A Chromosome-Level Genome Assembly of the Non-Hematophagous Leech Whitmania pigra (Whitman 1884): Identification and Expression Analysis of Antithrombotic Genes.

Despite being a non-hematophagous leech, Whitmania pigra is widely used in traditional Chinese medicine for the treatment of antithrombotic diseases. In this study, we provide a high quality genome of W. pigra and based on which, we performed a systematic identification of the potential antithrombotic genes and their corresponding proteins. We identified twenty antithrombotic gene families including thirteen coagulation inhibitors, three platelet aggregation inhibitors, three fibrinolysis enhancers, and one tissue penetration enhancer. Unexpectedly, a total of 79 antithrombotic genes were identified, more than a typical blood-feeding Hirudinaria manillensis, which had only 72 antithrombotic genes. In addition, combining with the RNA-seq data of W. pigra and H. manillensis, we calculated the expression levels of antithrombotic genes of the two species. Five and four gene families had significantly higher and lower expression levels in W. pigra than in H. manillensis, respectively. These results showed that the number and expression level of antithrombotic genes of a non-hematophagous leech are not always less than those of a hematophagous leech. Our study provides the most comprehensive collection of antithrombotic biomacromolecules from a non-hematophagous leech to date and will significantly enhance the investigation and utilization of leech derivatives in thrombosis therapy research and pharmaceutical applications.

Synergistic effects and molecular mechanisms of DL-3-n-butylphthalide combined with dual antiplatelet therapy in acute ischemic stroke.

DL-3-n-butylphthalide (NBP) is isolated from the seeds of Apium graveolens L., and has been recently used as a neuroprotective agent for acute ischemic stroke. The present study aimed to determine the efficacy and safety of the combined use of dual antiplatelet therapy (DAPT) and NBP for treating of acute ischemic stroke in rats and to explore the synergistic mechanism of this treatment strategy in rat middle cerebral artery occlusion models. The efficacy of DAPT combined with NBP was evaluated by determining neurological deficits, infarction status, and histological changes. Changes in body weight, blood glucose level, blood count, and serum biochemical parameters were detected to evaluate the safety. To explore the synergistic pharmacological mechanism, the mRNA expression and protein levels of key proteins in the pyroptosis-inflammatory pathway, and the pyroptosis ratio of microglias were examined. Compared with the administration of NBP or DAPT alone, combination of them significantly improved neurological deficits, reduced infarct area, and repaired tissue injury and inflammation after cerebral ischemia. No hepatorenal toxicity was observed. The mRNA expression and protein levels of key proteins in the pyroptosis-inflammation pathway, and the pyroptosis ratio of microglias were significantly downregulated in the combined administration group than in the monotherapy group. We demonstrated that the combined use of NBP and DAPT exhibits better efficacy and high safety and plays a synergistic role by inhibiting the pyroptosis-inflammation pathway in the brain tissues, particularly in microglial cells.

Switching from Dual Antiplatelet Therapy with Aspirin Plus a P2Y12 Inhibitor to Dual Pathway Inhibition with Aspirin Plus Vascular-Dose Rivaroxaban: The Switching Anti-Platelet and Anti-Coagulant Therapy (SWAP-AC) Study.

BACKGROUND: To date, there are no data on switching to dual pathway inhibition (DPI) patients who have completed a guideline-recommended dual antiplatelet therapy (DAPT) regimen. OBJECTIVES: To assess the feasibility of switching from DAPT to DPI and to compare the pharmacodynamic (PD) profiles of these treatments. METHODS: This was a prospective, randomized, PD study conducted in 90 patients with chronic coronary syndrome (CCS) on DAPT with aspirin (81 mg/qd) plus a P2Y12 inhibitor (clopidogrel [75 mg/qd; n = 30], ticagrelor [90 mg/bid; n = 30], or prasugrel [10 mg/qd; n = 30]). Patients in each cohort were randomized to maintain DAPT or switch to DPI (aspirin 81 mg/qd plus rivaroxaban 2.5 mg/bid). PD assessments included: VerifyNow P2Y12 reaction units; light transmittance aggregometry following stimuli with adenosine diphosphate (ADP), tissue factor (TF), and a combination of collagen, ADP, and TF (maximum platelet aggregation %); thrombin generation (TG). Assays were performed at baseline and 30 days postrandomization. RESULTS: Switching from DAPT to DPI occurred without major side effects. DAPT was associated with enhanced P2Y12 inhibition, while DPI with reduced TG. Platelet-mediated global thrombogenicity (primary endpoint) showed no differences between DAPT and DPI in the ticagrelor (14.5% [0.0-63.0] vs. 20.0% [0.0-70.0]; p = 0.477) and prasugrel (20.0% [0.0-66.0] vs. 4.0% [0.0-70.0]; p = 0.482), but not clopidogrel (27.0% [0.0-68.0] vs. 53.0% [0.0-81.0]; p = 0.011), cohorts. CONCLUSION: In patients with CCS, switching from different DAPT regimens to DPI was feasible, showing enhanced P2Y12 inhibition with DAPT and reduced TG with DPI, with no differences in platelet-mediated global thrombogenicity between DPI and ticagrelor- and prasugrel-, but not clopidogrel-, based DAPT. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov Unique Identifier: NCT04006288.

Dual antithrombotic therapy dose-dependently alters hemostatic plug structure and function.

BACKGROUND: Antithrombotic medications carry an inherent risk of bleeding, which may be exacerbated when anticoagulant and antiplatelet therapeutics are combined. Prior studies have shown different effects of antiplatelet vs anticoagulant drugs on the structure and function of hemostatic plugs in vivo. OBJECTIVES: We examined whether dual antithrombotic treatment consisting of combined antiplatelet and anticoagulant therapeutics alters hemostatic plug structure and function differently from treatment with either therapeutic alone. METHODS: Mice were treated with the P2Y12 antagonist clopidogrel and the factor Xa inhibitor rivaroxaban across a range of doses, either alone or in combination. The hemostatic response was assessed using a mouse jugular vein puncture injury model. Platelet accumulation and fibrin deposition were evaluated using quantitative multiphoton fluorescence microscopy, and bleeding times were recorded. RESULTS: Mice treated with clopidogrel alone exhibited a decrease in platelet accumulation at the site of injury, with prolonged bleeding times only at the highest doses of clopidogrel used. Mice treated with rivaroxaban alone instead showed a reduction in fibrin deposition with no impact on bleeding. Mice treated with both clopidogrel and rivaroxaban exhibited platelet and fibrin accumulation that was similar to that with either drug given alone; however, dual antithrombotic therapy resulted in impaired hemostasis at doses that had no impact on bleeding when given in isolation. CONCLUSION: Combined administration of antiplatelet and anticoagulant therapeutics exacerbates bleeding as compared to that with either drug alone, potentially via combined loss of both adenosine 5'-diphosphate- and thrombin-mediated platelet activation. These findings enhance our understanding of the bleeding risk associated with dual antithrombotic therapy.

Redefining Clinically Significant Hematuria After Holmium Enucleation of the Prostate.

Introduction and Objective: Holmium laser enucleation of the prostate (HoLEP) is often offered for symptomatic prostatic enlargement at high risk for bleeding. However, prior studies define clinically significant hematuria (CSH) narrowly as the need for blood transfusion or significant decrease in hemoglobin. We sought to evaluate risk factors contributing to a broader definition of CSH, which may contribute to alteration of clinical course. Methods: We analyzed 164 patients in a prospectively maintained database who underwent HoLEP at a single institution across two surgeons from November 2020 to April 2023. HoLEP was performed using Moses 2.0 (Boston Scientific) laser and the Piranha enucleation system (Richard Wolf). We defined CSH broadly as follows: clot retention, return to operating room, perioperative management variation due to hematuria, or continued gross hematuria past 1 month postoperatively. Univariable and multivariable ANOVAs were used. Multivariable analysis of CSH risk based on the use of antiplatelet (AP) agents or anticoagulants included correction for age, enucleation time (surrogate for case difficulty), and prostate volume. Results: 17.7% (29/164) of our patients developed CSH after HoLEP. Longer enucleation time was a mild risk factor for developing CSH (multivariate odds ratio [OR] 1.01, p = 0.02). The strongest predictor of CSH was the use of anticoagulation or AP agents (OR 2.71 p < 0.02 on univariable analysis, OR 2.34 p < 0.02 on multivariable analysis), even when aspirin 81 mg was excluded. Conclusion: With a broadened definition, 18% of patients developed CSH following HoLEP, which impacted the clinical course. Our data suggest that the current definition of significant hematuria is too narrow and does not capture many patients whose clinical course is affected by hematuria. While safe, anticoagulants and APs significantly predicted an increased CSH risk, and patients should be counseled accordingly.

Panax quinquefolius saponins combined with dual antiplatelet therapy enhanced platelet inhibition with alleviated gastric injury via regulating eicosanoids metabolism.

BACKGROUND: Panax quinquefolius saponin (PQS) was shown beneficial against platelet adhesion and for gastroprotection. This study aimed to investigate the integrated efficacy of PQS with dual antiplatelet therapy (DAPT) on platelet aggregation, myocardial infarction (MI) expansion and gastric injury in a rat model of acute MI (AMI) and to explore the mechanism regarding arachidonic acid (AA)-derived eicosanoids metabolism. METHODS: Wistar rats were subjected to left coronary artery occlusion to induce AMI model followed by treatment with DAPT, PQS or the combined therapy. Platelet aggregation was measured by light transmission aggregometry. Infarct size, myocardial histopathology was evaluated by TTC and H&E staining, respectively. Gastric mucosal injury was examined by scanning electron microscope (SEM). A comprehensive eicosanoids profile in plasma and gastric mucosa was characterized by liquid chromatography-mass spectrometer-based lipidomic analysis. RESULTS: PQS+DAPT further decreased platelet aggregation, lessened infarction and attenuated cardiac injury compared with DAPT. Plasma lipidomic analysis revealed significantly increased synthesis of epoxyeicosatrienoic acid (EET) and prostaglandin (PG) I2 (potent inhibitors for platelet adhesion and aggregation) while markedly decreased thromboxane (TX) A2 (an agonist for platelet activation and thrombosis) by PQS+DAPT, relative to DAPT. DAPT induced overt gastric mucosal damage, which was attenuated by PQS co-administration. Mucosal gastroprotective PGs (PGE2, PGD2 and PGI2) were consistently increased after supplementation of PQS+DAPT. CONCLUSIONS: Collectively, PQS+DAPT showed synergistic effect in platelet inhibition with ameliorated MI expansion partially through upregulation of AA/EET and AA/PGI2 synthesis while suppression of AA/TXA2 metabolism. PQS attenuated DAPT-induced gastric injury, which was mechanistically linked to increased mucosal PG production.

Bleeding risk after acupuncture in patients taking anticoagulant drugs: A case control study based on real-world data.

OBJECTIVES: Patients on anticoagulant medications may be at a higher risk of bleeding after acupuncture. This study aimed to assess the association between anticoagulant drug use and bleeding after acupuncture. DESIGN: Case control study SETTING: We analysed the diagnosis and treatment records (2000-2018) of a random sample of two million patients from the National Health Insurance Research Database in Taiwan. INTERVENTIONS: anticoagulant and antiplatelet drugs MAIN OUTCOME MEASURES: The incidence rates of major (visceral bleeding or ruptured blood vessels requiring transfusion) and minor (skin bleeding or contusion) bleeding after acupuncture RESULTS: We included the records of 13,447,563 acupuncture sessions in 821,946 participants and followed up the patients for 14 days after each session. The incidence of minor bleeding was 8.31 per 10,000 needles, whereas that of major bleeding was 4.26 per 100,000 needles. Anticoagulants significantly increased the risk of minor bleeding (adjusted OR = 1.15 (1.03-1.28)), but the risk of major bleeding did not reach statistical significance (adjusted OR = 1.18 (0.8 0-1.75)). Anticoagulants, such as warfarin (adjusted OR = 4.95 (2.55-7.64)), direct oral anticoagulants (adjusted OR = 3.07 (1.23-5.47)), and heparin (adjusted OR = 3.72 (2.18-6.34)) significantly increased the risk of bleeding. However, antiplatelet drug was not significantly associated with post-acupuncture bleeding. Comorbidities including liver cirrhosis, diabetes, and coagulation defects, were the risk factors for bleeding after acupuncture. CONCLUSIONS: Anticoagulant drugs may increase the risk of bleeding after acupuncture. We encourage physicians to ask patients in detail about their medical history and drug use prior to acupuncture treatment.

Occurrence of intraocular hemorrhages under monotherapy or combination therapy of antiplatelets and anticoagulants using the Japanese Adverse Drug Event Report database.

Purpose: An intraocular hemorrhage is an adverse event that can lead to visual acuity impairment. Antithrombotic therapy with antiplatelet agents and anticoagulants may increase intraocular hemorrhage. However, since their frequency is low, studies on the risk of intraocular hemorrhage with these drugs, especially under combination therapy, are limited. This study aimed to investigate the occurrence of intraocular hemorrhages under monotherapy and combination therapy with antiplatelets and anticoagulants by analyzing a large pharmacovigilance database. Methods: Intraocular hemorrhage signals with oral antiplatelets and anticoagulants were evaluated by calculating reporting odds ratios and information components using the Japan Adverse Drug Reactions Report database from April 2004 to March 2022. In addition, differences in signals between younger and elderly patients, affecting factors, and time-to-onset from initial antiplatelet and anticoagulant treatments were analyzed. Results: Aspirin, clopidogrel, warfarin, apixaban, and rivaroxaban, but not ticagrelor, ticlopidine, prasugrel, dabigatran, and edoxaban showed intraocular hemorrhage signals under monotherapy. In combination therapy, dual therapy (aspirin + P2Y12 inhibitors, warfarin, direct oral anticoagulants, and P2Y12 inhibitors + warfarin) and triple therapy (aspirin + P2Y12 inhibitors + warfarin) resulted in intraocular hemorrhage signals. Intraocular hemorrhage signals were observed in younger patients receiving monotherapy with aspirin and in elderly patients receiving monotherapy and combination therapy with warfarin. Affecting factors were diabetes mellitus in patients with prasugrel, use of medications for intravitreal injections, and posterior sub-Tenon injections with some antiplatelets and anticoagulants. The median period of intraocular hemorrhage occurrence after starting monotherapy with aspirin, clopidogrel, warfarin, or rivaroxaban was within 90 days. Conclusion: In addition to monotherapy with several antiplatelets and anticoagulants, combination therapy using aspirin, P2Y12 inhibitors, and warfarin has the potential risk of intraocular hemorrhage. Particular attention should be paid to the occurrence of intraocular hemorrhages in younger patients taking aspirin, in elderly patients taking warfarin, and within the first 90 days of antiplatelet and anticoagulant use.

Optimal Anticoagulation on TAVI Patients Based on Thrombotic and Bleeding Risk and the Challenge Beyond: A Systematic Review and Meta-Analysis.

Transcatheter Aortic Valve Replacement (TAVR) has been established as the treatment of choice for symptomatic aortic stenosis, while it is expanding in all risk-related group categories of patients, gaining gradually ground over the surgical approach. However, complications and adverse events are yet to be effectively limited and diminished with thrombotic and hemorrhagic events being rooted as a crucial topic of discussion. Favorable anticoagulation pharmacotherapy options are constantly being revised and tested, whilst guidelines are being modified to meet current clinical evidence. This review aims to systematically assess already existing guidelines on anticoagulation in post-TAVI patients and examine novel regimens for the specific use, like apixaban, rivaroxaban, and other anticoagulants, essentially constructing a holistic point of view on future progress on this matter. The added complexity brought by coagulation-affecting comorbidities such as atrial fibrillation, coronary artery disease, and more contributes to the direct association of the topic to the quality of healthcare as a public service. The literature was systematically searched to examine the effectiveness and safety of various anticoagulation treatments and cross-evaluate them based on the according category of patients that were assigned to. Clinical trials, observational studies and systematic reviews were included and, eventually, conclusive remarks and future considerations were developed and presented. In the category of patients without prior indication to anticoagulation, SAPT was proven safer and still effective, when antiplatelet therapies were compared, while a comparison of antiplatelet versus anticoagulation strategies noted the first one, with limited data, as the optimal one. Lastly, direct oral anticoagulants were shown to be safe substitutes for vitamin K antagonists for patients with prior indication to anticoagulation.

Antithrombotic therapy and cardiovascular outcomes after transcatheter aortic valve implantation in patients without indications for chronic oral anticoagulation: a systematic review and network meta-analysis of randomized controlled trials.

AIMS: As the antithrombotic regimen that may best prevent ischaemic complications along with the lowest bleeding risk offset following transcatheter aortic valve implantation (TAVI) remains unclear, we aimed to compare the safety and efficacy of antithrombotic regimens in patients without having an indication for chronic oral anticoagulation. METHODS AND RESULTS: We conducted a PROSPERO-registered (CRD42021247924) systematic review and network meta-analysis of randomized controlled trials evaluating post-TAVI antithrombotic regimens up to April 2022. We estimated the relative risk (RR) and 95% confidence intervals (95% CIs) using a random-effects model in a frequentist pairwise and network metanalytic approach. We included seven studies comprising 4006 patients with a mean weighted follow-up of 12.9 months. Risk of all-cause death was significantly reduced with dual antiplatelet therapy (DAPT) compared with low-dose rivaroxaban + 3-month single antiplatelet therapy (SAPT) (RR 0.60, 95% CI 0.41-0.88), while no significant reduction was observed with SAPT vs. DAPT (RR 1.02, 95% CI 0.67-1.58) and SAPT and DAPT compared with apixaban or edoxaban (RR 0.60, 95% CI 0.32-1.14 and RR 0.59, 95% CI 0.34-1.02, respectively). SAPT was associated with a significant reduction of life-threatening, disabling, or major bleeding compared with DAPT (RR 0.45, 95% CI 0.29-0.70), apixaban or edoxaban alone (RR 0.45, 95% CI 0.25-0.79), and low-dose rivaroxaban + 3-month SAPT (RR 0.30, 95% CI 0.16-0.57). There were no differences between the various regimens with respect to myocardial infarction, stroke, or systemic embolism. CONCLUSION: Following TAVI in patients without an indication for chronic oral anticoagulant, SAPT more than halved the risk of bleeding compared with DAPT and direct oral anticoagulant-based regimens without significant ischaemic offset.

Antiplatelet effect of ginkgo diterpene lactone meglumine injection in acute ischemic stroke: A randomized, double-blind, placebo-controlled clinical trial.

This study was designed to evaluate antiplatelet effect and therapeutic effect of ginkgo diterpene lactone meglumine injection (GDLI) in acute ischemic stroke (AIS) patients. In this randomized, double-blind, placebo-controlled trial, we randomly assigned 70 inpatients within 48 hr after the onset of AIS to combination therapy with GDLI and aspirin (GDLI at a dose of 25 mg/d for 14 days plus aspirin at a dose of 100 mg/d for 90 days) or to placebo plus aspirin in a ratio of 1:1. Platelet function, the National Institute of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) were evaluated. A good outcome was defined as NIHSS scores decrease ≥5 or mRS scores decrease ≥2. Results showed that arachidonic acid induced maximum platelet aggregation rate (AA-MAR) and mean platelet volume (MPV) of the GDLI-aspirin group were much lower than that of the aspirin group (p = 0.013 and p = 0.034, respectively) after the 14-day therapy. The combination of GDLI and aspirin was superior to aspirin alone, and had significant impact on the good outcome at day 90 (ORadj 7.21 [95%CI, 1.03-50.68], p = 0.047). In summary, GDLI has antiplatelet effect and can improve the prognosis of AIS patients.

Development of the whole tomato and olive-based food supplement enriched with anti-platelet aggregating nutrients.

BACKGROUND: Platelet dysfunctions are shared by cardiovascular diseases and a wide range of inflammatory diseases. AIMS: To determine the ability of a new whole tomato-based food supplement (WTBFS) containing carotenoid and olive polyphenols to inhibit platelet aggregation. METHODS: Aggregation was evaluated in platelet-rich plasma using microtiter plates and a plate reader. RESULTS: Platelets treated with WTBFS showed a >70% reduction of 5 µM adenosine diphosphate (ADP)-induced platelet aggregation; at 10 µM of ADP, the inhibitory effect of WTBFS was reduced of about 50%. Similarly, 78% and 48% reduction were obtained using 5 µg/mL and 10 µg /mL of collagen as an agonist. CONCLUSION: Since the compounds in WTBFS share the ability to inhibit STAT3, the inhibition of its signaling pathway may represent the mechanism underlying the antiplatelet activities. The activity of a lipophilic solution prepared from WTBS was in vitro tested on the platelet aggregation in response to ADP agonists and Collagen.

Mechanism of platelet activation and potential therapeutic effects of natural drugs.

BACKGROUND: Cardiovascular disease is one of the most concerning chronic diseases in the world. Many studies have shown that platelet overactivation is a very important factor in the occurrence and development of cardiovascular diseases. At present, the widely used antiplatelet drugs have some defects, such as drug resistance and adverse reactions. PURPOSE: The purpose of this article is to summarize the main mechanisms and pathways of platelet activation, the main targets of antiplatelet aggregation, and the antiplatelet aggregation components of natural drugs and their mechanisms of action to provide new research ideas for the development and application of antiplatelet drugs. STUDY DESIGN AND METHODS: In this review, we systematically searched the PubMed, Google Scholar, Web of Science, and CNKI databases and selected studies based on predefined eligibility criteria. We then assessed their quality and extracted data. RESULTS: ADP, AA, THR, AF, collagen, SDF-1α, and Ca2+ can induce platelet aggregation and trigger thrombosis. Natural drugs have a good inhibitory effect on platelet activation. More than 50 kinds of natural drugs and over 120 kinds of chemical compounds, including flavonoids, alkaloids, saponins, terpenoids, coumarins, and organic acids, have significantly inhibited platelet activation activity. The MAPK pathway, cGMP-PKG pathway, cAMP-PKA pathway, PI3K-AKT pathway, PTK pathway, PLC pathway, and AA pathway are the main mechanisms and pathways of platelet activation. CONCLUSION: Natural drugs and their active ingredients have shown good activity and application prospects in anti-platelet aggregation. We hope that this review provides new research ideas for the development and application of antiplatelet drugs.

Tongue diagnostic parameters-based diagnostic signature in coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention.

BACKGROUND: Credible diagnostic stratification remains a challenge for coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention. Tongue diagnostic parameters-based diagnostic signatures might predict clopidogrel resistance. METHODS: Clinical and tongue diagnostic parameters data were obtained from coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention patients and then analyzed. Tongue diagnostic parameters-based diagnostic signatures were developed through univariate and multivariate logistic regression analysis. The diagnostic prediction was assessed using a receiver operating characteristic curve. RESULTS: A total of 101 patients were consecutively identified. Then, tongue diagnostic parameters were identified as significantly associated with clopidogrel resistance diagnosis and were combined with risk factors to develop a model. The receiver operating characteristic curve analysis showed that tongue diagnostic parameters-based diagnostic signatures performed well in diagnosing clopidogrel resistance with an area under the receiver operating characteristic curve value of 0.819. CONCLUSIONS: This study identified a novel tongue diagnostic parameters-based diagnostic signature to reliably distinguish clopidogrel resistance diagnosis in coronary artery disease patients undergoing percutaneous coronary intervention. Further larger, multicenter prospective studies are desired to validate this model.

Clopidogrel resistance is common in patients undergoing vascular and coronary interventions.

OBJECTIVES: "Clopidogrel resistance," also defined as heightened platelet reactivity (HPR) while on clopidogrel therapy, may lead to a sub-optimal antiplatelet effect and a potential thrombotic event. There is limited literature addressing the prevalence of HPR in a large cohort of patients receiving either coronary or endovascular interventions. METHODS: In a large integrated healthcare system, patients with a P2Y12 reaction units (PRU) test were identified. HPR was defined as a PRU ≥ 200 during clopidogrel therapy. Vascular and coronary interventions were identified utilizing CPT codes, HPR prevalence was calculated, and Fischer's exact test was used to determine significance. RESULTS: From an initial cohort of 2,405,957 patients (October 2014 to January 2020), we identified 3301 patients with PRU tests administered. Of these, 1789 tests had a PRU ≥ 200 (HPR overall prevalence, 54%). We then identified 1195 patients who underwent either an endovascular or coronary procedure and had a PRU measurement. This corresponded to 935 coronary and 260 endovascular interventions. In the coronary cohort, the HPR prevalence was 54% (503/935). In the vascular cohort, the HPR prevalence was 53% (137/260); there was no difference between cohorts in HPR prevalence (p = 0.78). CONCLUSION: "Clopidogrel resistance" or HPR was found to be present in nearly half of patients with cardiovascular disease undergoing intervention. Our data suggest HPR is more common in the cardiovascular patient population than previously appreciated. Evaluating patients for HPR is both inexpensive ($25) and rapid (< 10 min). Future randomized studies are warranted to determine whether HPR has a clinically detectable effect on revascularization outcomes.

Sex-Related Differences in Platelet Aggregation: A Literature Review Supplemented with Local Data from a Group of Generally Healthy Individuals.

The process of platelet aggregation is often influenced by several factors including sex and age. A literature review confirmed the existence of sex-related differences in platelet aggregation. Although 68 out of 78 papers found such differences, there are still some controversies regarding these differences, which can be due to multiple factors (age, trigger, concomitant disease, sample handling, etc.). These outcomes are discussed in line with novel results obtained from a local study, in which blood samples from a total of 53 overall healthy women and men with ages ranging from 20 to 66 years were collected. Aggregation was induced with seven different triggers (ristocetin, thrombin receptor activating peptide 6 [TRAP-6], arachidonic acid [AA], platelet-activating factor 16 [PAF-16], ADP, collagen, or thromboxane A2 analog U-46619) ex vivo. In addition, three FDA-approved antiplatelet drugs (vorapaxar, ticagrelor, or acetylsalicylic acid [ASA]) were also tested. In general, women had higher aggregation responses to some agonists (ADP, TRAP), as well as lower benefit from inhibitors (ASA, vorapaxar). The aggregatory responses to AA and TRAP decreased with age in both sexes, while responses to ADP, U-46619, and PAF were affected by age only in women. In conclusion, more studies are needed to decipher the biological importance of sex-related differences in platelet aggregation in part to enable personalized antiplatelet treatment.

To study the mechanism of panax notoginseng in the treatment of aspirin resistance in the secondary prevention of stroke based on TLR4/MyD88/NF-κB signaling pathway: A study protocol.

INTRODUCTION: Aspirin, as an typical antiplatelet therapy for secondary stroke prevention, have been proved that can significantly reduce incidence and recurrence of cerebrovascular ischemic events. However, due to drugs biological characteristics, aspirin resistance (AR) often occurs in clinical practice, which significantly influence secondary prevention in stroke patients. The growing evidence of activating blood and removing stasis herbs medicine (Sanqi) for AR is promising. However, the efficacy and mechanism of Panax notoginseng (Sanqi) for AR in secondary stroke prevention has not been confirmed. METHODS/DESIGN: This is a prospective 2-center, assessor and statistician blinded, randomized, controlled trial. We will allocate 106 subjects aged between 45 and 65 years old, diagnosed with aspirin semi-resistance after stroke to 2 groups randomly in a ratio of 1:1. Patients in the experimental group will be treated with conventional treatments plus Panax notoginseng (Sanqi) while the others in the control group will be treated with only conventional treatments. All will be given different medications for 30 days. Patients will be measured with the platelet aggregation rate and serum TLR4, MyD88, NF-κB, COX-2, IL-6, CRP, TXB2 level for clinical efficacy and mechanisms at baseline and the 14th, 30th day of treatment. Baseline characteristics of patients will be summarized by groups and compared with Chi-square for categorical variables, and Student's independent t test or nonparametric Mann-Whitney U test for the continuous variables. Primary and secondary outcomes will be analyzed with 2-way repeated measures Anova, and Post Hoc test. CONCLUSION: The present study aims to investigate short-term add-on efficacy and mechanism of Panax notoginseng (Sanqi) for aspirin resistance in secondary stroke prevention via TLR4/MyD88/NF-κB signaling pathway. With this, we expect to find out an appropriate partial substitute of aspirin for aspirin resistance individuals. TRIAL REGISTRATION: The trial was registered on Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) with the ID ChiCTR2100045773 at April 24, 2021.