Platelet Inhibitory Effects Research Articles

Abstract 17453: In vitro Aspirin Responsiveness Can Predict Platelet Hyperreactivity and Cardiovascular Risk

Background: While antiplatelet therapy decreases cardiovascular events, insufficient platelet aggregation suppression by antiplatelet therapy is associated with an increased risk of cardiovascular events. In this study, we developed a diagnostic tool to establish an individual’s “aspirin (ASA) responsiveness” in vitro and investigated its association with other metrics of platelet activity and cardiovascular risk. Methods: In 115 subjects off all antiplatelet therapy, platelet aggregation in response to high-dose of arachidonic acid (AA; 1.5 mM) with and without incubation of platelet-rich plasma with ASA (3 mM) was measured by light transmission aggregometry (LTA). ASA responsiveness was defined as ([% aggregation to AA - % aggregation to AA + ASA] / % aggregation to AA) x 100. Next, we correlated ASA responsiveness with other metrics of platelet activity. Finally, we evaluated its clinical significance in a cohort of patients undergoing lower extremity revascularization (LER) followed longitudinally for cardiovascular events. Results: Among 115 participants (mean age 50.3 years old, 65% female, and 43.5% underrepresented minorities, off all antiplatelet therapy), mean % aggregation to high-dose AA was 89.5% ± 3.5. In vitro ASA responsiveness was variable, mean 73.72% ± 15 (range: 13.7% to 97.6%). ASA responsiveness was lower in older (P<0.05) and female participants (P<0.05) and was not associated with race/ethnicity, diabetes, or platelet count. Lower ASA responsiveness was associated with a significant increase in platelet aggregation to epinephrine (0.4 μM, P=0.0004), ADP (1.0 μM, P=8.89x10 -9 ), and collagen (0.2 μg/mL, P=1.16x10 -9 ). In an independent cohort of 67 patients undergoing LER, lower in vitro ASA responsiveness (e.g. a reduced platelet-inhibiting effect), was associated with a significantly increased risk of major adverse cardiac and limb events (1 st tertile-63.6%, 2 nd tertile-50.0% and 3 rd tertile-27.3%; P=0.016 for trend). Conclusions: Reduced ASA responsiveness is associated with increased platelet activity and a higher risk of cardiovascular events. We propose that this rapid, relatively simple assay may be used preclinically for ASA testing and to identify individuals at high cardiovascular risk.

Effect of ticagrelor and clopidogrel dual antiplatelet therapy on MPVLR, MAADP, and AA inhibition rate in acute coronary syndrome patients after percutaneous coronary intervention.

To explore the effects of ticagrelor and clopidogrel dual antiplatelet therapy on the mean platelet volume-to-lymphocyte ratio (MPVLR), maximum amplitude of adenosine diphosphate-induced platelet-fibrin clots (MAADP), and arachidonic acid (AA) inhibition rates in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). A total of 120 patients with ACS undergoing elective PCI in our hospital between March 2020 and November 2021 were recruited. Patients were divided into 2 groups using the random number table method, with 60 patients in each group. The control group received clopidogrel + aspirin dual antiplatelet therapy, while the study group received ticagrelor + aspirin dual antiplatelet therapy. MPVLR, MAADP, and AA inhibition rates were compared between the 2 groups. Platelet activation indices, platelet micro PNA-223, and platelet gelsolin levels were measured before and 4 weeks after PCI. Changes in cardiac function indices, bleeding rates, and major adverse cardiovascular events (MACE) were compared between groups. The MAADP score of the study group was lower than that of the control group 3 days after surgery (P < .05). Compared with before surgery, CD62p, CD63, miR-223, PAC-1, platelet membrane glycoprotein IIb/IIIa complex, and gelsolin levels markedly decreased in both groups 4 weeks after surgery (P < .05). The platelet activation index and platelet miR-223 and gelsolin levels were significantly lower in the study group than in the control group 4 weeks after surgery (P < .05). The overall platelet inhibition effect was significantly better in the study group than in the control group (P < .05). Compared with before surgery, the left ventricular ejection fraction and stroke volume were significantly increased, and the left ventricular end-diastolic volume and left ventricular end-diastolic diameter significantly decreased in both groups 4 weeks after surgery (P < .05). No significant differences were found between the 2 groups in terms of the incidence of bleeding events or MACE (P > .05). Ticagrelor is more effective than clopidogrel for platelet inhibition after PCI in patients with ACS and is worthy of clinical recommendation.

Randomized, Double-Blind, Active Comparator Pharmacodynamic Study of Platelet Inhibition with Crushed and Integral Formulations of Clopidogrel and Ticagrelor in Acute Coronary Syndrome.

Crushed formulations of specific antiplatelet agents produce earlier and stronger platelet inhibition. We studied the platelet inhibitory effect of crushed clopidogrel in patients with acute coronary syndrome (ACS) and its relative efficacy compared with integral clopidogrel, crushed and integral ticagrelor. We aimed to compare the platelet inhibitory effect of crushed and integral formulations of clopidogrel and ticagrelor in patients with acute coronary syndrome (ACS). Overall, 142 patients with suspected ACS were randomly assigned to receive crushed or integral formulations of clopidogrel or ticagrelor. Platelet inhibition at baseline and 1 and 8h was assessed using the VerifyNow assay. High on-treatment platelet reactivity (HTPR) ≥ 235 P2Y12reaction units (PRUs) 1h after the medication loading dose was also determined. The PRU and percentage inhibition median (interquartile range) at 1h for the different formulations were as follows: crushed clopidogrel: 196.50 (155.50, 246.50), 9.36 (- 1.79, 25.10); integral clopidogrel: 189.50 (159.00, 214.00), 2.32 (- 2.67, 19.89); crushed ticagrelor: 59.00 (10.00, 96.00), 75.53 (49.12, 95.18); and integral ticagrelor: 126.50 (50.00, 168.00), 40.56 (25.59, 78.69). There was no significant difference in PRU or percentage platelet inhibition between the crushed and integral formulations of clopidogrel (p=0.990, p=0.479); both formulations of ticagrelor were superior to the clopidogrel formulations (p<0.05). On paired comparison, crushed ticagrelor showed robust early inhibition of platelets compared with the integral formulation (p=0.03). Crushed clopidogrel exhibited the maximal HTPR of 34.3%, but was < 3% for both formulations of ticagrelor. The platelet inhibitory effect of crushed clopidogrel is not superior to integral preparation in patients with ACS. Crushed ticagrelor produced maximal platelet inhibition acutely. HTPR rates in ACS are similar and very low with both formulations of ticagrelor, and maximal with crushed clopidogrel. Clinical Trials Registry of India identifier number CTRI/2020/06/025647.

The HABIT: Heparin and Aspirin on Birth in Inherited Thrombophilia, an International Multicenter Phase IIb Randomized Triple Blinded Clinical Trial

Background/Objective: In pregnant women with inherited thrombophilia (IT) and recurrent pregnancy loss, there is no higher-level evidence proving the beneficial effects of anticoagulation or platelet inhibition in preventing miscarriages. We hypothesize that anticoagulation with low molecular weight heparin (LMWH) and/or platelet aggregation inhibition with aspirin will increase the proportion of live birth in this population. Methods: In this phase IIb, factorial, randomized, triple blinded, placebo-controlled (double dummy) clinical trial, pregnant women age 18 to 40 with a history of IT and 2 or more previous miscarriages will be randomized and stratified by age and number of miscarriages in a 2x2 factorial design will be allocated equally to one of the four arms. The primary outcome of live birth will be analyzed through logistic regression analysis, controlling for strata, and results will be reported as odds ratio (OR) and 95% confidence intervals (CIs). Analyzed similarly, the secondary outcomes will include pregnancy loss, maternal mortality, major bleeding events, medication-associated adverse events, placental abruption, preterm birth, and gestational age at delivery. We will perform subgroup analysis for smoking status, weight, age, number of miscarriages, and type of thrombophilia. Discussion: There is lack of evidence for the use of anticoagulants to prevent pregnancy loss in women with inherited thrombophilia, despite the common diverging prescribing practice predominantly extrapolated from observations in acquired thrombophilia. With this study, we aim to provide an evidence base to create a standard of care in cases of recurrent pregnancy loss in women with IT. Keywords: heparin; aspirin; inherited thrombophilia; pregnant; live birth

351 MULTIPLE PHARMACODYNAMIC ASSESSMENTS OF CANGRELOR EFFECTS IN ELECTIVE COMPLEX PCI: DATA FROM PHARMACODYNAMIC EFFECTS OF CANGRELOR IN PATIENTS WITH ACUTE OR CHRONIC CORONARY SYNDROME UNDERGOING PERCUTANEOUS CORONARY INTERVENTION REGISTRY

Abstract Aims Complex percutaneous coronary intervention (PCI) patients have greater risk of peri-procedural complications, with potential to be associated with poor short-term and late prognosis. Cangrelor is an intravenous P2Y12 receptor inhibitor characterized by rapid onset and offset effect of platelet inhibition which reduced the risk of thrombotic complications. Cangrelor use is currently approved in patients naïve from oral P2Y12 inhibitors with chronic (CCS) or acute coronary syndrome (ACS) undergoing PCI with a IIb recommendation by European guidelines. Yet, the process of switching from cangrelor to oral P2Y12 inhibitor remains uncertain. Methods and Results POMPEII study (NCT04790032) is a prospective registry conducted at Federico II University of Naples enrolling all patients undergoing PCI and receiving cangrelor administration. Pharmacodynamic (PD) assessments were performed at baseline, at 30 minutes, 3 hours and 4-6 hours after cangrelor initiation with 3 assays: 1) the gold standard light transmittance aggregometry (LTA) (20- and 5-µM adenosine diphosphate [ADP] stimuli); 2) VerifyNow P2Y12-test; 3) Multiplate electrode aggregometry (MEA), ADP-test. We enrolled 41 patients undergoing elective complex PCI. All patients were P2Y12 inhibitor naïve and received aspirin, unfractionated heparin, and cangrelor (30-µg/kg bolus followed by 4-µg/kg/min infusion for 2 hours) prior to the start of PCI per standard of care. All patients showed low P2Y12 reactivity at 30 minutes during cangrelor infusion with a mean inhibition of platelet aggregation (IPA, %) of 55.7±18.0% at LTA 20-µM ADP test (34% with IPA ≤50%, 19.5% with IPA≥70%, 4.9% with IPA ≥80% and none IPA ≥90%). High residual platelet reactivity (HRPR) was observed in 1 case (2.4%) as shown by LTA (both 20- and 5-µM ADP stimuli) but not confirmed by VerifyNow and MEA. HRPR was observed in 55% at at 3h and 22.5% at 4-6h at LTA 20-µM and consistently with other assays. All patients with HRPR after cangrelor stop had received clopidogrel as switching drug, while no HRPR was observed in the 4 patients switching to ticagrelor. Conclusions Cangrelor showed to be effective and safe in patients undergoing complex PCI at high thrombotic risk. The switch from cangrelor to clopidogrel could expose patients to a variable period of on-treatment HRPR with inadequate platelet inhibition probably due to the fast offset of cangrelor effect and delay of oral drug effect, while the use of ticagrelor soon after cangrelor start might be ideal to cover the gap. This might be of relevance in such a delicate clinical setting.

Antiplatelet efficacy of ticagrelor versus clopidogrel in Mediterranean patients with diabetes mellitus and chronic coronary syndromes: A crossover pharmacodynamic investigation.

Patients with diabetes mellitus (DM) have augmented platelet reactivity and diminished responsiveness to clopidogrel. Ticagrelor, a more potent P2Y12 inhibitor, is clinically superior to clopidogrel in acute coronary syndromes, although its role in chronic coronary syndromes (CCS) is still the subject of debate. The aim of this investigation was to compare the pharmacodynamic effectiveness of ticagrelor and clopidogrel in Mediterranean DM patients with CCS. In this prospective, randomized, crossover study, patients (n = 20) were randomized (1:1) to receive, on top of aspirin therapy, either ticagrelor 180 mg loading dose (LD)/90 mg maintenance dose (MD) b.i.d. or clopidogrel 600 mg LD/75 mg MD o.d. for 1 week in a crossover fashion with a 2-4 week washout period between regimens. Platelet function measurements were performed at 4 timepoints in each period (baseline, 2 h and 24 h after LD, and 1 week), including light transmission aggregometry (LTA, primary endpoint), VASP assay, Multiplate and VerifyNow P2Y12. The ticagrelor LD achieved greater platelet inhibitory effect than clopidogrel LD, assessed with LTA (20 μM ADP as agonist), at 2 h (34.9 ± 3.9% vs. 63.6 ± 3.9%; p < 0.001) and 24 h (39.4 ± 3.5% vs. 52.3 ± 3.8%; p = 0.014). After 1 week of therapy, platelet reactivity was again significantly inferior with ticagrelor compared to clopidogrel (30.7 ± 3.0% vs. 54.3 ± 3.0%; p < 0.001). The results were consistent with the other platelet function assays employed. In Mediterranean patients with DM and CCS, ticagrelor provides a more potent antiplatelet effect than clopidogrel after the LD and during the maintenance phase of therapy. [ClinicalTrials.gov], identifier [NCT02457130].

Extraction, Characterization, and Platelet Inhibitory Effects of Two Polysaccharides from the Cs-4 Fungus.

Cardiovascular diseases are associated with platelet hyperactivity, and downregulating platelet activation is one of the promising antithrombotic strategies. This study newly extracted two polysaccharides (purified exopolysaccharides, EPSp and purified intercellular exopolysaccharides, IPSp) from Cordyceps sinensis Cs-4 mycelial fermentation powder, and investigated the effects of the two polysaccharides and their gut bacterial metabolites on platelet functions and thrombus formation. EPSp and IPSp are majorly composed of galactose, mannose, glucose, and arabinose. Both EPSp and IPSp mainly contain 4-Galp and 4-Glcp glycosidic linkages. EPSp and IPSp significantly inhibited human platelet activation and aggregation with a dose-dependent manner, and attenuated thrombus formation in mice without increasing bleeding risk. Furthermore, the EPSp and IPSp after fecal fermentation showed enhanced platelet inhibitory effects. The results have demonstrated the potential value of Cs-4 polysaccharides as novel protective ingredients for cardiovascular diseases.

Effect of anticoagulant and platelet inhibition on the risk of bacteremia among patients with acute pyelonephritis: a retrospective cohort study

BackgroundAn increasing number of patients are being prescribed anticoagulants and platelet inhibitors (antithrombotic treatment). Basic research has suggested an association between antithrombotic treatment and bacteremia during kidney infection. Here, we investigated the association between antithrombotic treatment, bacteremia and acute kidney injury in patients with acute pyelonephritis.MethodsA retrospective cohort study was conducted in a large university hospital in Sweden. Data were retrieved from electronic medical records for adult patients with acute pyelonephritis in 2016. The main outcome was bacteremia and secondary outcome acute kidney injury. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated through multiple logistic regression. Treatment with different groups of antithrombotic agents were compared to no antithrombotic treatment.Results1814 patients with acute pyelonephritis were included, in whom bacteremia developed in 336 (18.5%). Low-molecular-weight heparin (LMWH) at prophylactic doses was associated with a lower risk of bacteremia, compared to no antithrombotic treatment (OR 0.5; 95% CI 0.3–0.7). Other antithrombotic treatments were not associated with a risk of bacteremia. Additionally, patients with prophylactic doses of LMWH had a lower risk of acute kidney injury (OR 0.5; 95% CI 0.3–0.8).ConclusionsWe found no association between antithrombotic treatment and an increased risk of bacteremia during acute pyelonephritis. Conversely, patients with prophylactic doses of LMWH had a slightly reduced risk of bacteremia. LMWH at prophylactic doses was also associated with a lower risk of acute kidney injury. Our results suggest that it is safe to continue antithrombotic treatment during acute pyelonephritis, in regards to bacteremia and acute kidney injury risk.

Effect of Platelet Inhibition by Cangrelor Among Obese Patients Undergoing Coronary Stenting: Insights From CHAMPION.

In randomized trials, cangrelor reduced periprocedural ischemic events related to percutaneous coronary intervention without increasing GUSTO severe bleeding. However, some antiplatelet agents have shown a differential treatment effect by body mass index (BMI). Patients from the 3 CHAMPION trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) who were randomized to cangrelor versus clopidogrel during percutaneous coronary intervention were stratified by BMI. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis within 48 hours. The principal safety outcome was GUSTO moderate or severe bleeding at 48 hours, although more sensitive bleeding measures such as Thrombolysis in Myocardial Infarction major bleeding were also assessed. We examined obese patients (defined as BMI≥30) versus nonobese patients. There were 24 893 patients, with 8979 (36.1%) having BMI of ≥30. There was no significant difference in the primary efficacy end point among obese versus nonobese patients (4.3% versus 4.2%; rate ratio, 1.01 [95% CI, 0.89-1.15]; P=0.82). There was a consistent benefit in the primary efficacy end point in patients who received cangrelor versus placebo who were obese (3.9% versus 4.7%, rate ratio, 0.83 [95% CI, 0.68-1.02]; P=0.07) and not obese (3.8% versus 4.7%; rate ratio, 0.81 [95% CI, 0.69-0.94]; P=0.0053); interaction P=0.77. There was no difference in GUSTO moderate or severe bleeding among patients who received cangrelor versus placebo who were obese (0.6% versus 0.6%; rate ratio, 0.99 [95% CI, 0.58-1.67]; P=0.96). Cangrelor at the time of percutaneous coronary intervention is effective and safe in obese and nonobese patients. There was no difference in short-term efficacy between obese and nonobese patients. Periprocedural cangrelor is an effective and safe antiplatelet agent, irrespective of BMI. URL: https://www. gov; Unique identifier: NCT01156571, NCT00385138, NCT00305162.

Prediction of Hematoma Expansion in Patients With Intracerebral Hemorrhage Using Thromboelastography With Platelet Mapping: A Prospective Observational Study

Background and Purpose: The purpose of the study was to evaluate the usefulness of thromboelastography with platelet mapping (TEG-PM) for predicting hematoma expansion (HE) and poor functional outcome in patients with intracerebral hemorrhage (ICH).Methods: Patients with primary ICH who underwent baseline computed tomography (CT) and TEG-PM within 6 h after symptom onset were enrolled in the observational cohort study. We performed univariate and multivariate logistic regression models to assess the association of admission platelet function with HE and functional outcome. In addition, a receiver operating characteristic (ROC) curve analysis investigated the accuracy of platelet function in predicting HE. A mediation analysis was undertaken to determine causal associations among platelet function, HE, and outcome.Results: Of 142 patients, 37 (26.1%) suffered HE. Multivariate logistic regression identified arachidonic acid (AA) and adenosine diphosphate (ADP) inhibition as significant independent predictors of HE. The area under the ROC curves was 0.727 for AA inhibition and 0.721 for ADP inhibition. Optimal threshold for AA inhibition was 41.75% (75.7% sensitivity; 67.6% specificity) and ADP inhibition was 65.8% (73.0% sensitivity; 66.7% specificity). AA and ADP inhibition were also associated with worse 3-month outcomes after adjusting for age, admission Glasgow Coma Scale score, intraventricular hemorrhage, baseline hematoma volume, and hemoglobin. The mediation analysis showed that the effect of higher platelet inhibition with poor outcomes was mediated through HE.Conclusions: These findings suggest that the reduced platelet response to ADP and AA independently predict HE and poor outcome in patients with ICH. Platelet function may represent a modifiable target of ICH treatment.

Platelet reactivity and bleeding outcomes in female patients presenting with ST-segment elevation myocardial infarction: a COMPARE CRUSH substudy

Abstract Background/Introduction Females presenting with ST-segment elevation myocardial infarction (STEMI) are characterized by an increased risk of bleeding after primary percutaneous coronary intervention (pPCI) compared with males. The reason for increased bleeding rates is multifactorial, including age, comorbidities, vessel anatomy and possible differences in platelet biology. Data about platelet reactivity levels in females versus males presenting with STEMI is scarce. Purpose Investigation of gender-driven variances in platelet reactivity and bleeding outcomes in STEMI patients planned to undergo pPCI. Methods The COMPARE CRUSH trial was a randomized multicenter ambulance trial assessing the effect of prehospital administration of P2Y12 inhibitor loading dose with crushed versus integral prasugrel tablets in STEMI patients. We assessed the occurrence of high platelet reactivity (HPR), predictors of HPR at baseline and bleeding outcomes between females and males. Blood samples were analyzed at four prespecified time points using VerifyNow. Results The COMPARE CRUSH trial included 633 STEMI patients in the period between November 2017 and March 2020. Females more frequently exhibited HPR at baseline than males (76% vs. 41%, odds ratio (OR), 4.58 [95% CI, 2.52 to 8.32], p&amp;lt;0.01). Moreover, female sex was a strong, independent predictor for HPR at baseline (OR, 4.93 [95% CI, 2.30 to 10.57], p&amp;lt;0.01). HPR rates at other time points were not significantly different between females and males. The risk of bleeding within the first 48 hours was significantly increased in females (OR, 6.02 [95% CI, 2.58 to 14.08], p&amp;lt;0.01), but after adjustment for baseline characteristics this increased risk was no longer statistically significant (OR, 2.61 [95% CI, 0.73 to 9.32], p=0.14). Conclusion Female sex is an independent predictor for occurrence of HPR at baseline in STEMI patients. However, females exhibit a stronger platelet inhibition effect by oral P2Y12 inhibitors than males, which may contribute to an increased bleeding risk. A more tailored antiplatelet therapy approach should be considered for female STEMI patients to reduce bleeding risk. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Unrestricted grants from Daiichi-Sankyo and Shanghai MicroPort Medical.

A review of the effects of ticagrelor on adenosine concentration and its clinical significance.

Ticagrelor is an oral antiplatelet drug that can reversibly bind to the platelet P2Y12 receptor. Ticagrelor is metabolized mainly by CYP3A4 and produces a rapid blood concentration-dependent platelet inhibitory effect. Unlike other P2Y12 receptor antagonists, many clinical features of ticagrelor are not related to P2Y12 receptor antagonism. This review aims to gather existing literature on the clinical effects of ticagrelor after inhibiting adenosine uptake. The current study reviewed literature related to the effects of ticagrelor on adenosine metabolism. The review also examined the drug's biological effects and clinical characteristics to see how it could be used in a clinical setting. Many studies have shown that ticagrelor can inhibit equilibrative nucleoside transporter 1 (ENT1). This inhibition leads to intracellular adenosine uptake, increased adenosine half-life and plasma concentration levels and an enhanced adenosine-mediated biological effect. Based on the studies reviewed, it wasfound that ticagrelor essentially inhibits adenosine absorption of adenosine into cells through ENT1, which increases the concentration in the blood and subsequently increases the protection of the heart muscle by adenosine. It also prevents platelet aggregation, and extends the biological effects of coronary arteries. Moreover, it leads to a lower mortality rate in acute coronary syndrome (ACS) patients.

Omeprazole-clopidogrel interaction and neurovascular complications after flow-diverter device placement

BackgroundOmeprazole is a common proton pump inhibitor that interferes with the hepatic activation of clopidogrel and potentially reduces its platelet-inhibitory effect. Omeprazole has been shown to increase P2Y12 levels and...

Curcumin at Low Doses Potentiates and at High Doses Inhibits ABT-737-Induced Platelet Apoptosis.

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions.

Effect of platelet inhibition with perioperative aspirin on survival in patients undergoing curative resection for pancreatic cancer: a propensity score matched analysis

BackgroundThe importance of platelets in the pathogenesis of metastasis formation is increasingly recognized. Although evidence from epidemiologic studies suggests positive effects of aspirin on metastasis formation, there is little clinical data on the perioperative use of this drug in pancreatic cancer patients.MethodsFrom all patients who received curative intent surgery for pancreatic cancer between 2014 and 2016 at our institution, we identified 18 patients that took aspirin at time of admission and continued to throughout the inpatient period. Using propensity score matching, we selected a control group of 64 patients without aspirin intake from our database and assessed the effect of aspirin medication on overall, disease-free, and hematogenous metastasis-free survival intervals as endpoints.ResultsAspirin intake proved to be independently associated with improved mean overall survival (OS) (46.5 vs. 24.6 months, *p = 0.006), median disease-free survival (DFS) (26 vs. 10.5 months, *p = 0.001) and mean hematogenous metastasis-free survival (HMFS) (41.9 vs. 16.3 months, *p = 0.005). Three-year survival rates were 61.1% in patients with aspirin intake vs. 26.3% in patients without aspirin intake. Multivariate cox regression showed significant independent association of aspirin with all three survival endpoints with hazard ratios of 0.36 (95% CI 0.15–0.86) for OS (*p = 0.021), 0.32 (95% CI 0.16–0.63) for DFS (**p = 0.001), and 0.36 (95% CI 0.16–0.77) for HMFS (*p = 0.009).ConclusionsPatients in our retrospective, propensity-score matched study showed significantly better overall survival when taking aspirin while undergoing curative surgery for pancreatic cancer. This was mainly due to a prolonged metastasis-free interval following surgery.

Time to peak effect of aspirin-induced platelet inhibition and ex vivo effects of desmopressin: an observational study

Objective: To investigate time to maximal platelet inhibition after an oral loading dose of ASA. The effect of ex vivo reversal platelet inhibition by desmopressin (DDAVP) was also studied. Methods: Ten healthy volunteers were given a 300 mg ASA-tablet. Blood was sampled at 0, 15, 30, 60, 120 and 180 minutes. DDAVP was added to the samples taken at 120 minutes. Samples were analysed with a Multiplate® platelet aggregometer (MEA) using arachidonic acid (AA), collagen and thrombin aggregation agonists. Results: Platelet inhibition was observed in the sample activated by AA at 15 minutes but not until 120 minutes in the samples activated by collagen. No platelet inhibition was seen in the samples activated by thrombin. The median time to maximal AA-induced platelet inhibition of <30 U was 30 (interquartile range 15-90) minutes. Ex vivo DDAVP did not reverse platelet inhibition. Subgroup analysis did not show any gender differences. Conclusions: ASA induces a strong platelet inhibition within 30 minutes of oral ingestion, with no gender differences. Ex vivo DDAVP did not reverse ASA’s platelet inhibition. (Less)

Platelet inhibition by ticagrelor is protective against diabetic nephropathy in mice.

Diabetic nephropathy (DN) is a major complication of diabetes and is associated with high risk for cardiovascular mortality, which is partially related to elevated platelet activity. Platelets are also active players in inflammation and fibrosis. In this study, we examine the effect of ticagrelor-induced platelet inhibition on the development of DN. DN was induced by unilateral nephrectomy followed by streptozotocin injections for 5days. Mice received ticagrelor (300mg/kg) or vehicle every other day, for 16weeks. Experimental groups: non-diabetic control, diabetic control, non-diabetic ticagrelor, and diabetic ticagrelor. Ticagrelor treatment in diabetic mice lowered urinary albumin excretion, it prevented diabetes-induced mesangial matrix expansion, podocyte effacement, and glomerular endothelial cell injury, which includes loss of endothelial fenestrations, ICAM-1 expression, and PECAM expression. In addition, ticagrelor treatment prevented collagen IV deposition and macrophage infiltration in the tubulointerstitium and these diabetic mice showed lower systemic and tubular inflammation and tubular apoptosis. This tubular protection is likely to be a result of protection to the glomerular endothelium by ticagrelor, which reduces albuminuria and albumin toxicity to the tubules and reduced tubular and interstitial inflammation and fibrosis. In conclusion, ticagrelor-induced platelet inhibition protects against renal injury in diabetic mice, likely by protecting the glomerular endothelial cells.

Synergistic platelet inhibition between Omega-3 and acetylsalicylic acid dose titration; an observational study

BackgroundOmega-3 and acetylsalicylic acid (ASA) are two widely used “over-the-counter” drugs. Previous research has shown multiple electrode aggregometry (MEA) can detect ASA and varying Omega-3 platelet inhibiting effects. Synergistic platelet inhibiting effects of ASA and Omega-3 have been found using other methods than MEA. The aim of this study was to investigate the antiplatelet effects of Omega-3, and ASA synergism with MEA.MethodsTen healthy male volunteers ingested Omega-3 (1260 mg/day) for 5 days. MEA was used to analyse platelet function before and after Omega-3 intake. Aggregation was initiated using three different agonists and measured as area under the curve (AUC): adenosine diphosphate (ADP), thrombin receptor activating peptide (TRAP) and arachidonic acid (ASPI). Two concentrations of ASA were dose titrated ex vivo to 2 out of 3 ASPI test cells in order to measure synergism between Omega-3 and ASA.ResultsFollowing 5 days Omega-3 intake, ADP, TRAP and ASPI AUC did not change significantly. In vitro ASA before Omega-3 intake, reduced ASPI AUC < 30 U, indicating a strong platelet inhibiting effect. Below this AUC level, the 5 days Omega-3 intake increased ASPI-AUC with the ex vivo added low dose ASA (P = 0.02) and high dose ASA (P = 0.04).ConclusionsNo synergism between ASA and Omega-3 was found using the MEA ASPI test. The surprising increase in ASPI-AUC following Omega-3 intake and ex vivo ASA suggest that there are methodological issuses with the MEA ASPI test.Trial registrationTrial registration ISRCTN78027929. Registered 19 May 2015.

Incidence of aspirin resistance is higher in patients with acute coronary syndrome and atrial fibrillation than without atrial fibrillation.

In patients with atrial fibrillation, standard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy with a P2Y12 inhibitor and aspirin is the standard of care after percutaneous coronary intervention (PCI). While this therapy reduces the risk of thrombosis and stroke, it increases the risk of bleeding. It is unclear whether the antiplatelet effect of aspirin and clopidogrel may worsen atrial fibrillation (AF). OBJECTIVE Thus we aimed to analyze platelet aspirin resistance (AR) and clopidogrel resistance (CR) in acute coronary (ACS) patients based on sinus rhythm (SR) and AF. METHODS In this prospective trial, we included 543 patients (mean age: 62± 12 years; range: 26 - 89 years) who were on aspirin and clopidogrel therapy after the diagnosis of acute coronary syndrome. AR and CR were analyzed by a Multiplate® MP-0120 device by using the method of whole blood aggregometry. RESULTS AF patients had significantly higher age, mean platelet volume, and High-Sensitivity C-Reactive Protein (p< 0.01 for each parameter). Similarly, Arachidonic-acid induced (ASPI) aggregation was higher in AF patients compared to SR patients (666±218 vs. 187±179, p<0.001). Among the ACS patients, significantly more female patients had AF (p<0.001). The incidence of hypertension in the AF group was higher compared to the SR group (p<0.001). However, adenosine diphosphate levels were not at a significant level in the two groups. CONCLUSION Our findings indicate that the platelet inhibitory effect of Aspirin was worse for patients with AF, suggesting that the effectiveness of aspirin may be less in the prophylaxis of thromboembolism and more a bleeding risk.

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition.

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y12 inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y12 inhibition. While P2Y12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.