Uderhardt et al. show that eosinophils accumulate in freshly formed thrombi, where they provide a procoagulant surface that is rich in oxidized phospholipids and allows assembly and activation of plasmatic coagulation factors. This mechanism stabilizes the thrombus and enables hemostasis but also contributes to thrombotic disease.

Patients with CKD exhibit increased platelet activation, and an attenuated response to dual antiplatelet therapy compared with patients without renal insufficiency.

Platelets are the smallest blood cells, numbering 150 to 350???109/L in healthy individuals. The ability of activated platelets to adhere to an injured vessel wall and form aggregates was first described in the 19th century. Besides their long-established roles in thrombosis and hemostasis, platelets are increasingly recognized as pivotal players in numerous other pathophysiological processes including inflammation and atherogenesis, antimicrobial host defense, and tumor growth and metastasis. Consequently, profound knowledge of platelet structure and function is becoming more important in research and in many fields of modern medicine. This review provides an overview of platelet physiology focusing particularly on the structure, granules, surface glycoproteins, and activation pathways of platelets.

CCBs decrease clopidogrel-mediated platelet inhibition in patients undergoing angioplasty and stenting for cardiovascular disease.

Objective Unlike currently approved adenosine diphosphate (ADP) receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y12 but also the second human platelet ADP receptor P2Y1, and may therefore be a promising antiplatelet drug candidate. The current study is the first to investigate the in vivo antithrombotic effects of GLS-409. Approach and Results We studied (1) the in vivo effects of GLS-409 on agonist-stimulated platelet aggregation in anesthetized rats, (2) the antithrombotic activity of GLS-409 and the associated effect on the bleeding time in a canine model of platelet-mediated coronary artery thrombosis, and (3) the inhibition of agonist-stimulated platelet aggregation by GLS-409 versus selective P2Y1 and P2Y12 inhibition in vitro in samples from healthy human subjects before and 2 hours after aspirin intake. In vivo treatment with GLS-409 significantly inhibited ADP- and collagen-stimulated platelet aggregation in rats. Further, GLS-409 attenuated cyclic flow variation, i.e., platelet-mediated thrombosis, in vivo in our canine model of unstable angina. The improvement in coronary patency was accompanied by a non-significant 30% increase in bleeding time. Of note, GLS-409 exerted its effects without affecting rat and canine hemodynamics. Finally, in vitro treatment with GLS-409 showed effects similar to that of cangrelor and the combination of cangrelor with the selective P2Y1 inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 hours after aspirin intake. Conclusions Synergistic inhibition of both P2Y1 and P2Y12 ADP receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy.

To cite this article: Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Adenosine diphosphate-inducible platelet reactivity shows a pronounced age dependency in the initial phase of antiplatelet therapy with clopidogrel. J Thromb Haemost 2010; 8: 37-42.Summary. Background: Until recently, there were hardly any data on the antiplatelet effect of clopidogrel in advanced age. Like other metabolic processes, the conversion of clopidogrel to its active metabolite may be impaired in older patients, leading to high on-treatment residual ADP-inducible platelet reactivity. Objective: To investigate the age dependency of clopidogrelmediated platelet inhibition. Patients and methods: This was a prospective observational study. We determined adenosine 5¢-diphosphate (ADP)-inducible platelet reactivity using light transmission aggregometry (LTA) and the VerifyNow P2Y12 assay in 191 patients on dual antiplatelet therapy after angioplasty and stenting for cardiovascular disease. Results: ADPinducible platelet reactivity increased linearly with age after adjustment for cardiovascular risk factors, type of intervention, medication, C-reactive protein (CRP) and renal function [using LTA 0.36% of maximal aggregation per year, 95% CI 0.08-0.64%, P = 0.013; using the VerifyNow P2Y12 assay 3.2 P2Y12 reaction units (PRU) per year, 95% CI 1.98-4.41 PRU, P < 0.001]. ADP-inducible platelet reactivity was significantly higher in patients aged 75 years or older compared with younger patients (P = 0.003 for LTA and P < 0.001 for the VerifyNow P2Y12 assay). Further, high on-treatment residual ADP-inducible platelet reactivity was significantly more common among patients aged 75 years or older (P = 0.02 for LTA and P < 0.001 for the VerifyNow P2Y12 assay). Conclusion:ADP-inducible platelet reactivity shows a pronounced age dependency in the initial phase of antiplatelet therapy with clopidogrel. The clinical implications of these findings need to be addressed in future trials.

Antiplatelet therapy is a cornerstone in the secondary prophylaxis of adverse cardiovascular events such as myocardial infarction and stroke. The cyclooxygenase inhibitor aspirin remains the most frequently prescribed antiplatelet drug, followed by adenosine diphosphate P2Y12 receptor blockers. Glycoprotein IIb‐IIIa antagonists are intravenously available antiplatelet agents preventing platelet‐to‐platelet aggregation via the fibrinogen receptor. The thrombin receptor inhibitor vorapaxar allows the targeting of yet a third pathway of platelet activation. Despite the advent of novel agents and major advances in antiplatelet treatment over the last decade, atherothrombotic events still impair the prognosis of many patients with cardiovascular disease. Consequently, antiplatelet therapy remains a field of intense research and a large number of studies on its various aspects are published each year. This review article summarizes recent developments in antiplatelet therapy in cardiovascular disease focusing particularly on the duration of dual antiplatelet therapy, new treatment regimens, the role of platelet function testing, and potential future targets of antiplatelet agents.

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