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Impact of Mon2 monocyte-platelet aggregates on human coronary artery disease.
Brown, RA, Lip, GYH, Varma, C, Shantsila, E
European journal of clinical investigation. 2018;(5):e12911
Abstract
BACKGROUND Monocyte-platelet aggregates (MPAs) form when Mon1, Mon2 or Mon3 monocyte subsets adhere to platelets. They are pathophysiologically linked to coronary artery disease (CAD). However, their individual roles in the occurrence of diffuse CAD remain unknown. MATERIALS AND METHODS Peripheral blood from 50 patients with diffuse CAD, 40 patients with focal CAD and 50 age-matched patients with normal coronary arteries was analysed by flow cytometry to quantify MPAs associated with individual monocyte subsets. Cutaneous forearm microcirculation was assessed using laser Doppler flowmetry at rest and after iontophoresis of acetylcholine (endothelium-dependent vasodilation) and sodium nitroprusside (endothelium-independent vasodilation) at 100 μA for 60 seconds. Patients with CAD had repeat assessment at 6 and 12 months. RESULTS Baseline counts of MPAs with Mon2 subset (CD14++CD16+CC2+ monocytes) were significantly higher in patients with diffuse CAD compared to focal CAD (P = .001) and patients without CAD (P = .006). On multivariate regression, MPAs with Mon2 independently predicted diffuse CAD (odds ratio 1.10, 95% confidence interval 1.02-1.19, P = .01) and correlated negatively with endothelium-dependent microvascular vasodilation (r = -.37, P = .008), an association which persisted after adjustment for covariates. Longitudinal observation confirmed the persistence of an inverse relationship between MPAs with Mon2 and endothelium-dependent microvascular function. CONCLUSION Monocyte-platelet aggregates with Mon2 are increased in patients with diffuse CAD and therefore could represent an important contributor to accelerated coronary atherosclerotic progression by a mechanism involving microvascular endothelial dysfunction.
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Unveiling novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl)quinolines as GPCR ligands via PI3-kinase/PAR-1 antagonism and platelet aggregation valuations; development of a new class of anticancer drugs with thrombolytic effects.
Thangarasu, P, Thamarai Selvi, S, Manikandan, A
Bioorganic chemistry. 2018;:468-480
Abstract
In the present study, novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl) quinolines (4a-l) were recognized and evaluated as G-Protein Coupled Receptor (GPCR) ligands through molecular evaluations. Thrombin mediates adhesion of mast cell, a type of cell abundantly found in connective tissue and releasing histamine and other substances during inflammatory and allergic reactions, through phosphoinositol 3-kinase pathway. With this background, as preliminary, 4a-l are resolute to be potential leads, designated from their effective phosphoinositol 3-kinase (PI3-Kinase) inhibition potentials, best-docked scores, comparative ligand efficiency, and significant structural attributes evaluated by ab initio simulations. Since thrombin is one of the main reason for various cancer invasion in association with PI3Kinase, a thrombolytic potential of the compounds also analyzed. The experimental in vitro studies confirmed the significant enhancement as PI3Kinase inhibitors and appreciable enhancement in MTT assay of breast and skin cancer cell lines. Significantly, acetophenone substituent in the quinoline scaffold could be coherent to note the significant binding affinity to all the evaluated drug targets.
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Effect of tailored use of tirofiban in patients with Non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: a randomized controlled trial.
Lee, W, Suh, JW, Park, JJ, Yoon, CH, Cho, YS, Youn, TJ, Chae, IH
BMC cardiovascular disorders. 2018;(1):201
Abstract
BACKGROUND We conducted a randomized controlled trial to investigate whether an additional platelet inhibition with tirofiban would reduce the extent of myocardial damage and prevent periprocedural myonecrosis in patients with Non-ST-elevation acute coronary syndrome (NSTE-ACS) with a high residual platelet activity (HPR). METHODS Patients with an HPR, defined as P2Y12 reaction unit (PRU) > 230, were randomly assigned to group A (tirofiban treatment, n = 30) or C1 (n = 30) and patients without an HPR to C2 (n = 78). Periprocedural myocardial damage was assessed using the area under the curve (AUC) of serial cardiac enzyme levels from the time of the procedure to post-36 h. Periprocedural myonecrosis incidence was evaluated. RESULTS The troponin I AUC was not different between the groups (197.2 [41.5395.7], 37.9 [8.9313.9], 121.3 [43.7481.8] h∙ng/mL; p = 0.088). The results did not change when the baseline levels were adjusted (365.3 [279.5, 451.1], 293.0 [207.1, 379.0], and 298.0 [244.7, 351.3] h∙ng/mL; p = 0.487). The rate of periprocedural myonecrosis was also not different between the groups (53.0% vs. 50.0% vs. 33.3%, p = 0.092). The CK-MB isoenzyme analysis showed similar results. No difference in complications was noted. CONCLUSION Additional tirofiban administration was not beneficial to patients with NSTE-ACS even with an HPR. TRIAL REGISTRATION Clinical trial no. NCT03114995 , registered 11 April, 2017, retrospectively.
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Anti-platelet effects of vitamin supplements in age-related macular degeneration: an in vitro study.
Moschos, MM, Laios, K, Androudi, S, Ladas, DS, Chatziralli, IP
Cutaneous and ocular toxicology. 2018;(3):207-209
Abstract
OBJECTIVE The purpose of this experimental study was to investigate the role of vitamin supplements (Ocuvite, Vitalux Omega, and Nutrof Total) as possible inhibitors of the onset of age-related macular degeneration (AMD). MATERIALS AND METHODS The anti-aggregating effect of each vitamin was determined against four accumulative factors namely, platelet activating factor (PAF), adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), and arachidonic acid (AA) in the platelet rich plasma (PRP) of healthy volunteers. RESULTS Ocuvite, Vitalux Omega, and Nutrof Total were more potent inhibitors against PAF and ADP compared to TRAP and AA. Among the three vitamins, Nutrof Total displayed more potent inhibitions against TRAP and AA, while against PAF and ADP all the three vitamins revealed similar IC50 values. CONCLUSIONS The vitamins Ocuvite, Vitalux Omega, and Nutrof Total have anti-aggregating effects and therefore can be used against AMD in healthy volunteers.
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Antiplatelet Effect of Ketorolac in Children After Congenital Cardiac Surgery.
Kim, JS, Kaufman, J, Patel, SS, Manco-Johnson, M, Di Paola, J, da Cruz, EM
World journal for pediatric & congenital heart surgery. 2018;(6):651-658
Abstract
BACKGROUND Ketorolac is used for pediatric analgesia after surgery despite its known platelet inhibition via the arachidonic acid (AA) pathway. The degree of platelet inhibitory effect after cardiac surgery is not well characterized. Thromboelastography with platelet mapping (TEG-PM) is emerging as a frequently used test to evaluate platelet inhibition via the AA pathway. METHODS Post hoc analysis of a data set collected in a prospective observational cohort study evaluating platelet inhibition in children after congenital heart surgery with cardiopulmonary bypass (CPB). Categorization into two groups: (1) received ketorolac and (2) did not receive ketorolac for analgesia after surgery. The TEG-PM was evaluated at two time points (prior to surgery and 12-48 hours after CPB). RESULTS Fifty-three children were studied; mean age was 6.6 (range: 0.07-16.7) years and 45% (n = 24) were female. Participants were distributed into two groups by ketorolac use, 41 within the ketorolac group and 12 in the no ketorolac group. All 41 participants who received ketorolac had platelet inhibition and 11 (91.7%) of 12 participants who did not receive ketorolac had normal platelet function after surgery ( P < .0001). There was no difference in patient characteristics or clinical data between the two groups. CONCLUSIONS Ketorolac use in a cohort of children after congenital cardiac surgery was associated with platelet inhibition via the AA pathway when evaluated by TEG-PM.
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Fentanyl Delays the Platelet Inhibition Effects of Oral Ticagrelor: Full Report of the PACIFY Randomized Clinical Trial.
Ibrahim, K, Shah, R, Goli, RR, Kickler, TS, Clarke, WA, Hasan, RK, Blumenthal, RS, Thiemann, DR, Resar, JR, Schulman, SP, et al
Thrombosis and haemostasis. 2018;(8):1409-1418
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Abstract
UNLABELLED Morphine delays oral P2Y12 platelet inhibitor absorption and is associated with adverse outcomes after myocardial infarction. Consequently, many physicians and first responders are now considering fentanyl as an alternative. We conducted a single-centre trial randomizing cardiac patients undergoing coronary angiography to intravenous fentanyl or not. All participants received local anaesthetic and intravenous midazolam. Those requiring percutaneous coronary intervention (PCI) with stenting received 180 mg oral ticagrelor intra-procedurally. The primary outcome was area under the ticagrelor plasma concentration-time curve (AUC0-24 hours). The secondary outcomes were platelet function assessed at 2 hours after loading, measured by P2Y12 reaction units (PRUs) and light transmission platelet aggregometry. Troponin-I was measured post-PCI using a high-sensitivity troponin-I assay (hs-TnI). All participants completed a survey of pain and anxiety. Of the 212 randomized, 70 patients required coronary stenting and were loaded with ticagrelor. Two participants in the no-fentanyl arm crossed over to receive fentanyl for pain. In as-treated analyses, ticagrelor concentrations were higher in the no-fentanyl arm (AUC0-24 hours 70% larger, p = 0.03). Platelets were more inhibited by 2 hours in the no-fentanyl arm (71 vs. 113 by PRU, p = 0.03, and 25% vs. 41% for adenosine diphosphate response by platelet aggregation, p < 0.01). Mean hs-TnI was higher with fentanyl at 2 hours post-PCI (11.9 vs. 7.0 ng/L, p = 0.04) with a rate of enzymatic myocardial infarction of 11% for fentanyl and 0% for no-fentanyl (p = 0.08). No statistical differences in self-reported pain or anxiety were found. In conclusion, fentanyl administration can impair ticagrelor absorption and delay platelet inhibition, resulting in mild excess of myocardial damage. This newly described drug interaction should be recognized by physicians and suggests that the interaction between opioids and oral P2Y12 platelet inhibitors is a drug class effect associated with all opioids. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov/ct2/show/NCT02683707 (: NCT02683707).
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Is there a Role for Oral Triple Therapy in Patients with Acute Coronary Syndromes Without Atrial Fibrillation?
Spinthakis, N, Farag, M, Akhtar, Z, Gorog, DA
Current vascular pharmacology. 2018;(5):427-436
Abstract
BACKGROUND Acute Coronary Syndrome (ACS) patients, despite treatment with Dual Anti- Platelet Therapy (DAPT), have up to 10% risk of recurrent Major Adverse Cardiac Events (MACE) in the short term. METHODS Here we review studies using more potent antithrombotic agent combinations to reduce this risk, namely Triple Therapy (TT) with the addition of an oral anticoagulant, PAR-1 antagonist, or cilostazol to DAPT (mainly aspirin and clopidogrel), and discuss the limitations of trials to date. RESULTS Generally speaking, TT leads to an increase in bleeding. Vorapaxar showed a signal for reducing ischaemic events, but increased intracranial haemorrhage 3-fold in the subacute phase of ACS, although remains an option for secondary prevention beyond the immediate subacute phase, particularly if prasugrel or ticagrelor are not available. Non-Vitamin K Oral Anticoagulants (NOACs) all increased bleeding, with only modest reduction in MACE noted with low dose rivaroxaban. Rivaroxaban can be considered combined with aspirin and clopidogrel in ACS patients at high ischaemic and low bleeding risk, without prior stroke/TIA. The combination of P2Y12 inhibitor and NOAC, without aspirin, looks promising. DAPT may be replaced, not by TT, but by dual therapy comprising a NOAC with a P2Y12 inhibitor. CONCLUSION More potent antithrombotic regimens increase bleeding and should only be considered on an individual basis, after careful risk stratification. Accurate risk stratification of ACS patients, for both ischaemic and bleeding risk, is essential to allow individualised treatment.
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Effect of resveratrol on platelet aggregation by fibrinogen protection.
Bonechi, C, Lamponi, S, Donati, A, Tamasi, G, Consumi, M, Leone, G, Rossi, C, Magnani, A
Biophysical chemistry. 2017;:41-48
Abstract
The effect of resveratrol (RSV) in inhibiting platelet adhesion and aggregation, as well as fibrinogen (FBG) conformational changes promoted by epinephrine (EP), were studied, by using complementary experimental techniques. NMR and IR spectroscopies were used to investigate possible protective effects by RSV towards FBG, in presence of EP. The protective effect of RSV towards FBG was highlighted by spin nuclear relaxation experiments that were interpreted for determining the thermodynamic equilibrium constants of FBG-EP interaction, and by infrared measurements, that showed EP-induced conformational changes of FBG. The ability of RSV in inhibiting platelet adhesion and aggregation promoted by EP was evaluated by scanning electron microscopy (SEM), measuring the platelet adhesion and aggregation degree, in comparison to data obtained for platelet aggregation in platelet rich plasma (PRP). The experimental combined approach pointed out that RSV is able to protect both FBG and platelets from the denaturant and aggregating action of EP at stress level concentration.
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[high on-treatment platelet reactivity in patients with chronic renal failure using acetylsalicylic acid].
Horyniecki, M, Łącka-Gaździk, B, Dworaczek, W, Śnit, M, Łabuz-Roszak, B
Wiadomosci lekarskie (Warsaw, Poland : 1960). 2017;(6 pt 1):1102-1107
Abstract
Cardiovascular diseases (CVD) are the most common cause of mortality in the world. Acetylsalicylic acid (ASA) is a widely used medicine in primary and secondary prevention of cardiovascular diseases. About 1-60% patients taking aspirin have high platelet reactivity (HOPR) despite aspirin treatment. HOPR is significantly more frequent in patients with chronic kidney disease (CKD) and it increases the risk of adverse cardiovascular events in these patients. The cause of HOPR in patients with CKD may be oxidative stress and inflammation. To the risk factors belong diabetes, female sex or decreased HDL cholesterol level.
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Effect of palm-based tocotrienols and tocopherol mixture supplementation on platelet aggregation in subjects with metabolic syndrome: a randomised controlled trial.
Gan, YL, Fu, JY, Lai, OM, Chew, BH, Yuen, KH, Teng, KT, Nesaretnam, K, Selvaduray, KR, Meganathan, P
Scientific reports. 2017;(1):11542
Abstract
Tocotrienols, the unsaturated form of vitamin E, were reported to modulate platelet aggregation and thrombotic mechanisms in pre-clinical studies. Using a Food and Drug Administration (FDA)-approved cartridge-based measurement system, a randomised, double-blind, crossover and placebo-controlled trial involving 32 metabolic syndrome adults was conducted to investigate the effect of palm-based tocotrienols and tocopherol (PTT) mixture supplementation on platelet aggregation reactivity. The participants were supplemented with 200 mg (69% tocotrienols and 31% α-tocopherol) twice daily of PTT mixture or placebo capsules for 14 days in a random order. After 14 days, each intervention was accompanied by a postprandial study, in which participants consumed 200 mg PTT mixture or placebo capsule after a meal. Blood samples were collected on day 0, day 14 and during postprandial for the measurement of platelet aggregation reactivity. Subjects went through a 15-day washout period before commencement of subsequent intervention. Fasting platelet aggregation reactivity stimulated with adenosine diphosphate (ADP) did not show substantial changes after supplementation with PTT mixture compared to placebo (p = 0.393). Concomitantly, changes in postprandial platelet aggregation reactivity remained similar between PTT mixture and placebo interventions (p = 0.408). The results of this study highlight the lack of inhibitory effect on platelet aggregation after short-term supplementation of PTT mixture in participants with metabolic syndrome.