Factor (vWF) (124 vs 100%, p<0.001, platelet count (236 vs 224 × 10(9)/l, p=0.008), total TFPI (68.4 vs 65.5 ng/ml, p=0.005) and ß-thromboglobulin (ß-TG) (33.3 vs 31.3 IU/ml, p=0.041) compared to patients with low on-aspirin RPR. No significant differences between the groups were observed in levels of endogenous thrombin generation (ETP), pro-thrombin fragment 1+2 (F1+2), D-dimer, soluble TF (sTF) or P-selectin (all p>0.05)., Conclusions: The high on-aspirin RPR as defined by PFA100® seems not to be due to increased thrombin activity as evaluated with ETP, sTF, F1+2 or D-dimer. The elevated levels of platelet count, ß-TG, TFPI and especially vWF might be explained by increased endothelial and platelet activation in these patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In patients with stable coronary heart disease (n = 1,001) we investigated the influence of tissue factor (TF) and TF pathway inhibitor (TFPI) polymorphisms on thrombin generation in vivo, measured by prothrombin fragment (F) 1 and 2, and the potential to generate thrombin ex vivo, measured by the calibrated automated thrombogram assay. Additionally, circulating levels of TF and TFPI were correlated to the different parameters of thrombin generation. The TF 5466 and TFPI -399 polymorphisms associated with higher thrombin generation in vivo, the latter also with a prolonged lag time of the thrombin generation ex vivo(p < 0.05 for all).The TF -1812 TT and the TF -603 GG genotypes were associated with lower peak thrombin and a decreased average net rate of thrombin activation during the propagation phases (p ≤ 0.05), and the TFPI -33 TC genotype with prolonged lag time (p < 0.05) and additionally time to peak (p = 0.06). Strong correlations between TFPI levels, prothrombin fragment 1 and 2 as well as calibrated automated thrombogram parameters were observed., (Copyright © 2011 S. Karger AG, Basel.)