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.

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 sensitiv- ity 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.

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.

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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.

BackgroundGrowth 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).MethodsFour 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.ResultsOverall 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 < 0.0001). In a multivariate regression analysis advanced age, DM, acute hyperglycemia (AHG), CRP and chronic kidney disease (CKD) were independent predictors of elevated GDF-15 levels (P < 0.05). Receiver operating curve analysis of GDF-15 for prediction of CV-death showed an area under the curve of 0.852 with a confidence interval of 0.745-0.960, P < 0.0001. The estimated cut-off was 2094.6 pg/ml with a sensitivity of 76 % and specificity of 80 %.ConclusionIn patients with CAD undergoing PCI with stent implantation, GDF-15 is determined by advanced age, acute and chronic hyperglycemia, inflammation and CKD. GDF-15 is a valuable predictor of CV-death in a population of CAD patients after PCI.

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