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The addition of clopidogrel to aspirin treatment reduces ischemic events in a wide range of patients with cardiovascular disease. However, recurrent ischemic event occurrence during dual antiplatelet therapy, including stent thrombosis, remains a major concern. Platelet function measurements during clopidogrel treatment demonstrated a variable and overall modest level of P2Y(12) inhibition. High on-treatment platelet reactivity to adenosine diphosphate (ADP) was observed in selected patients. Multiple studies have now demonstrated a clear association between high on-treatment platelet reactivity to ADP measured by multiple methods and adverse clinical event occurrence. However, the routine measurement of platelet reactivity has not been widely implemented and recommended in the guidelines. Reasons for the latter include: 1) a lack of consensus on the optimal method to quantify high on-treatment platelet reactivity and the cutoff value associated with clinical risk; and 2) limited data to support that alteration of therapy based on platelet function measurements actually improves outcomes. This review provides a consensus opinion on the definition of high on-treatment platelet reactivity to ADP based on various methods reported in the literature and proposes how this measurement may be used in the future care of patients.

Summary Aim To determine whether an association exists between mean platelet volume (MPV) and acute myocardial infarction (AMI) and other cardiovascular events. Platelet activity is a major culprit in atherothrombotic events. MPV, which is widely available in clinical practice, is a potentially useful biomarker of platelet activity in the setting of cardiovascular disease. Methods and Results We performed a systematic review and meta-analysis investigating the association between MPV and AMI, all-cause mortality following myocardial infarction, and restenosis following coronary angioplasty. Results were pooled using random-effects modeling. Pooled results from 16 cross-sectional studies involving 2809 patients investigating the association of MPV and AMI indicated that MPV was significantly higher in those with AMI than those without AMI [mean difference 0.92 fL, 95% confidence interval (CI) 0.67–1.16, P < 0.001). In subgroup analyses, significant differences in MPV existed between subjects with AMI, subjects with stable coronary disease (P < 0.001), and stable controls (P < 0.001), but not vs. those with unstable angina (P = 0.24). Pooled results from three cohort studies involving 3184 patients evaluating the risk of death following AMI demonstrated that an elevated MPV increased the odds of death as compared with a normal MPV (11.5% vs. 7.1%, odds ratio 1.65, 95% CI 1.12–2.52, P = 0.012). Pooled results from five cohort studies involving 430 patients who underwent coronary angioplasty revealed that MPV was significantly higher in patients who developed restenosis than in those who did not develop restenosis (mean difference 0.98 fL, 95% CI 0.74–1.21, P < 0.001). Conclusions Elevated MPV is associated with AMI, mortality following myocardial infarction, and restenosis following coronary angioplasty. These data suggest that MPV is a potentially useful prognostic biomarker in patients with cardiovascular disease. Whether the relationship is causal, and whether MPV should influence practice or guide therapy, remains unknown.

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary intervention. In an earlier consensus document, we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post-percutaneous coronary intervention ischemic events for various platelet function tests (PFTs). Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention, although routine testing is not recommended (Class III). Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor. Recent prospective randomized trials of PFT did not demonstrate clinical benefit, thus questioning whether treatment modification based on the results of current PFT platforms can actually influence outcomes. However, there are major limitations associated with these randomized trials. In addition, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Therefore, a therapeutic window concept has been proposed for P2Y12 inhibitor therapy. In this updated consensus document, we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events. In addition, we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy.

We are too much accustomed to attribute to a single cause that which is the product of several, and the majority of our controversies come from that. Marcus AureliusThe Covid-19 pandemic has introduced an array of organspecific and systemic phenotypes-some previously observed in viral infections, including severe acute respiratory syndrome (SARS) and others that appear to be unique to SARScoronavirus (CoV)-2. Rapidly emerging information from clinical observations, autopsy-based findings, extrapolations from in vitro and ex vivo studies and dynamic modeling are informing management guidelines; however, many questions remain unanswered and clinical trials that are required to provide evidence have not been completed in most areas. Among the many questions that require careful thought, reflection and investigation are the mechanism(s) underlying the development of a systemic coagulopathy and acquired thrombophilia characterized in a majority of cases by a proclivity for venous, arterial and microvascular thrombosis.The following review summarizes emerging insights into the pathobiology, mechanism(s), diagnosis, management, foundations for research and either planned or ongoing clinical trials for Covid-19-associated coagulopathy.

BACKGROUND It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding. METHODS We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding. RESULTS In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], −0.6 to 0.8; P = 0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P = 0.005 for superiority). CONCLUSIONS In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.)

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