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Background Increased platelet turnover and high platelet reactivity are associated with short-term major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) or stable coronary artery disease (SCAD). We investigated the impact of platelet turnover on long-term MACE. Methods Consecutive patients presenting with ACS or SCAD undergoing PCI between 2009 and 2010 were included. All patients received clopidogrel and aspirin as dual antithrombotic therapy regimen. Multivariable Cox proportional hazard models were applied to assess the prognostic impact of platelet turnover (reticulated platelet count [RPC], mean platelet volume [MPV]) and function on long-term MACE, a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. Results In total, 477 patients were eligible. Mean age was 64.3 ± 12.7 years, 68.8% were male. Median follow-up was 5.8 (IQR 4.2-6.5) years. Median RPC was 7.6 (IQR 5.6-10.4) g/L and median MPV was 10.7 (IQR 10.1-11.3) fL. In univariable analysis, RPC was associated with MACE, both as continuous (HR 1.064 [95%CI 1.021-1.111]; P = .006) and dichotomized (HR 1.693 [95%CI 1.156-2.481]; P = .006) variable. After adjustment, continuous RPC (HR 1.055 [95%CI 1.012-1.099]; P = .010) and dichotomized RPC (HR 1.716 [95%CI 1.152-2.559]; P = .007) remained significantly associated with MACE. Neither MPV nor platelet function testing was associated with long-term adverse outcome. Conclusion Increased platelet turnover is associated with long-term adverse outcome in patients with coronary artery disease undergoing PCI. Platelet turnover represents a new marker of atherothrombotic risk and might help to guide composition or duration of antiplatelet therapy.

Summary Background Atrial fibrillation (AF) is associated with raised levels of P-selectin and an apparent prothrombotic state. However, levels of tissue plasminogen activator (t-PA)-antigen are increased also. We investigated whether high levels of endogenous t-PA-antigen or soluble P-Selectin (sP-Selectin), independently of CHADS2- or CHA2DS2VASc-scores, predict major adverse cardiovascular events (MACE) in patients with AF when treated according to current guidelines. Methods This prospective, longitudinal single-center study included 269 patients with AF. Blood samples were analyzed for sP-Selectin and t-PA-antigen concentration by means of commercially available enzyme-linked immunoassays. Results Patients were followed for a median duration of 1933 (1517–2277) days, during which 78 MACE and 82 deaths occurred. In multivariable analyses t-PA-antigen above the median of 4.22 ng mL−1 was associated with MACE and all-cause death (HR 2.55 [1.43–4.57]; P = 0.002) and (HR 2.54 [1.38–4.68]; P = 0.003), respectively. There was no association of sP-Selectin with MACE or all-cause death. Furthermore, t-PA-antigen above the median independently of the CHADS2- or CHA2DS2VASc-scores predicted MACE and all-cause death. In patients with low and intermediate-risk for cardiovascular events according to the CHADS2-score the addition of high t-PA-antigen levels (> 4.22 ng mL−1) had a significant impact on the patients' outcome (low-risk group, HR 3.25 [1.13–9.38]; P = 0.029 and intermediate-risk group, HR 2.33 [1.27–4.26]; P = 0.006, respectively). Conclusion High endogenous t-PA-antigen independently predicts MACE and all-cause death in patients with AF. Accordingly, t-PA-antigen as an indicator of a prothrombotic state represents a novel biomarker, which might add to risk stratification in patients with AF.

SummaryElevated platelet turnover contributes to high platelet reactivity. High platelet reactivity after percutaneous coronary intervention (PCI) is associated with major adverse cardiovascular events (MACE). The purpose of this study was to determine the prognostic value of platelet turnover and function with regard to MACE after PCI with stent implantation. In this prospective observational study, 486 consecutive patients after PCI on aspirin and clopidogrel were included to determine platelet turnover (mean platelet volume (MPV), reticulated platelet fraction (RPF)) and platelet function (multiple electrode aggregometry (MEA), vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) assay). At six-months follow-up, MACE occurred in 10.7 % of patients. RPF (odds ratio [OR]=1.173 (95% confidence interval [CI 95 %] 1.040–1.324), p=0.009) and MPV (OR=1.459 (CI 95 % 1.059–2.008), p=0.021) were univariable predictors of MACE, whereas VASP-P (OR=1.016 (CI 95 % 1.000–1.032), p=0.052) and MEA (OR=0.999 (CI 95 % 0.980–1.017), p=0.895) failed to predict MACE. RPF remained the only platelet variable independently associated with MACE. The best model to predict MACE included: troponin I (OR=1.007 (CI 95 % 1.002–1.012), p=0.009), RPF (OR=1.136 (CI 95 % 1.001–1.288), p=0.048), CRP (OR=1.008 (CI 95 % 1.001–1.014), p=0.023) and history of myocardial infarction (OR=2.039 (CI 95 % 1.093–3.806), p=0.025). RPF (OR=1.211 (CI 95 % 1.042–1.406), p=0.012) was also independently associated with in-hospital bleedings. In conclusion, RPF as index of platelet turnover is an independent predictor of MACE and bleeding events in PCI patients on dual antiplatelet therapy. Since RPF can reliably be quantified along with routine haemograms, RPF might easily be applied in the setting of cardiovascular risk prediction.

Background Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor ß family and has been associated with inflammation, cancer, aging, diabetes mellitus (DM) and atherosclerosis. Determinants of GDF-15 have been investigated in several conditions. We aimed to investigate determinants of GDF-15 plasma levels in patients with angiographically proven coronary artery disease (CAD). Methods Four hundred and seventy three consecutive patients with CAD were investigated between May 2009 and February 2011. Patients were separated into those with stable CAD (SCAD) and with ST-elevation and non-ST-elevation myocardial infarction (STEMI and NSTEMI). Blood samples for determination of GDF-15 were obtained before coronary angiography. Determinant of GDF-15 levels were analyzed by logistic regression analysis in unadjusted and adjusted models. Study endpoints were cardiovascular death (CV-death), myocardial infarction, unstable angina, unplanned revascularization, stent thrombosis and stroke assessed at a mean follow-up of 188 (177.2–243) days. Results Overall median and (25–27th percentile) GDF-15 level was 1212.8 pg/ml (833.2–1957 pg/ml). GDF-15 was significantly higher in STEMI compared to SCAD and NSTEMI groups (P

SummaryThe vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) flow-cytometric assay is mainly used in clinical trials to measure thienopyridine effects. However, there are remarkable differences in the reported optimal cut-offs, ranging from 48–61% platelet reactivity index (PRI). We therefore investigated whether a lack of standardisation might explain the differences in the cut-offs. We measured VASP-P in 62 individuals. PRI was calculated using the mean, geometric mean and median fluorescence intensities (FI). Stability of the blood-samples (time-to-assay, 0–2 days) and stability of the processed samples (0–120 minutes) within the recommended time-span were tested. Time-to-assay significantly influenced the PRI (p

SummaryVon Willebrand factor (vWF) plays an essential role in platelet adhesion and thrombus formation. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 antigen levels compared to controls. Little is known about vWF and ADAMTS13 in AF patients treated with cardioversion (CV). Thus we investigated the alterations of plasma vWF and ADAMTS13 after CV and evaluated the predictive value of these parameters for recurrence of AF. In this observational study we determined plasma levels of vWF and ADAMTS13 in 77 patients before and immediately after CV, as well as 24 hours (h) and six weeks thereafter, by means of commercially available assays. The vWF/ ADAMTS13-ratio was significantly elevated immediately after CV (p=0.02) and 24 h after CV (p=0.002) as compared to baseline levels. ADAMTS13, 24 h after CV, exhibited a significant association with recurrence of AF (HR: 0.97; p=0.037). Accordingly, tertiles of ADAMTS13 showed a stepwise inverse correlation with the risk of recurrent AF (HR: 0.50; p=0.009). After adjustment for confounders, ADAMTS13 remained significant as an independent predictor of recurrent AF (HR: 0.61; p=0.047). Similarly, the vWF/ADAMTS13-ratio, 24 h after CV, was associated with rhythm stability and remained an independent predictor of recurrent AF (HR: 1.88; p=0.028). The regulation of vWF and its cleaving protease ADAMTS13 after CV might play a critical role in producing a pro-thrombotic milieu immediately after CV for AF. Since ADAMTS13 plasma concentration and the vWF/ADAMTS13-ratio are independently associated with rhythm stability, these indexes might be used for prediction of recurrence of AF.

SummaryReduced antiplatelet effect of clopidogrel assessed with multiple electrode aggregometry (MEA) and vasodilator stimulated phosphoprotein-phosphorylation (VASP-P) assay has been proven to predict major adverse cardiovascular events (MACE) after coronary stenting. So far no consecutive registry has evaluated the usefulness of different adenosine diphosphate-based platelet function tests to predict outcome in unselected patients. Hence, our objective was to determine the feasibility of MEA and VASP-P for clinical routine and whether low-response to clopidogrel as determined by MEA and/or the VASP-P assays predicts MACE in a “real-life” population undergoing coronary stenting. Threehundred consecutive patients were included in this prospective registry. Blood was sampled 6–24 hours after stenting to measure MEA and VASP-P. The use of glycoprotein-IIb/IIIa-blockers limited MEA to 196 measurements. Concerning the VASP-P assay, 300 measurements were achieved. Receiver Operating Characteristics (ROC)-curves of sensitivity and specificity estimates for MACE were plotted for VASP-P assay. The area under the ROC-curve was 0.683 (p=0.014) for the platelet reactivity index (PRI) calculated from median fluorescence intensities (FI) with an optimal cut-off at 60.2% PRI. Patients above 60.2% had a significantly increased risk for MACE at six months follow-up (p=0.007). Estimating the cut-offs for the PRI from mean FI (52%) or from geometric mean FI (56.6%) led to clinically relevant differences. VASP-P assay is feasible for clinical routine to measure clopidogrel effects and to predict post-procedural MACE in unselected patients. With regard to differing cut-offs, exact standardisation of the VASP-P assay is mandatory. The use of GP-IIb/IIIa-blockers prevents MEA testing and limits its usability in unselected patients.

Response to clopidogrel therapy is subject to inter-individual variability. However, data with regard to on-treatment platelet reactivity over time in patients undergoing coronary stenting are scarce. For this prospective observational study, 102 consecutive patients on dual antiplatelet therapy undergoing coronary stenting due to stable coronary artery disease (CAD; n = 29), non ST-elevation acute coronary syndrome (NSTE-ACS; n = 45) and ST-elevation myocardial infarction (STEMI; n = 28) were enrolled. Vasodilator-stimulated phosphoprotein-phosphorylation assay was performed at baseline, as well as 1, 3 and 6 months thereafter. Platelet reactivity index (PRI) measured after 1, 3 and 6 months was lower compared to baseline values (p 0.001). Variables responsible for reduced response to clopidogrel at baseline (reticulated platelet fraction, simvastatin therapy) and during steady-state phase (body mass index, blood glucose concentrations, cholesterol/HDL-ratio and quality of life score) were different. High on-treatment platelet reactivity (HTPR)-phenotype (cut-off = 50% PRI) within the first month changed in 31% of stable CAD, 33% of NSTE-ACS and 39% of STEMI patients, respectively. HTPR-phenotype in the steady-state phase (month 1 to 6) changed in 45% of stable CAD, 33% of NSTE-ACS and 25% of STEMI patients. Response to clopidogrel and accordingly platelet function might vary over time, especially when a cut-off based approach, is used. There was a significant reduction of on-treatment platelet reactivity within the first month after percutaneous coronary intervention with stenting which was maintained for up to 6 months. Variables associated with reduced response to clopidogrel at baseline and during steady-state phase were different, as the latter mainly reflected an unfavorable metabolic profile, comprising elevated BMI, blood glucose levels as well as cholesterol/HDL-ratio.

Background The von Willebrand factor (vWF) is essential for platelet adhesion and arterial thrombosis. It is degraded into less active multimers by ADAMTS13. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 antigen levels. The vWF/ADAMTS13-ratio might help to estimate the pro-thrombotic risk of patients with AF. We therefore investigated whether a high ratio of vWF/ADAMTS13, independently of clinical risk scores, predicts major adverse cardiovascular events (MACE) in patients with AF. Methods This prospective longitudinal single center study included 269 patients with AF. Blood samples were analyzed for vWF and ADAMTS13-antigen concentration by means of enzyme-linked immunoassay kits. Results After adjustment for all univariable predictors for MACE (p≤0.1), ADAMTS13≤49.77% (HR 1.833 (95% CI 1.089–3.086); p=0.023) and vWF/ADAMTS13-ratio>27.57 (HR 2.174 (95% CI 1.238–3.817); p=0.007) remained independently associated with outcome. vWF>1434.92mU/ml (HR 1.539 (95% CI 0.883–2.682); p=0.128) alone failed to independently predict MACE. In patients with low and intermediate risk for MACE according to the CHADS 2 -score the addition of high vWF/ADAMTS13-ratio levels (>27.57) had significant impact on the patients' outcome. Conclusion A high ratio of vWF/ADAMTS13 independently predicts MACE in patients with AF. Therefore, vWF and its cleaving protease ADAMTS13 might play an important role in the development and perpetuation of vascular disease in AF patients. This might be a novel target for future treatment strategies or an additional help for risk stratification in AF patients.

The crucial role of platelets in primary hemostasis and repair of injured endothelium is well established, as is their role in atherothrombosis. No other single cell type is responsible for as much morbidity and mortality, since death from ischemic heart disease or stroke is by far the leading cause of death worldwide. There is no doubt that our understanding of atherothrombosis has guided current antithrombotic strategies that have dramatically reduced ischemic complications and cardiovascular mortality within the last decades. Yet the rate of ischemic complications after optimal revascularization therapy remains disappointingly high. There is still a strong need for new and smart antiplatelet drugs. The ideal antithrombotic drug would spare physiological platelet function, hemostasis and vascular repair in order to avoid bleeding complications, but would exclusively target the pathological atherothrombotic process. As platelet activity might be determined early in the bone marrow, this review starts with insights into the birth of platelets, describes the essential and primary role of platelets in hemostasis with new evidence in signaling cascades, and closes with the deleterious role of platelets in atherosclerosis and atherothrombosis, with a focus on acute coronary syndromes.

Is increased platelet turnover responsible for low responsiveness to different thienopyridienes? A case report of recurrent stent thromboses