Antiplatelet Effects Research Articles

Can Isoquinoline Alkaloids Affect Platelet Aggregation in Whole Human Blood?

Isoquinoline alkaloids have multiple biological activities, which might be associated with positive pharmacological effects as well as negative adverse reactions. As bleeding was suggested to be a side effect of the isoquinoline alkaloid berberine, we decided to ascertain if different isoquinoline alkaloids could influence hemocoagulation through the inhibition of either platelet aggregation or blood coagulation. Initially, a total of 14 compounds were screened for antiplatelet activity in whole human blood by impedance aggregometry. Eight of them demonstrated an antiplatelet effect against arachidonic acid-induced aggregation. Papaverine and bulbocapnine were the most potent compounds with biologically relevant IC50 values of 26.9 ± 12.2 μM and 30.7 ± 5.4 μM, respectively. Further testing with the same approach confirmed their antiplatelet effects by employing the most physiologically relevant inducer of platelet aggregation, collagen, and demonstrated that bulbocapnine acted at the level of thromboxane receptors. None of the alkaloids tested had an effect on blood coagulation measured by a mechanical coagulometer. In conclusion, the observed antiplatelet effects of isoquinoline alkaloids were found mostly at quite high concentrations, which means that their clinical impact is most likely low. Bulbocapnine was an exception. It proved to be a promising antiplatelet molecule, which may have biologically relevant effects.

Antithrombotic therapy to prevent cognitive decline in people with small vessel disease on neuroimaging but without dementia.

Cerebral small vessel disease is a progressivedisease of the brain'sdeep perforating blood vessels.It is usually diagnosed based on lesions seen on brain imaging. Cerebral small vessel disease is a common cause of stroke but can also cause a progressive cognitive decline. As antithrombotic therapy is anestablished treatment for stroke prevention, we sought to determinewhether antithrombotic therapy might also be effective in preventing cognitive decline in people with small vessel disease. To assess the effects of antithrombotic therapy for prevention of cognitive decline in people with small vessel disease on neuroimaging but without dementia. We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Review Group's Specialised Register, and the Cochrane Stroke Group's Specialised Register; the most recent search was on 21 July 2021. We also searched MEDLINE, Embase, four other databases and two trials registries. We searched the reference lists of the articles retrieved from these searches. As trials with a stroke focus may include relevant subgroup data, we complemented these searches with a focussed search of all antithrombotic titles in the Cochrane Stroke Group database. SELECTION CRITERIA: We included randomised controlled trials (RCT) of people with neuroimaging evidence of at least mild cerebral small vessel disease (defined here as white matter hyperintensities, lacunes of presumed vascular origin and subcortical infarcts) but with no evidence of dementia. The trials had to compareantithrombotic therapy of minimum 24 weeks' duration to no antithrombotic therapy (either placebo or treatment as usual), or comparedifferent antithrombotic treatment regimens. Antithrombotic therapy could include antiplatelet agents (as monotherapyor combination therapy), anticoagulants or a combination. Two review authors independently screened all the titlesidentified by the searches. We assessed full texts for eligibility for inclusion according to our prespecified selection criteria, extracted data to a proforma and assessed risk of bias using the Cochrane tool for RCTs. We evaluated the certainty of evidence using GRADE. Due to heterogeneity across included participants, interventions and outcomes of eligible trials, it was not possible to perform meta-analyses. We included threeRCTs (3384 participants). One study investigated the effect of antithrombotic therapy in participants not yet on antithrombotic therapy; two studies investigated the effect of additional antithrombotic therapy, one in a population already taking a single antithrombotic agent and one in a mixed population (participants on an antithrombotic drug and antithrombotic-naive participants). Intervention and follow-up durations varied from 24 weeks to four years. Jia 2016 was a placebo-controlled trial assessing 24 weeks of treatment with DL-3-n-butylphthalide (a compound with multimodal actions, including a putative antiplatelet effect) in 280 Chinese participants with vascular cognitive impairment caused by subcortical ischaemic small vessel disease, but without dementia. There was very low-certainty evidence for a small difference in cognitive test scores favouring treatment with DL-3-n-butylphthalide, as measured by the 12-item Alzheimer's Disease Assessment Scale-Cognitive subscale (adjusted mean difference -1.07, 95% confidence interval (CI) -2.02 to -0.12), but this difference may not be clinically relevant. There was also very low-certainty evidence for greater proportional improvement measured with the Clinician Interview-Based Impression of Change-Plus Caregiver Input (57% with DL-3-n-butylphthalide versus 42% with placebo; P = 0.01), but there was no difference in other measures of cognition (Mini-Mental State Examination and Clinical Dementia Rating) or function. There was no evidence of a difference in adverse events between treatment groups. The SILENCE RCT compared antithrombotic therapy (aspirin) and placebo during four years of treatment in 83 participants with 'silent brain infarcts' who were on no prior antithrombotic therapy. There was very low-certainty evidence for no difference between groups across various measures of cognition and function, rates of stroke or adverse events. The Secondary Prevention of Subcortical Stroke Study (SPS3) compared dual antiplatelet therapy (clopidogrel plus aspirin) to aspirin alone in 3020 participants with recent lacunar stroke. There was low-certainty evidence of no effect on cognitive outcomes as measured by the Cognitive Abilities Screening Instruments (CASI) assessed annually over five years. There was also low-certainty evidence of no difference in the annual incidence of mild cognitive decline between the two treatment groups (9.7% with dual antiplatelet therapy versus 9.9% with aspirin), or the annual stroke recurrence rate(2.5% with dual antiplatelet therapy versus 2.7% with aspirin). Bleeding risk may be higher with dual antiplatelet therapy (hazard ratio (HR) 2.15, 95% CI 1.49 to 3.11; low certainty evidence), but there may be no significant increase in intracerebral bleeding risk(HR 1.52, 95% CI 0.79 to 2.93; low-certainty evidence). None of the included trials assessed the incidence of new dementia. We found no convincing evidence to suggest any clinically relevant cognitive benefit of using antithrombotic therapy in addition tostandard treatment in people with cerebral small vessel disease but without dementia, but there may be an increased bleeding risk with this approach. There was marked heterogeneityacross the trials and the certainty of the evidence was generally poor.

Ligustrazine prevents coronary microcirculation dysfunction in rats via suppression of miR-34a-5p and promotion of Sirt1

IntroductionThe coronary microembolization contributes to coronary microvascular dysfunction (CMD), in which miR-34a-5p may play a critical role. Ligustrazine has been reported to improve CMD. The present study was designed to discuss the role of miR-34a-5p/Sirt1 pathway in CMD and explore the underlying mechanism of ligustrazine. MethodsCoronary microembolization (CME) was induced by left ventricle injection of sodium laurate in rats. CME formation and cardiac function were examined by HE staining and hemodynamic tests to evaluate CMD. The expressions of miR-34a-5p, Sirt1 and the downstream proteins were detected by RT-qPCR and western blot. Dual-luciferase reporter (DLR) assay was performed to confirm the connection between miR-34a-5p and Sirt1. The blood markers of endothelial dysfunction, platelet activation and inflammation were examined with ELISA. ResultsOvert CME and cardiac dysfunction as well as up-regulated miR-34a-5p and down-regulated Sirt1 were observed in CME rats. Overexpressing miR-34a-5p aggravated while silencing miR-34a-5p inhibited CME formation. DLR assay confirmed that miR-34a-5p directly inhibited Sirt1 mRNA expression. Ligustrazine pretreatment suppressed miR-34a-5p and promoted Sirt1 expression, which alleviated endothelial dysfunction, inhibited platelet activation and inflammation, and in turn reduced CME. Overexpressing miR-34a-5p diminished the positive effects of ligustrazine; while after silencing miR-34a-5p, ligustrazine failed to further promote Sirt1 expression and inhibit CME formation. ConclusionMiR-34a-5p contributes to CMD by inhibiting Sirt1 expression. Ligustrazine exerts endothelial-protective, anti-platelet and anti-inflammatory effects to prevent CMD via suppressing miR-34a-5p and promoting Sirt1.

Assessment of on-treatment platelet reactivity at high and low shear stress and platelet activation status after the addition of dipyridamole to aspirin in the early and late phases after TIA and ischaemic stroke

BackgroundData are limited on the ability of dipyridamole to additionally inhibit platelet function/reactivity in ischaemic cerebrovascular disease (CVD) patients on aspirin. AimsTo assess inhibition of platelet function/reactivity and platelet activation with dipyridamole in CVD. MethodsThis prospective, observational study assessed TIA/ischaemic stroke patients before (baseline; N = 60), at 14 ±7 days (14d, N = 39) and ≥ 90 days (90d, N = 31) after adding dipyridamole to aspirin. Platelet function/reactivity at high shear stress (PFA-100® C-ADP) and low shear stress (VerifyNow® P2Y12 and Multiplate® ADP assays), and platelet activation status (% expression of CD62P, CD63 and leucocyte-platelet complexes on whole blood flow cytometry) were quantified. ‘Dipyridamole-high on-treatment platelet reactivity (HTPR)’ was defined as failure to inhibit ADP-induced platelet aggregation +/- adhesion compared with the patient's baseline on aspirin monotherapy by more than twice the coefficient-of-variation of the assay after adding dipyridamole to aspirin. ResultsDipyridamole-HTPR was identified in 71.4–75% of patients on PFA-100 C-ADP, 83.9–86.8% of patients on VerifyNow P2Y12, and 81.5–83.3% of patients on Multiplate ADP assays. There were no changes in CD62P/CD63 expression (P ≥ 0.18), or consistent changes in leucocyte-platelet complexes in CVD patients overall at 14d or 90d vs. baseline after commencing dipyridamole. Monocyte-platelet complexes increased in the patient subgroup with dipyridamole-HTPR at 14d and 90d on PFA-100, and at 14d on VerifyNow (P ≤ 0.04), but not in those without dipyridamole-HTPR. DiscussionAdditional antiplatelet effects of dipyridamole are detectable under high and low shear stress conditions with user-friendly platelet function/reactivity tests ex vivo. Increasing circulating monocyte-platelet complexes over time are associated with dipyridamole-HTPR.

Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage: Systematic Review and Meta-Analysis

For patients with atrial fibrillation who survive an intracranial hemorrhage (ICrH), the decision to offer oral anticoagulation (OAC) is challenging and necessitates balancing risk of thromboembolic events with risk of recurrent ICrH. This systematic review assesses the effectiveness and safety of OAC and/or antiplatelets in patients with atrial fibrillation with nontraumatic ICrH. Bibliographic databases CENTRAL, MEDLINE, EMBASE, and CINAHL were searched. Articles on adults with atrial fibrillation with spontaneous ICrH (intracerebral, subdural, and subarachnoid), receiving antithrombotic therapy for stroke prevention were eligible for inclusion. Twenty articles (50 470 participants) included 2 randomized controlled trials (n=304)' 8 observational studies, 8 cohort studies, and 2 studies that meta-analyzed individual-level data from observational studies. OAC therapy was associated with a significant reduction in thromboembolic events (summary relative risk [sRR], 0.51 [95% CI, 0.30-0.86], heterogeneity I2=2%; P=0.39, n=5 studies) and all-cause mortality (sRR, 0.52 [95% CI, 0.38-0.71], heterogeneity I2=0; P=0.44, n=3 studies). OAC therapy was not associated with an increased risk of recurrent ICrH (sRR, 1.44 [95% CI, 0.38-5.46], heterogeneity I2=70%, P=0.02, n=5 studies). Nonvitamin K antagonist OACs were more effective at reducing the risk of thromboembolic events (sRR, 0.65 [95% CI, 0.44-0.97], heterogeneity I2=72%, P=0.03, n=3 studies) and were associated with a lower risk of recurrent ICrH (sRR, 0.52 [95% CI, 0.40-0.67], heterogeneity I2=0%, P=0.43, n=3 studies) than warfarin. In nontraumatic ICrH survivors with atrial fibrillation, OAC therapy is associated with a reduced risk of thromboembolic events and all-cause mortality without significantly increasing risk of recurrent ICrH. This finding is primarily based on observational data, and further larger randomized controlled trials are needed to corroborate or refute these findings.

Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function.

Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as signal transducer and activator of transcription, STAT, inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by platelet agonists. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function.

Efficacy of a parenteral nutrition mixture in correcting the nutritional status of elderly patients with severe novel coronavirus infection COVID-19

In the context of a decrease in the infection of the population with the novel coronavirus infection, as well as a decline in the severity of the course and mortality of COVID-19 patients, the management of patients after the infection remains relevant in the conditions of the so-called «long COVID» (post-COVID syndrome). Currently, the symptom complex of post-COVID syndrome most often includes tiredness, fatigue, pain (myalgia and arthralgia), decreased physical strength and endurance, decreased performance, quality of life, and daily activities. Common mental health problems include anxiety disorders, depression and emotional stress, among other symptoms. Pharmacotherapy of post-COVID syndrome may include anti-inflammatory and analgesic drugs, neurocytoprotectors, antiaggregants and anticoagulants, vitamins, and psychotropic drugs. According to various researchers, fluvoxamine is a drug that can not only have its direct psychotropic effect and be used during the early rehabilitation of patients, but also be considered in the prevention and treatment of the novel coronavirus infection as an antiviral drug, providing anti-inflammatory, antiplatelet and immunomodulatory effects.

Human milk oligosaccharide, 2′-Fucosyllactose, attenuates platelet activation in arterial thrombosis

A schematic model of GPVI-mediated platelet activation pathway inhibited by 2′-Fucosyllactose (2′-FL). 2′-FL inhibits multiple aspects of the GPVI activation pathway, including Syk signalosome, granule secretion, calcium mobilization, integrin αIIbβ3 activation and aggregation. GPVI, glycoprotein VI; IP3, inositol 1,4,5-trisphosphate; PLC, phospholipase C; Syk, spleen tyrosine kinase. • 2′-FL effectively reduces the platelet thrombus formation in vitro. • Oral administration of 2′-FL has immediate benefits in thrombus formation and a mouse model of ischemia/reperfusion-induced stroke in vivo. The ingestion of supplemental human milk oligosaccharides (HMOs) is associated with a lower risk of inflammatory diseases and infections. However, whether HMOs play an important role in regulating platelet aggregation and thrombus formation remains unclear. The current study aimed to investigate the antiplatelet and antithrombotic effects of HMOs. Among all HMOs, 2′-fucosyllactose (2′-FL) could significantly inhibit collagen-related peptide-induced platelet aggregation, granule secretion, and intracellular calcium mobilization. Notably, the inhibitory effect of 2′-FL was associated with the inhibition of glycoprotein VI-mediated platelet signal transduction during cell activation. In accordance with antiplatelet activities, the oral administration of 2′-FL was effective in blocking ferric chloride-induced arterial thrombus formation in vivo without prolonging bleeding time. Studies using a mouse model of ischemia-/reperfusion-induced stroke revealed that treatment with 2′-FL reduced infarct volume in stroke. Hence, the therapeutic potential of 2′-FL supplementation may play a protective role against thrombotic diseases.

A Sticky Situation: Variable Agreement Between Platelet Function Tests Used to Assess Anti-platelet Therapy Response.

BackgroundPlatelet function testing to monitor antiplatelet therapy is important for reducing thromboembolic complications, yet variability across testing methods remains challenging. Here we evaluated the agreement of four different testing platforms used to monitor antiplatelet effects of aspirin (ASA) or P2Y12 inhibitors (P2Y12-I).MethodsBlood and urine specimens from 20 patients receiving dual antiplatelet therapy were analyzed by light transmission aggregometry (LTA), whole blood aggregometry (WBA), VerifyNow PRUTest and AspirinWorks. Result interpretation based on pre-defined cutoff values was used to calculate raw agreement indices, and Pearson's correlation coefficient determined using individual units of measure.ResultsAgreement between LTA and WBA for P2Y12-I-response was 60% (r = 0.65, high-dose ADP; r = 0.75, low-dose ADP). VerifyNow agreed with LTA in 75% (r = 0.86, high-dose ADP; r = 0.75, low-dose ADP) and WBA in 55% (r = 0.57) of cases. Agreement between LTA and WBA for ASA-response was 45% (r = 0.09, high-dose collagen WBA; r = 0.19, low-dose collagen WBA). AspirinWorks agreed with LTA in 60% (r = 0.32) and WBA in 35% (r = 0.02, high-dose collagen WBA; r = 0.08, low-dose collagen WBA) of cases.ConclusionsOverall agreement varied from 35 to 75%. LTA and VerifyNow demonstrated the highest agreement for P2Y12-I-response, followed by moderate agreement between LTA and WBA. LTA and AspirinWorks showed moderate agreement for aspirin response, while WBA showed the weakest agreement with both LTA and AspirinWorks. The results from this study support the continued use of LTA for monitoring dual antiplatelet therapy, with VerifyNow as an appropriate alternative for P2Y12-I-response. Integration of results obtained from these varied testing platforms with patient outcomes remains paramount for future studies.

Multivisceral Transplant in a Patient With Portopulmonary Hypertension: A Case Report

Portopulmonary hypertension, a type of pulmonary arterial hypertension in the setting of cirrhotic or noncirrhotic portal hypertension, is associated with elevated morbidity and mortality during and after transplantation. Uncontrolled portopulmonary hypertension may prevent or delay listing for transplant candidates, and the prognosis without treatment and ultimately transplant is extremely poor. We present a 29-year-old White woman, who had a post-liver transplant at infancy due to biliary atresia. Later on, she developed extensive portal vein thrombosis and portopulmonary hypertension and underwent a multivisceral transplant (liver, stomach, pancreaticoduodenal complex, and small and large intestine). Preoperative mean pulmonary artery pressure was <30 mm Hg with a pulmonary vascular resistance of <300 dynes.s/cm5 on oral sildenafil and intravenous epoprostenol. Intraoperatively, management required comprehensive transfusion protocols, a careful balance between correcting blood loss and preventing thrombosis. Intravenous epoprostenol, sildenafil, milrinone, and inhaled nitric oxide were used to reduce elevated mean pulmonary artery pressure and right ventricular strain associated with vascular clamping, reperfusion, and massive fluid shifts. Nitric oxide and epoprostenol use unleashed antiplatelet effects on a patient already susceptible to coagulopathy. A multimodal and multidisciplinary approach continued throughout the surgery and in the postoperative period, which led to a successful outcome.

Cardioprotective Effects of Malus Domestica (Apple) May be Mediated Through Antiplatelet, Calcium Channel Blocking, and Antioxidant Properties

Research on the cardioprotective potential of Malus domestica (MD or apple) has been of considerable importance and efforts are being increasingly focused on investigating their effects on human health. However, relatively little work has been done to investigate the cardioprotective effects of crude extract of MD. In the present study, the antioxidant potential of crude methanolic extract of MD fruit part was investigated by measuring its effects on glutathione peroxidase (GPx), superoxide dismutase (SOD) enzymes, and total antioxidant status (TAS) in blood samples. Anti-platelet and calcium channel blocking activities were also investigated. Our results reveal that crude methanolic extract of MD showed a significant concentration-dependent increase in GPx, and SOD, but not in TAS compared with saline solution (0.9% NaCl) used as negative control and vitamin C, as a positive control. Furthermore, crude extract of MD inhibited calcium channels and showed strong antiplatelet effects against arachidonic acid and platelet-activating factor-induced platelet aggregation. These results suggest that the cardioprotective effects of MD may be mediated through multiple pathways including calcium antagonizing, antiplatelet, and antioxidant properties.

A pilot study assessing the implementation of 96-well plate-based aggregometry (Optimul) in Australia

Identification of disordered platelet function is important to guide peri-operative bleeding management as well as long term treatment and prognostic strategies in individuals with platelet bleeding disorders. Light transmission aggregometry (LTA), the current gold standard diagnostic test of platelet function is a time consuming technique almost exclusively performed in specialised laboratories and almost universally unavailable in regional centres in Australia, where there is an unmet need for access to specialised platelet function diagnostic services. 96-well plate-based aggregometry (Optimul, UK), has been utilised in research laboratories as a novel platform to investigate platelet function. We evaluated the Optimul assay at two centres in Australia, one regional and one tertiary metropolitan, to assess its feasibility as a screening test applicable to remote regional centres. Concentration-response curves were established from 45 healthy volunteers at the participating regional hospital and from 31 healthy volunteers at the tertiary institution. Optimul successfully detected anti-platelet effects in individuals taking aspirin (n=4), NSAID (n=2), clopidogrel (n=2) and dual therapy with aspirin and clopidogrel (n=1). When tested in parallel to LTA in individuals referred for the evaluation of abnormal bleeding symptoms there was overall a very good level of agreement between Optimul and LTA [Cohen's kappa (k2)=0.84], supporting its role as a useful screening tool in the assessment of platelet function. Optimul assay performance was quick and the methodology simple, requiring no specialised training or resources to be implemented at either the regional or metropolitan laboratory. Widespread implementation, particularly in regional laboratories within Australia where specialised platelet function testing is unavailable, has the potential to drastically improve the inequity of access to such services.

Traditional Chinese medicine injections with activating blood circulation, equivalent effect of anticoagulation or antiplatelet, for acute myocardial infarction: A protocol for the systematic review and meta-analysis of randomized clinical trials.

BackgroundIn spite of a growing number in the use of percutaneous coronary intervention (PCI) in China, the mortality of acute myocardial infarction (AMI) has not decreased. Traditional Chinese medicine injections for Activating Blood Circulation (TCMi-ABC), equivalent effect of anticoagulation or antiplatelet, are widely used in China; however, the improvement of fatality towards AMI is unclear. Therefore, we intend to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of TCMi-ABC in treatment with AMI.MethodsBased on the “National Medical Products Administration of China,” TCMi-ABC with AMI treatment indication will be selected, including Danhong injection, Sodium Tanshinone IIA Sulfonate injection, Danshen Chuanxiongqin injection, and Puerarin injection. Randomized controlled studies will be searched from as follows: PubMed, Embase, the CENTRAL in Cochrane Library, Chinese Biomedical Literature Database (SinoMed), China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang Data Knowledge Service Platform. Two researchers will work independently on literature selection, data extraction, and quality assessment. The outcomes focus on the effects of TCMi-ABC on fatality of patients with AMI in hospitalization and in the long term, the incidence of malignant arrhythmia, left ventricular ejection fraction, and adverse events. RevMan 5.4.1 software was used for mate analysis.ResultsThis study will conduct a comprehensive literature search and provide a systematic synthesis of current published data to explore the efficacy and safety of TCMi-ABC for AMI.ConclusionThis study will provide high-quality evidence for treatment of AMI with TCMi-ABC in terms of efficacy and safety, which may help clinicians make a better complementary treatment schedule of patients with AMI.

TPU-based antiplatelet cardiovascular prostheses prepared using fused deposition modelling

This work describes the use of fused deposition modelling (FDM) to prepare antiplatelet thermoplastic polyurethane (TPU)-based tubular grafts. FDM 3D-printing technology is widely available and provides the ability to easily design tubular grafts on demand, enabling the customisation of vascular prosthesis dimensions. An antiplatelet drug, dipyridamole (DIP), was combined with TPU using hot-melt extrusion to prepare filaments. DIP cargos ranged between 5 and 20% (w/w). The resulting filaments were used to prepare small diameter vascular grafts using FDM. These grafts were characterised. Moreover, DIP release kinetics, antiplatelet activity andin vitrohemo- and cytocompatibility were evaluated. The results suggested that the materialscould providesustained DIP release for 30 days. Moreover, the presence of 5% DIP in the material showed a clear antiplatelet effect compared with pristine TPU. Alternatively, higher DIP loadings resulted higher surface roughness leading to higher platelet adhesion. Therefore, the biocompatibility of 5% DIP samples was tested showing that this type of materials allowed higher HUVEC cell proliferation compared to pristine TPU samples. Finally, DIP loaded TPU was combined with rifampicin-loaded TPU to prepare double-layered tubular grafts. These grafts demonstrated a clear antimicrobial activity against bothStaphylococcus aureusandEscherichia coli.

Mechanism and Potential Target of Blood-Activating Chinese Botanical Drugs Combined With Anti-Platelet Drugs: Prevention and Treatment of Atherosclerotic Cardiovascular Diseases.

Atherosclerotic cardiovascular diseases (ASCVDs) are the most important diseases that endanger people’s health, leading to high morbidity and mortality worldwide. In addition, various thrombotic events secondary to cardiovascular and cerebrovascular diseases need must be considered seriously. Therefore, the development of novel anti-platelet drugs with high efficiency, and fewer adverse effects has become a research focus for preventing of cardiovascular diseases (CVDs). Blood-activation and stasis-removal from circulation have been widely considered as principles for treating syndromes related to CVDs. Blood-activating Chinese (BAC botanical drugs, as members of traditional Chinese medicine (TCM), have shown to improve hemodynamics and hemorheology, and inhibit thrombosis and atherosclerosis. Modern medical research has identified that a combination of BAC botanical drugs and anti-platelet drugs, such as aspirin or clopidogrel, not only enhances the anti-platelet effects, but also reduces the risk of bleeding and protects the vascular endothelium. The anti-platelet mechanism of Blood-activating Chinese (BAC) botanical drugs and their compounds is not clear; therefore, their potential targets need to be explored. With the continuous development of bioinformatics and “omics” technology, some unconventional applications of BAC botanical drugs have been discovered. In this review, we will focus on the related targets and signaling pathways of anti-atherosclerotic treatments involving a combination of BAC botanical drugs and anti-platelet drugs reported in recent years.

Ticagrelor prevents infective endocarditis by mitigating Staphylococcus aureus virulence

Infective endocarditis (IE) is a deadly disease mainly caused by the gram-positive and highly virulent bacteria Staphylococcus aureus (SA). Due to lack of efficacy of current antibiotic therapy, there is an urgent need to discover new strategies that could prevent this disease. To assess the ability of the antiplatelet drug ticagrelor, which also displays antibacterial activity against gram-positive bacteria, to prevent SAIE. We used a mouse model of infective endocarditis induced by a SAIE clinical isolate. Ticagrelor was administered orally at a conventional dosage (3 mg/kg, single dose) prior to infection and local histamine infusion on the aortic valve. Infected vegetation presence was determined by Gram staining on heart sections after three days. Antibacterial effect of ticagrelor at dosages equivalent to plasma levels achieved in patients (0.75–1.25 μg/mL) was assessed in vitro in human blood. Ticagrelor significantly prevented the formation of infected vegetation, with IE in only 14.3% of ticagrelor-treated mice ( n = 21) compared to 52.3% of vehicle-treated mice ( n = 37). Ex vivo ADP-induced platelet aggregation assays confirmed rapid reversibility of antiplatelet activity (4 hours), which made it unlikely that solely the antiplatelet effect would explain IE prevention by ticagrelor. Bacterial survival in blood was not diminished three days post-infection. We therefore assessed whether ticagrelor could affect bacterial virulence. We found that growing SA in the presence of 1.25 μg/mL ticagrelor inhibited a-toxin RNA expression and protein secretion, which was corroborated with drastically reduced hemolysis and platelet aggregation induced by bacterial supernatants. Ticagrelor-treated bacteria could no longer adhered to fibrinogen, and in whole blood perfusion experiments, flow-dependent bacterial adhesion on activated endothelial cells was severely impaired. Our study demonstrates the unprecedented ability of ticagrelor to prevent IE by a novel mechanism of directly mitigating bacterial virulence. Hence, clinical trials using ticagrelor as adjunct therapy to antibiotics in patients at risk for IE are warranted.

Four-Week Supplementation of Water-Soluble Tomato Extract Attenuates Platelet Function in Chinese Healthy Middle-Aged and Older Individuals: A Randomized, Double-Blinded, and Crossover Clinical Trial.

Background and AimsPlatelets are linked to atherosclerotic development and pathological thrombosis. Single dose of water-soluble tomato extract (WTE) which is a natural extraction can exert anti-platelet effects after 3 or 7 h in British healthy people. However, the effects of WTE supplementation on platelet function in Chinese healthy middle-aged and older individuals have not been studied, and the effects or safety of 4-week WTE supplementation also remain unclear. The present study aims to determine the effects of WTE on platelet function, and explore the safety of 4-week WTE supplementation in Chinese healthy middle-aged and older individuals.MethodsA randomized, double-blinded, and crossover clinical trial was conducted. Firstly, 105 individuals were randomly divided into two groups that received WTE (150 mg/day) or placebo for 4 weeks. Then, after a washout period of 2 weeks, two groups exchanged groups and continued for another 4-week intervention. Platelet aggregation, P-selectin, activated GPIIbIIIa, plasma platelet factor 4 (PF4), β-thromboglobulin (β-TG), and thromboxane B2 (TXB2) were tested at baseline, 4, 6, and 10 weeks.ResultsCompared with the placebo group, 150 mg/day WTE supplement for 4 weeks significantly reduced ADP-induced or collagen-induced platelet aggregation (−10.8 ± 1.8 or −3.9 ± 1.5%, P < 0.05), ADP-induced or collagen-induced platelet P-selectin expression (−6.9 ± 1.5 or −6.6 ± 1.3%, P < 0.05), ADP-induced or collagen-induced activated GPIIbIIIa (−6.2 ± 2.0 or −3.8 ± 2.0%, P < 0.05). Besides, 4-week intervention of 150 mg WTE per day also resulted in significant reductions in plasma PF4 (−120.6 ± 33.2 ng/mL, P < 0.05) and β-TG (−129.7 ± 27.5 ng/mL, P < 0.05) and TXB2 (−42.0 ± 4.0 ng/mL, P < 0.05), while had no effects on coagulation function and liver or renal function. Interestingly, 2-week washout period is enough to reverse the inhibitory effect of 4-week WTE supplementation on platelet function.ConclusionWTE supplementation for 4 weeks could moderately reduce platelet activation, aggregation, and granule secretion in Chinese healthy middle-aged and older individuals, and these effects are safe. After 2-week washout period, the inhibitory effect of 4-week WTE on platelet function can be eliminated.Clinical Trial Registration[http://www.chictr.org.cn/], identifier [ChiCTR-POR-17012927].

Abstract No. 117 Effect of preprocedural antiplatelet and anticoagulant use on antegrade access site complication rate during lower extremity peripheral arterial disease interventions

To determine the complication rate of antegrade femoral artery access in patients on anti-platelet and/or anticoagulant medications during peripheral arterial interventions

Polysaccharide-protein complex from coelomic fluid of Dendrobaena veneta earthworm exerts a multi-pathway antiplatelet effect without coagulopathy and cytotoxicity

There is a pressing need to identify novel antiplatelet agents, an alternative to acetylsalicylic acid and thienopyridines, to broaden the prevention of cardiovascular events, the leading cause of global morbidity and mortality. Invertebrate coelomocytes structurally and functionally resemble the thrombocyte-like cells of vertebrates; therefore, the coelomic fluid in which they are suspended may contain agents controlling their clumping abilities. However, whether coelomocytes-free coelomic fluid may also affect human platelet activities was not a subject of any study. This study aimed to screen the in vitro antiplatelet and anticoagulant activities of the polysaccharide-protein complex from Dendrobaena veneta coelomic fluid (25–100 µg/mL) (PPC-DV). All tested fluid concentrations induced significant (42.4–52.5%) inhibition of adenosine-5′-diphosphate (ADP)-induced aggregation of human platelets at a level comparable to that of 140 µmol/L acetylsalicylic acid. Its relevant antiplatelet effect (27.2–45.9%) was also evidenced in the thrombin receptor-activating peptide-6 (TRAP-6) assay. Moreover, 50 and 100 µg/mL of PPC-DV inhibited arachidonic acid-inducible aggregation. No coagulopathic or cytotoxic effects of PPC-DV were observed. The study indicates that PPC-DV, at a concentration of at least 50 µg/mL, exerts a favorable antiplatelet effect by targeting at least three pathways (P2Y12 receptor, cyclooxygenase-1, and protease-activated receptor-1), justifying further experimental and clinical investigations on its use in cardiovascular disease prevention.

Effective components and mechanism analysis of anti-platelet aggregation effect of Justicia procumbens L.

Ethnopharmacological relevanceJusticia procumbens L. is a traditional Chinese medicine, first recorded in "Shen Nong's Herbal Classic", for the treatment of lumbar pain and fever. As a widely distributed herb, it has also been documented in India, Nepal, and Malaysia. In “Tang Materia Medica”, a famous medicinal book of Tang Dynasty in ancient China, it was first used to treat diseases associated with blood stasis. Blood stasis syndrome is closely related to thrombus formation and platelet aggregation. Although some compounds isolated from this plant have anti-platelet aggregation effects, the main chemical components and mechanism of J. procumbens in terms of these effects are little known. Aims of the studyThrough in vivo and in vitro experiments, this studsy revealed the characteristic components and action mechanism of anti-platelet aggregation by J. procumbens from an overall perspective. Materials and methodsThe effective crude extracts of the whole plant were screened via an in vitro anti-platelet aggregation test. After incubating these extracts with apheresis platelets, high affinity compounds were detected by HPLC-MS and regulatory genes were detected using gene chips. The effective components and potential target proteins were analyzed using computational docking technology. Furthermore, the compound with the strongest predicted activity was evaluated in vivo via an anti-thrombotic test. ResultsIntegrin aⅡbβ3, PKCα, PI3Kγ, and mitogen-activated protein kinase 14 were found to be potential targets. Justicidin B, tuberculatin, chinensinaphthol methyl ether, and neojusticin B were effective compounds that inhibited human platelet aggregation by suppressing Gq-PLC-PKC and Gi-PI3K-MAPK signaling pathways. Among the compounds that bind to platelets, justicidin B showed the strongest virtual binding force. The test of carotid artery thrombosis induced by ferric chloride in SD rats confirmed that justicidin B inhibited thrombus formation. ConclusionExperimental investigation showed that arylnaphthalene lignan aglycones with one methylenedioxy group and two methoxy groups are effective components for anti-platelet aggregation by J. procumbens. These compounds inhibit Gq-PLC-PKC and Gi-PI3K-MAPK signaling pathways by suppressing the expression of genes such as ITGB3, PRKCA, PIK3CG, and MAPK14. These results reflected the characteristics of multi-component and multi-target synergistic treatment of Chinese medicine.