Generalized Drug Eruption Secondary to Ticagrelor: A Case Report and Review of the Literature.

Currently, guidelines recommend ticagrelor over clopidogrel as part of dual antiplatelet therapy with aspirin in treating individuals with acute coronary syndrome. As there is an increased usage of ticagrelor, it is important to keep in mind uncommon adverse events, including hypersensitivity skin reactions. To date, only a few studies have been published regarding ticagrelor-induced skin eruptions. Additionally, there is no consensus on antiplatelet therapy management after a hypersensitivity reaction to antiplatelet agents. Hereinafter, we describe a case of an 81-year-old female who presents with a diffuse erythematous hypersensitivity eruption, including palms and soles, secondary to ticagrelor use. Ticagrelor transitioned to clopidogrel, and the patient was started on steroid taper with an antihistamine. The patient's rash progressively improved after the treatment. Our case demonstrates a rare adverse effect of ticagrelor, which needs prompt diagnosis and switching to one of the thienopyridines to prevent thrombosis.

Safety and Efficacy of Low-dose Prasugrel in the Endovascular Treatment of Unruptured Aneurysms in the Elders (≥ 75 Years).

PURPOSE: The effectiveness and safety of low-dose prasugrel (PSG) premedication for endovascular treatment of unruptured intracranial aneurysms (UIAs) have been widely reported. In this study, we evaluated the clinical outcomes of elders patients (≥ 75 years) treated with PSG. METHODS: A total of 200 patients with 209 UIAs who were administered PSG as premedication (20 mg loading and 5 mg maintenance with 100 mg aspirin) between March 2018 and December 2021 were retrospectively enrolled. Among them, 39 patients were aged 75 years or over (elders group), and 161 patients were aged under 75 years (control group). Patients' clinical data were collected, and outcomes were compared between the two groups. RESULTS: Of the 200 patients with PSG, 9 cases (4.5%) had overall complications (7 ischemic, 2 hemorrhagic). In the comparison between the elders group and the control group, no significant differences were observed in the overall complication rates (elders group vs. control group; 2.6% vs. 5.0%, P = 1.00). Moreover, the rates of poor clinical outcome were comparable (2.6% vs. 1.2%, P = 0.48). The subgroup analysis of patients with stent-assisted procedures revealed no significant differences in complication rates (0% vs. 1.6%, P = 1.00) or poor clinical outcomes (0% vs. 0%, P = 1.00) during maintenance with aspirin 100 mg or PSG 5 mg. CONCLUSION: The complication rates in the elders treated with low-dose PSG premedication were similar to those in the control. Low-dose PSG premedication could be prescribed without any additional risk for the endovascular treatment of UIAs in elders patients.

Discordance in tests used to detect inhibition of the P2Y12 receptor in patients undergoing interventional neuroradiology procedures.

BACKGROUND: Clopidogrel is an inhibitor of the P2Y12 platelet receptor but testing to demonstrate a drug effect is controversial since there are often discordant results between different tests methods. METHODS: Samples from patients taking clopidogrel prior to intracranial flow-diversion procedures were tested using light transmission aggregometry (LTA), whole blood impedance aggregometry (WBIA) and the VerifyNow device (VND). Samples were classified as concordant if all test results were either responsive (inhibition) or resistant. Discordant results were separated using the VND into those with a responsive versus a resistant test result. RESULTS: Samples from 96 patients were studied. Concordance for all three tests was seen in 53/96 (55%) of samples, of which 41 (43%) were responsive and 12 (12%) were resistant. Discordance was observed in 43 samples (45%), 37 (28%) of which were caused by responsive VND and either a resistant WBIA or LTA and 6 (7%) of which were caused by a resistant VND but a responsive test result using either WBIA or LTA. These two discordant groups differed in both platelet count and hematocrit, but no such difference was present between the two concordant groups. CONCLUSION: Discordance in P2Y12 inhibition testing may be partly explained by sample platelet count and hematocrit.

2-Substituted thienotetrahydropyridine derivatives: Allosteric ectonucleotidase inhibitors.

The antithrombotic prodrugs ticlopidine and clopidogrel are thienotetrahydro-pyridine derivatives that are metabolized in the liver to produce thiols that irreversibly block adenosine diphosphate (ADP)-activated P2Y12 receptors on thrombocytes. In their native, nonmetabolized form, both drugs were reported to act as inhibitors of ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39). CD39 catalyzes the extracellular hydrolysis of nucleoside tri- and diphosphates, mainly adenosine 5'-triphosphate (ATP) and ADP, yielding adenosine monophosphate, which is further hydrolyzed by ecto-5'-nucleotidase (CD73) to produce adenosine. While ATP has proinflammatory effects, adenosine is a potent anti-inflammatory, immunosuppressive agent. Inhibitors of CD39 and CD73 have potential as novel checkpoint inhibitors for the immunotherapy of cancer and infection. In the present study, we investigated 2-substituted thienotetrahydropyridine derivatives, structurally related to ticlopidine, as CD39 inhibitors. Due to their substituent on the 2-position, they will not be metabolically transformed into reactive thiols and can, therefore, be expected to be devoid of P2Y12 receptor-antagonistic activity in vivo. Several of the investigated 2-substituted thienotetrahydropyridine derivatives showed concentration-dependent inhibition of CD39. The most potent derivative, 32, showed similar CD39-inhibitory potency to ticlopidine, both acting as allosteric inhibitors. Compound 32 showed an improved selectivity profile: While ticlopidine blocked several NTPDase isoenzymes, 32 was characterized as a novel dual inhibitor of CD39 and CD73.

Design, synthesis, characterization and biological evaluation of Thieno[2,3-b]pyridines-chitosan nanocomposites as drug delivery systems for colon targeting.

Thieno[2,3-b]pyridine derivatives DATPa-c have been synthesized based on Thorpe-Ziegler Cyclization. The reaction of arylidene malononitrile derivatives (Ia-c) with thiocyanoacetamide (II) in basic medium (piperidine) followed by alkylation using ethyl chloroacetate and finally, cyclization in sodium ethoxide yielded DATPa-c. Thieno[2,3-b]pyridine-chitosan nanocomposites CS-DATPa-c were prepared from the DATPa-c and CS nanoparticles using sodium tripolyphosphate (TPP). CS-DATPa-c nanocomposites were characterized using FTIR, TEM and XRD techniques and showed a relatively narrow size distribution of monodispersed nanoparticles with the average size of 14-78 nm. The in vitro release studies of CS-DAΤPa-c nanocomposites were investigated and showed that the drug release rate is pH-dependent and the trend is as follows: basic > neutral > acidic. The faster release rate in basic medium effectively prolongs drug delivery in gastric pH. Additionally, the antibacterial investigation showed that DATPa-c and CS-DATPa-c nanocomposites exhibited antibacterial activity against both Gram-positive and Gram-negative bacteria but CS-DATPa-c nanocomposites showed much higher antibacterial activity compared to the DATPa-c, which in agreement with the particle size measurements as DATPa-c are in the bulky structure whereas, CS-DATPa-c are in the nanostructure. The results may have applications of drug design for colon targeting.

Omalizumab for the Treatment of Persistent Drug Induced Urticaria Elicited by Thienopyridines: A Case Report.

The anti-IgE Omalizumab may be helpful to treat clopidogrel hypersensitivity without stopping thienopyridine administration in patients requirining continuous antiplatellet therapy after coronary stent placement.

Synthesis, Docking Studies, and In Vitro Evaluation of Some Novel Thienopyridines and Fused Thienopyridine-Quinolines as Antibacterial Agents and DNA Gyrase Inhibitors.

A series of novel thienopyridines and pyridothienoquinolines (3a,b-14) was synthesized, starting with 2-thioxo-1,2-dihydropyridine-3-carbonitriles 1a and 1b. All compounds were evaluated for their in vitro antimicrobial activity against six bacterial strains. Compounds 3a,b, 4a, 5b, 6a,b, 7a, 9b, 12b, and 14 showed significant growth inhibition activity against both Gram-positive and Gram-negative bacteria compared with the reference drug. The most active compounds (4a, 7a, 9b, and 12b) against Staphylococcus aureus were also tested for their in vitro inhibitory action on methicillin-resistant Staphylococcus aureus (MRSA). The tested compounds showed promising inhibition activity, with the performance of 12b being equal to gentamicin and that of 7a exceeding it. Moreover, the most promising compounds were also screened for their Escherichia coli DNA gyrase inhibitory activity, compared with novobiocin as a reference DNA gyrase inhibitor. The results revealed that compounds (3a, 3b, 4a, 9b, and 12b) had the highest inhibitory capacity, with IC50 values of 2.26-5.87 µM (that of novobiocin is equal to 4.17 µM). Docking studies were performed to identify the mode of binding of the tested compounds to the active site of E. coli DNA gyrase B.

Antiplatelet Agents for Cancer Prevention: Current Evidences and Continuing Controversies.

Over the past two decades, aspirin has emerged as a promising chemoprotective agent to prevent colorectal cancer (CRC). In 2016, the mounting evidence supporting its chemoprotective effect, from both basic science and clinical research, led the US Preventive Services Task Force to recommend regular use of low-dose aspirin in some subgroups of patients for whom the benefits are deemed to outweigh the risks. In contrast, data on the chemoprotective effect of aspirin against other cancers are less clear and remain controversial. Most data come from secondary analyses of cardiovascular prevention trials, with only a limited number reporting cancer outcomes as a prespecified endpoint, and overall unclear findings. Moreover, the potential chemoprotective effect of aspirin against other cancers has been recently questioned with the publication of 3 long-awaited trials of aspirin in the primary prevention of cardiovascular diseases reporting no benefit of aspirin on overall cancer incidence and cancer-related mortality. Data on the chemoprotective effects of other antiplatelet agents remain scarce and inconclusive, and further research to examine their benefit are warranted. In this narrative review, we summarize current clinical evidence and continuing controversies on the potential chemoprotective properties of antiplatelet agents against cancer.

Characterizing CDK8/19 Inhibitors through a NFκB-Dependent Cell-Based Assay.

Cell-based assays for CDK8/19 inhibition are not easily defined, since there are no known cellular functions unique to these kinases. To solve this problem, we generated derivatives of 293 cells with CRISPR knockout of one or both of CDK8 and CDK19. Double knockout (dKO) of CDK8 and CDK19 together (but not individually) decreased the induction of transcription by NFκB (a CDK8/19-potentiated transcription factor) and abrogated the effect of CDK8/19 inhibitors on such induction. We generated wild type (WT) and dKO cell lines expressing luciferase from an NFκB-dependent promoter. Inhibitors selective for CDK8/19 over other CDKs decreased TNFα-induced luciferase expression in WT cells by ~80% with no effect on luciferase induction in dKO cells. In contrast, non-selective CDK inhibitors flavopiridol and dinaciclib and a CDK7/12/13 inhibitor THZ1 (but not CDK4/6 inhibitor palbociclib) suppressed luciferase induction in both WT and dKO cells, indicating a distinct role for other CDKs in the NFκB pathway. We used this assay to characterize a series of thienopyridines with in vitro bone anabolic activity, one of which was identified as a selective CDK8/19 inhibitor. Thienopyridines inhibited luciferase induction in the WT but not dKO cells and their IC50 values in the WT reporter assay showed near-perfect correlation (R2 = 0.98) with their reported activities in a bone anabolic activity assay, confirming that the latter function is mediated by CDK8/19 and validating our assay as a robust and quantitative method for CDK8/19 inhibition.

Structure-activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines.

BACKGROUND: Malaria is one of the most prevalent tropical infectious diseases. Since recently cases of artemisinin resistance were reported, novel anti-malarial drugs are required which differ from artemisinins in structure and biological target. The plasmodial glycogen synthase kinase-3 (PfGSK-3) was suggested as a new anti-malarial drug target. 4-Phenylthieno[2,3-b]pyridines were previously identified as selective PfGSK-3 inhibitors with antiplasmodial activity. The present study aims at identifying a molecular position on this scaffold for the attachment of side chains in order to improve solubility and antiplasmodial activity. Furthermore, the role of axial chirality in the compound class for antiplasmodial activity and PfGSK-3 inhibition was investigated. METHODS: 4-Phenylthieno[2,3-b]pyridines with substituents in 4-position of the phenyl ring were docked into the ATP binding site of PfGSK-3. The compounds were synthesized employing a Thorpe reaction as final step. The enantiomers of one congener were separated by chiral HPLC. All derivatives were tested for inhibition of asexual erythrocytic stages of transgenic NF54-luc Plasmodium falciparum. Selected compounds with promising antiplasmodial activity were further evaluated for inhibition of HEK293 cells as well as inhibition of isolated PfGSK-3 and HsGSK-3. The kinetic aqueous solubility was assessed by laser nephelometry. RESULTS: The para position at the 4-phenyl ring of the title compounds was identified as a suitable point for the attachment of side chains. While alkoxy substituents in this position led to decreased antiplasmodial activity, alkylamino groups retained antiparasitic potency. The most promising of these congeners (4h) was investigated in detail. This compound is a selective PfGSK-3 inhibitor (versus the human GSK-3 orthologue), and exhibits improved antiplasmodial activity in vitro as well as better solubility in aqueous media than its unsubstituted parent structure. The derivative 4b was separated into the atropisomers, and it was shown that the (+)-enantiomer acts as eutomer. CONCLUSIONS: The attachment of alkylamino side chains leads to the improvement of antiplasmodial activity and aqueous solubility of selective PfGSK-inhibitors belonging to the class of 4-phenylthieno[2,3-b]pyridines. These molecules show axial chirality, a feature of high impact for biological activity. The findings can be exploited for the development of improved selective PfGSK-3 inhibitors.

Structure-activity relationship of pyrazolo pyrimidine derivatives as inhibitors of mitotic kinesin Eg5 and anticancer agents.

Human kinesin Eg5 is a potential inhibiting site for cancer chemotherapy. Blocking metaphase by binding foreign inhibitors with Eg5 eventually leads to apoptotic cell death. Here, we report the pyrazolopyrimidine derivates as potent inhibitors of Eg5 that prevents mitotic kinesin progression. IC50 values were evaluated against the motor domain of Eg5 using steady-state ATPase assay. To better understanding, we have performed molecular docking simulation. It reveals that the interactions of the proposed inhibitors with both the allosteric sites (helices α2, α3 and loopL5, and helices α4 & α6). Out of fifteen pyrazolopyrimidine derivates, three compounds (12, 25, and 27) have shown significant inhibition of Eg5. The synthesized compounds (12, 25, and 27) were tested for their in-vitro anticancer activity against cervical cancer cell line (HeLa).

Risk factors for upper gastrointestinal bleeding among aspirin users: An old issue with new findings from a population-based cohort study.

BACKGROUND/PURPOSE: We aimed to identify the risk factors of first-time occurrence of non-variceal upper gastrointestinal bleeding (UGIB) among aspirin users after adjusting for confounding factors like age, gender, underlying co-morbidities, and medications. METHODS: Using the National Health Insurance Research Database of Taiwan and matching age, gender, underlying co-morbidities and enrollment time by propensity score, 11105 aspirin users and 11105 controls were identified for comparison from a cohort dataset of 1,000,000 randomly sampled subjects. Cox proportional hazard regression models were used to identify independent risk factors for first-time occurrence of non-variceal UGIB in the study cohort and in the aspirin users after adjusting for age, gender, underlying co-morbidities, and medications (e.g., non-steroidal anti-inflammatory drugs [NSAIDs], cyclooxygenase-2 [COX-2] inhibitors, steroids, thienopyridines, selective serotonin reuptake inhibitors, warfarin, and dipyridamole). RESULTS: By Cox proportional hazard regression analysis, aspirin use increased the risk of first-time occurrence of UGIB (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.28-1.72). Age, male gender, Helicobacter pylori (H. pylori)infection, diabetes, chronic kidney disease (CKD), cirrhosis, history of uncomplicated peptic ulcer disease (PUD), and use of NSAIDs, COX-2 inhibitors, steroids, and thienopyridines were independent risk factors for UGIB among aspirin users. CONCLUSION: In addition to age, male gender, H. pylori infection, and concomitant use of NSAIDs, COX-2 inhibitors, steroids, and thienopyridines, underlying co-morbidities including diabetes, CKD, cirrhosis, history of PUD are also important risk factors for first-time occurrence of non-variceal UGIB in aspirin users.

Comparing Allergist and Cardiologist Considerations for the Optimal Management of Thienopyridines Hypersensitivity.

BACKGROUND AND OBJECTIVE: The thienopyridine family includes ticlopidine, clopidogrel and prasugrel which are antiplatelet drugs largely used, mainly associated to aspirin, for treatment of acute coronary syndromes and after percutaneous coronary interventions, to avoid thrombosis. In some patients, thienpyridines may cause hypersensitivity reactions which jeopardize the optimal therapeutic and preventive approach to vascular diseases. The management of thienopyridine hypersensitivity seems to be best done as an interdisciplinary collaboration between the allergist and cardiologist. METHOD: The present study investigates the management of thienopyridines hypersensitivity on the basis of published case reports and studies, comparing the pro and contro of pharmacological treatments, different desensitization protocols to thienopyridines and substitution of antiplatelet agents eaches others, according to the point of view of cardiologist and allergist. For the cardiologist, the important issues are the necessity of continuing therapy, the desired duration of therapy based on the clinical indication of the individual patient and appropriateness of using one of the alternative P2Y12 inhibitors. For the allergist, the important issues are weighing the risk and benefits of the various therapeutic options: treating "through" desensitization, or switching to an alternative agent. RESULTS AND CONCLUSION: All the data seem to suggest that only working together, a cardio-allergy team of specialists may evaluate and offer the best approach to clinical decision-making for the individual patient.

Is preoperative clopidogrel resistance a predictor of bleeding and risks in patients undergoing emergency cabg surgery?

Abstract Objective: The aims of this study were to determine whether the detection of preoperative clopidogrel resistance in patients undergoing cardiac surgery while using clopidogrel could play a guiding role in the prediction of postoperative excessive bleeding, transfusion requirements, and risks and to provide clinically significant data. Methods: Two hundred and twenty-two patients [median age: 59.4 (38-83) years; 38 females] undergoing emergency and elective coronary artery bypass graft (CABG) surgeries in our clinic were evaluated prospectively. Patients with multiple systemic diseases, other than diabetes mellitus (DM) and hypertension (HT), were excluded. Patients receiving clopidogrel were also evaluated for clopidogrel resistance and grouped according to the results of this test. Assessments of platelet functions were performed by multiplate impedance aggregometry method and adenosine diphosphate test. Results: The use of postoperative fresh blood replacement and platelet transfusion was higher in patients receiving clopidogrel than in those not receiving it (P=0.001, P=0.018). DM, HT, myocardial infarction, and the number of presentation to the emergency room were significantly higher in patients receiving clopidogrel than in those not receiving it (P<0.05). No significant difference was determined between patients with and without clopidogrel resistance regarding the amount of bleeding during and after surgery, erythrocyte suspension and fresh-frozen plasma transfusion rates, preoperative troponin values, ejection fraction values, and length of hospital stays (P>0.05). Conclusion: We think that resistance studies in patients receiving clopidogrel before cardiac surgery are not efficient to predict bleeding and bleeding-related complications in patients undergoing emergency and elective CABG surgeries.

Synthesis of a Novel Series of Amino Acid Prodrugs Based on Thienopyridine Scaffolds and Evaluation of Their Antiplatelet Activity.

The thienopyridines class of drugs used as P2Y12 receptor antagonists plays a vital role in antiplatelet therapy. To further optimized this compound class, we designed and synthesized a series of amino acid prodrugs of 2-hydroxytetrahydrothienopyridine. All compounds were then evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats and then ED50 and bleeding time of the most potent compounds were compared with commercial drugs. The results showed compound 5c could be a potent and safe candidate for further research.

Differential impact of diabetes mellitus on antiplatelet effects of prasugrel and clopidogrel.

BACKGROUND: Although prasugrel exerts stronger antiplatelet effects compared with clopidogrel, the factors affecting platelet reactivity under prasugrel have not been fully determined. This study aimed to find the novel mechanistic differences between two thienopyridines and identify the factor that influence platelet reactivity to each drug. METHODS: Forty patients with stable angina who underwent elective percutaneous coronary intervention were randomly assigned to receive either prasugrel (20 mg) or clopidogrel (300 mg) as a loading dose. Platelet function (light transmission, laser light scattering, and vasodilator-stimulated phosphoprotein phosphorylation) and plasma active metabolite levels were measured after the loading dose. RESULTS: Prasugrel consistently inhibited adenosine diphosphate receptor P2Y12 signalling to abolish amplification of platelet aggregation. Prasugrel abolished even small platelet aggregates composed of less than 100 platelets. On the other hand, clopidogrel inhibited large aggregates but increased small and medium platelet aggregates. Diabetes was the only independent variable for determining antiplatelet effects and active metabolite concentration of prasugrel, but not clopidogrel. Sleep-disordered breathing was significantly correlated with platelet reactivity in patients who had clopidogrel. CONCLUSIONS: Prasugrel efficiently abolishes residual P2Y12 signalling that causes small platelet aggregates, but these small aggregates are not inhibited by clopidogrel. Considering the differential effect of diabetes on antiplatelet effects between these two drugs, the pharmacokinetics of prasugrel, other than cytochrome P450 metabolism, might be affected by diabetes. TRIAL REGISTRATION: UMIN-CTR UMIN000017624, retrospectively registered 21 May 2015.

Cerebrovascular Outcomes With Proton Pump Inhibitors and Thienopyridines: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Pharmacokinetic and prior studies on thienopyridine and proton pump inhibitors (PPI) coadministration provide conflicting data for cardiovascular outcomes, whereas there is no established evidence on the association of concomitant use of PPI and thienopyridines with adverse cerebrovascular outcomes. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials and cohort studies from inception to July 2017, reporting following outcomes among patients treated with thienopyridine and PPI versus thienopyridine alone (1) ischemic stroke, (2) combined ischemic or hemorrhagic stroke, (3) composite outcome of stroke, myocardial infarction (MI), and cardiovascular death, (4) MI, (5) all-cause mortality, and (6) major or minor bleeding events. After the unadjusted analyses of risk ratios, we performed additional analyses of studies reporting hazard ratios adjusted for potential confounders. RESULTS: We identified 22 studies (12 randomized controlled trials and 10 cohort studies) comprising 131 714 patients. Concomitant use of PPI with thienopyridines was associated with increased risk of ischemic stroke (risk ratio, 1.74; 95% confidence interval [CI], 1.41-2.16; P<0.001), composite stroke/MI/cardiovascular death (risk ratio, 1.14; 95% CI, 1.01-1.29; P=0.04), and MI (risk ratio, 1.19; 95% CI, 1.00-1.40; P=0.05). Likewise, in adjusted analyses concomitant use of PPI with thienopyridines was again associated with increased risk of stroke (hazard ratios adjusted, 1.30; 95% CI, 1.04-1.61; P=0.02), composite stroke/MI/cardiovascular death (hazard ratios adjusted, 1.23; 95% CI, 1.03-1.47; P=0.02), but not with MI (hazard ratios adjusted, 1.19; 95% CI, 0.93-1.52; P=0.16). CONCLUSIONS: Co-prescription of PPI and thienopyridines increases the risk of incident ischemic strokes and composite stroke/MI/cardiovascular death. Our findings corroborate the current guidelines for PPI deprescription and pharmacovigilance, especially in patients treated with thienopyridines.

Impact of Dual Antiplatelet Therapy Beyond 1 Year on Clinical Outcomes of Patients With Stent Fracture or Peri-Stent Contrast Staining After Sirolimus-Eluting Stent Implantation.

BACKGROUND: Stent fracture (SF) and peri-stent contrast staining (PSS) after sirolimus-eluting stent (SES) implantation are considered to be related to very late stent thrombosis (VLST). How dual antiplatelet therapy (DAPT) beyond 1 year affects the clinical outcomes of patients with SF or PSS remains unclear.Methods and Results:Based on their DAPT status, 1,962 patients undergoing SES implantation were classified as on-thienopyridine (n=1,404) or off-thienopyridine (n=558). The 6-year incidence of VLST was significantly lower in the on-thienopyridine patients (0.56% vs. 1.8%, P=0.01), whereas cardiac death and myocardial infarction (MI) were similar (5.0% vs. 6.2%, P=0.31; 3.2% vs. 4.0%, P=0.33; respectively). The 1,962 patients were also classified as having SF/PSS (n=256) or non-SF/PSS (n=1,706). In the SF/PSS group, VLST and MI were significantly lower in on-thienopyridine patients (1.9% vs. 10.1%, P=0.003; 3.5% vs. 10.3%, P=0.02; respectively). In the non-SF/PSS group, VLST and MI were similar (0.36% vs. 0.45%, P=0.78; 3.2% vs. 3.0%, P=0.93; respectively). In both groups, cardiac death was similar (3.6% vs. 4.3%, P=0.78; 5.2% vs. 6.5%, P=0.32; respectively). CONCLUSIONS: Prolonged DAPT was associated with significantly lower incidences of VLST and MI in the SF/PSS group, but had no effect on cardiac death, VLST, or MI in the non-SF/PSS group.

Platelet Aggregometry Testing: Molecular Mechanisms, Techniques and Clinical Implications.

Platelets play a fundamental role in normal hemostasis, while their inherited or acquired dysfunctions are involved in a variety of bleeding disorders or thrombotic events. Several laboratory methodologies or point-of-care testing methods are currently available for clinical and experimental settings. These methods describe different aspects of platelet function based on platelet aggregation, platelet adhesion, the viscoelastic properties during clot formation, the evaluation of thromboxane metabolism or certain flow cytometry techniques. Platelet aggregometry is applied in different clinical settings as monitoring response to antiplatelet therapies, the assessment of perioperative bleeding risk, the diagnosis of inherited bleeding disorders or in transfusion medicine. The rationale for platelet function-driven antiplatelet therapy was based on the result of several studies on patients undergoing percutaneous coronary intervention (PCI), where an association between high platelet reactivity despite P2Y12 inhibition and ischemic events as stent thrombosis or cardiovascular death was found. However, recent large scale randomized, controlled trials have consistently failed to demonstrate a benefit of personalised antiplatelet therapy based on platelet function testing.

Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies.

OBJECTIVE: Aspirin together with thienopyridine P2Y12 inhibitors, commonly clopidogrel, is a cornerstone of antiplatelet therapy. However, many patients receiving this therapy display high on-treatment platelet reactivity, which is a major therapeutic hurdle to the prevention of recurrent thrombotic events. The emergence of uninhibited platelets after thrombopoiesis has been proposed as a contributing factor to high on-treatment platelet reactivity. Here, we investigate the influences of platelet turnover on platelet aggregation in the face of different dual-antiplatelet therapy strategies. APPROACH AND RESULTS: Traditional light transmission aggregometry, cytometry, advanced flow cytometric imaging, and confocal microscopy were used to follow the interactions of populations of platelets from healthy volunteers and patients with stable cardiovascular disease. Newly formed, reticulated platelets overproportionately contributed to, and clustered at, the core of forming aggregates. This phenomenon was particularly observed in samples from patients treated with aspirin plus a thienopyridine, but was absent in samples taken from patients treated with aspirin plus ticagrelor. CONCLUSIONS: Reticulated platelets are more reactive than older platelets and act as seeds for the formation of platelet aggregates even in the presence of antiplatelet therapy. This is coherent with the emergence of an uninhibited subpopulation of reticulated platelets during treatment with aspirin plus thienopyridine, explained by the short pharmacokinetic half-lives of these drugs. This phenomenon is absent during treatment with ticagrelor, because of its longer half-life and ability to act as a circulating inhibitor. These data highlight the important influences of pharmacokinetics on antiplatelet drug efficacies, especially in diseases associated with increased platelet turnover.