Thrombosis Research Articles

Aging-related alterations in mechanistic target of rapamycin signaling promote platelet hyperreactivity and thrombosis

BackgroundAging is an independent risk factor for the development of cardiovascular, thrombotic, and other chronic diseases. However, mechanisms of platelet hyperactivation in aging remain poorly understood. ObjectivesHere, we examine whether and how aging alters intracellular signaling in platelets to support platelet hyperactivity and thrombosis. MethodsQuantitative mass spectrometry with tandem mass tag labeling systematically measured protein phosphorylation in platelets from healthy aged (>65 years) and young human (<45 years) subjects. The role of platelet mechanistic target of rapamycin (mTOR) in aging-induced platelet hyperreactivity was assessed using pharmacologic mTOR inhibition and a platelet-specific mTOR-deficient mouse model (mTORplt−/−). ResultsQuantitative phosphoproteomics uncovered differential site-specific protein phosphorylation within mTOR, Rho GTPase, and MAPK pathways in platelets from aged donors. Western blot confirmed constitutive activation of the mTOR pathway in platelets from both aged humans and mice, which was associated with increased aggregation compared with that in young controls. Inhibition of mTOR with either Torin 1 in aged humans or genetic deletion in aged mice reversed platelet hyperreactivity. In a collagen–epinephrine pulmonary thrombosis model, aged wild-type (mTORplt+/+) mice succumbed significantly faster than young controls, while time to death of aged mTORplt−/− mice was similar to that of young mTORplt+/+ mice. Mechanistically, we noted increased Rac1 activation and levels of mitochondrial reactive oxygen species in resting platelets from aged mice, as well as increased p38 phosphorylation upstream of thromboxane generation following agonist stimulation. ConclusionAging-related changes in mTOR phosphorylation enhance Rac1 and p38 activation to enhance thromboxane generation, platelet hyperactivity, and thrombosis.

Association between lipoprotein levels and outcomes after coronary artery bypass grafting surgery: a systematic review and meta-analysis.

Lipoprotein(a) (Lp[a]) is a variant of low-density lipoprotein (LDL) and has been associated with increased risk of vascular inflammation and thrombosis. Coronary artery bypass grafting (CABG) has been associated with local inflammation of the myocardium. It is plausible, therefore, that patients with elevated baseline Lp(a) may be prone to unfavorable clinical outcomes following CABG. We evaluate differences in outcomes between CABG patients with high and low serum Lp(a) in this meta-analysis. A comprehensive literature search was performed to identify studies reporting outcomes in CABG patients stratified by preoperative Lp(a) level. When possible, the outcomes were pooled in a meta-analysis. We assessed post-operative mortality, major cardiovascular events, stroke occurrence and saphenous graft occlusion. Eight studies involving 8681 patients were included. Articles used varying cut-offs for high versus low Lp(a), and outcomes varied. In the three studies evaluating mortality, two showed no statistically significant difference between groups while one reported increased mortality associated with high Lp(a) level. Both studies investigating major adverse cardiovascular events reported higher risk in patients with high Lp(a). A study-level meta-analysis of four studies reporting saphenous vein graft occlusion incidence after CABG was performed. High (≥30 mg/dL) preoperative Lp(a) was not associated with an increased risk of graft occlusion compared with low (<30 mg/dL) preoperative Lp(a) (OR=1.88, 95% CI: 0.66-5.36; P=0.15). Studies evaluating the impact of Lp(a) on outcomes in CABG patients are few, with heterogenous cut-offs and outcomes. In the limited published studies, Lp(a) level was not associated with graft occlusion.

Particulate matter, polycyclic aromatic hydrocarbons and metals, platelet parameters and blood pressure alteration: Multi-pollutants study among population

Epidemiological findings have determined the linkage of fine particulate matter (PM2.5) and the morbidity of hypertension. However, the mode of action and specific contribution of PM2.5 component in the blood pressure elevation remain unclear. Platelets are critical for vascular homeostasis and thrombosis, which may be involved in the increase of blood pressure. Among 240 high-PM2.5 exposed, 318 low-PM2.5 exposed workers in a coking plant and 210 workers in the oxygen plant and cold-rolling mill enrolled in present study, both internal and external exposure characteristics were obtained, and we performed linear regression, adaptive elastic net regression, quantile g-computation and mediation analyses to analyze the relationship between urine metabolites of polycyclic aromatic hydrocarbons (PAHs) and metals fractions with platelets indices and blood pressure indicators. We found that PM2.5 exposure leads to increased systolic blood pressure (SBP) and pulse pressure (PP). Specifically, for every 10 μg/m3 increase in PM2.5, there was a 0.09 mmHg rise in PP. Additionally, one IQR increase in urinary 1-hydroxypyrene (1.06 μmol/mol creatinine) was associated with a 3.43 % elevation in PP. Similarly, an IQR increment of urine cobalt (2.31 μmol/mol creatinine) was associated with a separate 1.77 % and 4.71 % elevation of SBP and PP. Notably, platelet-to-lymphocyte ratio (PLR) played a mediating role in the elevation of SBP and PP induced by cobalt. Our multi-pollutants results showed that PAHs and cobalt were deleterious contributors to the elevated blood pressure. These findings deepen our understanding of the cardiovascular effects associated with PM2.5 constituents, highlighting the importance of increased vigilance in monitoring and controlling the harmful components in PM2.5.

Cardiovascular mortality in bipolar disorder: Population-based cohort study.

Limited evidence base on cause-specific excess cardiovascular disease (CVD) mortality in bipolar disorder (BD) is a barrier to developing preventive interventions aimed at reducing the persistent mortality gap in BD. To investigate cause-specific CVD mortality in BD. We identified all individuals aged 15+ years during 2004-2018 with a diagnosis of BD using Finnish nationwide routine data. Standardised mortality ratios (SMR) with 95% confidence intervals (CI) were calculated using the mortality rates in the general population as weights. 53,273 individuals with BD (57% women; median age at BD diagnosis, 40 years), were followed up for 428,426 person-years (median, 8.2 years). There were 5988 deaths due to any cause, of which 26% were due to CVD. The leading cause of absolute excess CVD mortality was coronary artery disease (CAD). The leading causes of relative excess mortality were cardiomegaly (SMR, 4.51; 95% CI, 3.58-5.43), venous thromboembolism (3.03; 2.26-3.81), cardiomyopathy (2.46; 1.95-2.97), and hypertensive heart disease (2.12; 1.71-2.54). The leading causes of absolute CVD mortality showed markedly lower relative excess, including CAD (1.47; 1.34-1.61), ischaemic stroke (1.31; 1.06-1.54), and acute myocardial infarction (1.12; 0.98-1.25). Due to the higher relative excess mortality, structural and functional heart disorders contributed as much as atherosclerotic and ischaemic disorders to the absolute excess mortality. Cardiomyopathy and hypertensive heart disease as the leading causes of relative excess mortality emphasise the contribution of structural and functional heart disorders to the overall excess mortality alongside coronary artery disease. Interventions targeted at these modifiable causes of death should be priorities in the prevention of premature excess CVD mortality in BD.

Dual-mode nanoprobe strategy integrating ultrasound and near-infrared light for targeted and synergistic arterial thrombolysis

Efficient thrombolysis in time is crucial for prognostic improvement of patients with acute arterial thromboembolic disease, while limitations and complications still exist in conventional thrombolytic treatment methods. Herein, our study sought to investigate a novel dual-mode strategy that integrated ultrasound (US) and near-infrared light (NIR) with establishment of hollow mesoporous silica nanoprobe (HMSN) which contains Arginine-glycine-aspartate (RGD) peptide (thrombus targeting), perfluoropentane (PFP) (thrombolysis with phase-change and stable cavitation) and indocyanine green (ICG) (thrombolysis with photothermal conversion). HMSN is used as the carrier, the surface is coupled with targeted RGD to achieve high targeting and permeability of thrombus, PFP and ICG are loaded to achieve the collaborative diagnosis and treatment of thrombus by US and NIR, so as to provide a new strategy for the integration of diagnosis and treatment of arterial thrombus. From the in vitro and in vivo evaluation, RGD/ICG/PFP@HMSN can aggregate and penetrate at the site of thrombus, and finally establish the dual-mode directional development and thrombolytic treatment under the synergistic effect of US and NIR, providing strong technical support for the accurate diagnosis and treatment of arterial thrombosis.Graphical

Bismuth Chelate-Mediated Digital Subtraction Angiography.

Digital subtraction angiography (DSA) is considered the "gold standard" for the diagnosis of vascular diseases. However, the contrast agents used in DSA are limited to iodine (I)-based small molecules, which are unsuitable for patients with contraindications. Here, iodine-free DSA utilizing a bismuth (Bi) chelate, Bi-DTPA Dimeglumine, is proposed for vascular visualization for the first time. Bi-DTPA Dimeglumine possesses a simple synthesis process without the need for purification, large-scale production ability (over 200g in the lab), superior X-ray imaging capability, renal clearance capacity, and good biocompatibility. Bi-DTPA-enhanced DSA can clearly display the arteries of the rabbit's head and lower limbs, with a minimum vascular resolution of 0.5mm. The displayed integrity of terminal vessels by Bi-DTPA-enhanced DSA is superior to that of iopromide-enhanced DSA. In a rabbit model of thrombotic disease, Bi-DTPA Dimeglumine-enhanced DSA enables the detection of embolism and subsequent reevaluation of vascular conditions after recanalization therapy. This proposed iodine-free DSA provides a promising and universal approach for diagnosing vascular diseases.

Bioinformatics Analysis Reveals HIST1H2BH as a Novel Diagnostic Biomarker for Atrial Fibrillation-Related Cardiogenic Thromboembolic Stroke.

Atrial fibrillation (AF) is a significant precursor to cerebral embolism. Our study sought to unearth new diagnostic biomarkers for atrial fibrillation-related cerebral embolism (AF-CE) by meticulously examining multiple GEO datasets and meta-analysis. The gene expression omnibus (GEO) database provided RNA sequencing data associated with AF and stroke. We began by pinpointing genes with varied expressions in AF-CE patient blood samples. A meta-analysis was subsequently undertaken using several RNA sequencing datasets to verify these genes. LASSO regression discerned key genes for AF-CE, with their diagnostic prowess verified through ROC curve examination. Active signaling pathways within stroke patients were discerned via GO and KEGG enrichment, with PPI interactions detailing gene interplay. Differential gene analysis revealed an upregulation of sixteen genes and a downregulation of four in stroke patient blood samples. Eight genes showcased varied expression in the meta-analysis. LASSO regression zeroed in on five of these, culminating in HIST1H2BH's identification as a characteristic gene. HIST1H2BH's prowess in predicting AF-CE was confirmed through ROC. Integrin signaling, platelet activation, ECM interactions, and the PI3K-Akt pathway were found active in stroke victims. HIST1H2BH's interaction with the notably upregulated ITGA2B was spotlighted by PPI. Additionally, HIST1H2BH exhibited links with NK cells and eosinophils. HIST1H2BH emerges as an insightful diagnostic beacon for AF-CE. Its presence, post AF, potentially modulates pathways, accentuating platelet activation and consequent thrombus generation, leading to cerebral embolism.

Chronic thromboembolic disease: Association with exercise-induced pulmonary hypertension and right ventricle deterioration

Chronic thromboembolic disease: Association with exercise-induced pulmonary hypertension and right ventricle deterioration

Utilization and safety of off-label prothrombin complex concentrate (4F-PCC) in a nonsurgical population.

The aim of this study was to evaluate and describe the utilization and safety of 4F-PCC in a nonanticoagulated, nonsurgical patient population at an academic, tertiary care center. This retrospective, single-center chart review evaluated nonanticoagulated adult patients at least 18 years of age who had at least one dose of 4F-PCC administered between January 1, 2017, and September 30, 2022, for a nonsurgical indication. Hemostatic efficacy following 4F-PCC administration was the primary outcome, and secondary outcomes included an assessment of blood product administration, thrombotic events within 30 days post4F-PCC administration, in-hospital mortality, and the length of hospital stay. A total of 59 patients met the inclusion criteria, and 10 patients received 4F-PCC for coagulopathy associated with liver disease, 34 for intracranial hemorrhage (ICH), and 15 for other indications. For the primary outcome of hemostatic efficacy, 17 non-ICH patients (85%) had achieved hemostasis post-4F-PCC, and among the ICH patient population, 18 (64%) did not show expansion on repeat CT post4F-PCC, suggesting hemostasis. Blood product and hemostatic agent usage was frequent, with 72.9% of patients requiring products post-4F-PCC. Acute thromboembolic events occurred in six patients (10.2%), and in-hospital mortality occurred in 55.9% of patients. Off-label 4F-PCC use is common despite a lack of robust guidance for use. Following 4F-PCC administration, blood product use was frequent, the incidence of in-hospital mortality was high, and thromboembolic complications such deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke were reported. Further studies are needed to validate the off-label administration of 4F-PCC in nonanticoagulated patients.

The impact of ABCB1, CYP3A4 and CYP3A5 gene polymorphisms on apixaban trough concentration and bleeding risk in patients with atrial fibrillation.

Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with nonvalvular atrial fibrillation (AF). Obviously, one of the ways to enhance effectiveness and safety of drug therapy is a personalized approach to therapy, which involves pharmacogenetic and pharmacokinetic tests. The study aims to investigate the effect of CYP3A4*22, CYP3A5*3 and ABCB1 polymorphisms on the pharmacokinetics of apixaban and the risk of bleeding. A total of 84 patients were enrolled in this prospective observational study. All patients received apixaban 5 or 2.5 mg twice daily. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. The C/D ratio was higher in patients aged >80 years (F(1)=11.209, p=0.00124) and was affected by serum creatinine (>133 μmol/L, F(1)=6.7, p=0.01124). ABCB1 (rs1045642 and rs4148738), CYP3A5 (rs776746) and CYP3A4 (rs35599367) polymorphisms did not show a correlation with C/D ratio of apixaban. Multivariate logistic regression analyses showed that none of the clinical or genetic factors predicted the fact of bleeding. We report no significant association between ABCB1 gene polymorphisms (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G and bleeding events on apixaban treatment. Complementing the existing criteria with pharmacogenetic and pharmacokinetics information for the patients with AF will enable further individualization of apixaban.

Current Gaps in the Provision of Safe and Effective Anticoagulation in Atrial Fibrillation and the Potential for Factor XI-Directed Therapeutics.

The global prevalence of atrial fibrillation is rapidly increasing, in large part due to the aging of the population. Atrial fibrillation is known to increase the risk of thromboembolic stroke by 5 times, but it has been evident for decades that well-managed anticoagulation therapy can greatly attenuate this risk. Despite advances in pharmacology (such as the shift from vitamin K antagonists to direct oral anticoagulants) that have increased the safety and convenience of chronic oral anticoagulation in atrial fibrillation, a preponderance of recent observational data indicates that protection from stroke is poorly achieved on a population basis. This outcomes deficit is multifactorial in origin, stemming from a combination of underprescribing of anticoagulants (often as a result of bleeding concerns by prescribers), limitations of the drugs themselves (drug-drug interactions, bioaccumulation in renal insufficiency, short half-lives that result in lapses in therapeutic effect, etc), and suboptimal patient adherence that results from lack of understanding/education, polypharmacy, fear of bleeding, forgetfulness, and socioeconomic barriers, among other obstacles. Often this adherence is not reported to treating clinicians, further subverting efforts to optimize care. A multidisciplinary, interprofessional panel of clinicians met during the 2023 International Society of Thrombosis and Haemostasis Congress to discuss these gaps in therapy, how they can be more readily recognized, and the potential for factor XI-directed anticoagulants to improve the safety and efficacy of stroke prevention. A full appreciation of this potential requires a reevaluation of traditional teaching about the "coagulation cascade" and decoupling the processes that result in (physiologic) hemostasis and (pathologic) thrombosis. The panel discussion is summarized and presented here.

Venous Anomalies in Overgrowth Syndromes

Overgrowth syndromes, particularly within the PIK3CA-related overgrowth syndrome (PROS)spectrum, are commonly associated with venous anomalies. The anomalies include spongiform venous malformations and persistent embryonic veins, such as the lateral marginal vein (of Servelle). The anomalous veins pose a significant risk of thromboembolic disease and should be occluded, preferably earlier in life. A thorough understanding of the conditions, anatomy, and interdisciplinary treatment of these complex anomalies is essential for optimal management. This review explores the clinical and imaging diagnosis of overgrowth syndromes and techniques for assessing and treating associated venous anomalies, particularly the endovenous closure of anomalous veins

Blood Flow Restriction Therapy After Anterior Cruciate Ligament Reconstruction

Anterior cruciate ligament reconstruction (ACLR) rehabilitation necessitates restoration of quadriceps strength to minimize reinjury and optimize return to sport (RTS). Patients recovering from ACLR are limited by pain and activity restrictions, resulting in quadriceps muscle atrophy. Blood flow restriction (BFR) therapy involves performing exercises while a specialized blood pressure cuff is applied to the proximal aspect of the operative extremity and inflated to 40% to 90% of the arterial occlusion pressure, as determined using Doppler ultrasonography. BFR is theorized to induce an anaerobic environment and metabolic stress during exercise, promoting muscle hypertrophy and strength gains. Although the physiological mechanism has not been fully elucidated, it is theorized that BFR combined with low-load resistance training could yield muscle adaptations comparable to those of high-load resistance training. For ACLR patients with pain and restrictions precluding high-intensity strength training, incorporation of BFR into postoperative rehabilitation protocols could help mitigate quadriceps weakness and promote RTS. Randomized controlled trials report a prolonged, dose-dependent relation between BFR use and quadriceps and hamstring strength gains, improved bone and muscle mass, and earlier RTS, whereas other studies report no significant difference in quadriceps size, strength, or patient satisfaction compared with controls. Furthermore, although generally considered safe, there are rare reports of associated adverse events such as rhabdomyolysis, and BFR should be avoided in patients with a history of thromboembolic disease or peripheral vasculopathy. The literature examining BFR after ACLR is heterogeneous; lacks standardization; and contains broad variation in reported cuff pressures, as well as timing and duration of BFR use, among protocols. Although the use of BFR after ACLR shows promise, further study is necessary to elucidate the efficacy, safety, and optimal protocols.

Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2

In the wake of the COVID-19 pandemic caused by SARS-CoV-2, questions emerged about the potential effects of Bacillus Calmette-Guérin (BCG) vaccine on the immune response to SARS-CoV-2 infection, including the neurodegenerative diseases it may contribute to. To explore this, an experimental study was carried out in BCG-stimulated and non-stimulated k18-hACE2 mice challenged with SARS-CoV-2. Viral loads in tissues determined by RT-qPCR, histopathology in brain and lungs, immunohistochemical study in brain (IHC) as well as mortality rates, clinical signs and plasma inflammatory and coagulation biomarkers were assessed. Our results showed BCG-SARS-CoV-2 challenged mice presented higher viral loads in the brain and an increased frequency of neuroinvasion, with the greatest differences observed between groups at 3–4 days post-infection (dpi). Histopathological examination showed a higher severity of brain lesions in BCG-SARS-CoV-2 challenged mice, mainly consisting of neuroinflammation, increased glial cell population and neuronal degeneration, from 5 dpi onwards. This group also presented higher interstitial pneumonia and vascular thrombosis in lungs (3–4 dpi), BCG-SARS-CoV-2 mice showed higher values for TNF-α and D-dimer values, while iNOS values were higher in SARS-CoV-2 mice at 3–4 dpi. Results presented in this study indicate that BCG stimulation could have intensified the inflammatory and neurodegenerative lesions promoting virus neuroinvasion and dissemination in this experimental model. Although k18-hACE2 mice show higher hACE2 expression and neurodissemination, this study suggests that, although the benefits of BCG on enhancing heterologous protection against pathogens and tumour cells have been broadly demonstrated, potential adverse outcomes due to the non-specific effects of BCG should be considered.

Epidemio-Clinical and Paraclinical Aspects of Venous Thromboembolic Diseases in a Cardiology Department in Mali

&amp;lt;i&amp;gt;Introduction&amp;lt;/i&amp;gt;: Venous thromboembolic diseases (VTED) include deep vein thrombosis of the lower limbs and pulmonary embolism (PE), which is its severe form due to its high mortality. The objective of our study was to determine the epidemio-clinical and paraclinical aspects of patients hospitalized for venous thromboembolic diseases. &amp;lt;i&amp;gt;Patients and method&amp;lt;/i&amp;gt;: Cross-sectional study with prospective recruitment from patient records hospitalized for (VTED) from January to December 2023 in the cardiology department of the Mother-Child University Hospital in Bamako, Luxembourg. &amp;lt;i&amp;gt;Results&amp;lt;/i&amp;gt;: We collected 55 out of 580 patient records hospitalized for (VTED), a hospital frequency of 9.48%. PE accounted for 58.20% of cases, 10.90% for deep vein thrombosis (DVT), and 30.90% for their association. The mean age of patients was 55.56 years ± 15.52 years. The majority of patients, 90%, were under 66 years of age. The predominance was female, 56%. In lower extremity DVT, calf pain and Homans&amp;apos; sign were present in 56% and 24% of patients. In pulmonary embolism, dyspnea and chest pain were present in 85.50% and 65.50% of patients. Etiological factors were dominated by neoplasia in 10.90%, contraception 5.45% and orthopedic surgery in 5.45% of cases. Cardiovascular risk factors were a sedentary lifestyle (50.90%), obesity (34.45%), high blood pressure (36.36%) and diabetes (21.81%). Laboratory abnormalities were elevation of troponin (46.87%), BNP (40.62%), D-Dimer (62.50%) and anemia (9.09%). Electrocardiographic abnormalities were tachycardia in 65.4% and S1Q3 in 21.81% of patients. Echocardiography showed dilation of the right cavities (47.27%), systolic pulmonary arterial hypertension (38.18%) and thrombus in the right cavitary (5.45%). On thoracic CT angiography, PE was proximal (36.40%), bilateral (61.80%) and massive (29.10%). On venous Doppler ultrasound, TVP was proximal in 65.21%. &amp;lt;i&amp;gt;Conclusion&amp;lt;/i&amp;gt;: VETD was more common in women and younger subjects.

Pulmonary embolism: Epidemiological and radiological aspects at the Niamey general reference hospital.

Introduction: Pulmonary Embolism is a diagnostic and therapeutic emergency. It is one of the clinical manifestations of venous thromboembolism (VTE) which is frequent and the most serious of the latter. The aim of our work is to study the characteristics of pulmonary embolism confirmed by chest CT angiography at the General Reference Hospital. More specifically, it is a question of describing the: epidemiological and radiological aspects of PE confirmed by chest CT angiography. Material and methods: This is a retrospective and prospective study, carried out at the Reference General Hospital over a period of 18 months: Retrospective over one (1) year from (July 2018 to June 2019), Prospective over six (6) months from July 2019 to December 2019. The study population included all patients referred to the radiology department for chest CT angiography with suspected pulmonary embolism and whose D-dimer dosage was greater than 500ng/ml. Chest x-ray and duplex ultrasound of the lower limbs were requested as additional basic examinations with the aim of exploring venous thromboembolic disease. Results: During this study, 84 chest CT angioscans were performed and 25 cases of pulmonary embolism were confirmed, representing a prevalence of 29.76%. The patients were classified according to the levels of clinical thromboembolic risk. Chest x-ray was performed in 16 patients or 64%. Cardiac Doppler ultrasound was performed in 16 patients (64%). Doppler ultrasound of the lower limbs was performed in only 3 patients. All patients had undergone chest CT angiography. Conclusion: The advent of chest CT angiography in the diagnostic approach allowed us to note an underestimation of the prevalence of PE in African countries. Thoracic CT angiography provided diagnostic confirmation.

Safety assessment of tranexamic acid: real-world adverse event analysis from the FAERS database.

In recent years, with the continuous expansion of the application scope of Tranexamic acid (TXA), its usage has surged. Despite numerous studies demonstrating its powerful efficacy, concerns regarding its adverse reactions persist, necessitating comprehensive safety assessment. This study analyzed real-world data from the U.S. Food and Drug Administration to investigate TXA-related adverse events, aiming to elucidate its safety and optimize patient treatment. The adverse drug event data concerning TXA from 2004 Q1 to 2023 Q3 were collected. Following data standardization, a variety of signal quantification techniques, including the reporting odds ratios, proportional reporting ratios, Bayesian confidence propagation neural network, and empirical Bayes geometric mean were used for analysis. After analyzing 16,692,026 adverse event reports, a total of 1,574 cases of adverse events related to TXA were identified, spanning 23 system organ classes and 307 preferred terms. In addition to the common thrombosis-related Vascular disorders (n = 386) and Cardiac disorders (n = 377), adverse reactions in the Nervous system disorders category were also observed (n = 785), including Myoclonus (n = 70), Status epilepticus (n = 43), and Myoclonic epilepsy (n = 17). Furthermore, this study uncovered adverse effects such as Renal cortical necrosis, Hepatic cyst rupture, and Vascular stent stenosis, which were not previously mentioned in the instructions. Although these occurred infrequently, they exhibited high signal strength. Both Retinal artery occlusion and Vascular stent thrombosis disorder were frequent and exhibited high signal strength as well. It is worth noting that 78 cases of adverse reactions were caused by confusion between incorrect product administration. Our research suggests that TXA has some adverse reactions that are being overlooked. As a cornerstone medication in hemorrhage treatment, it's crucial to monitor, identify, and address these adverse reactions effectively.

Non-clinical investigations about cytotoxic and anti-platelet activities of gamma-terpinene.

Gamma-terpinene (γ-TPN) is a cyclohexane monoterpene isolated from plant essential oils, such as tea tree (Melaleuca alternifolia), oregano (Origanum vulgare), rosemary (Rosmarinus officinalis L.), thyme (Thymus vulgaris Marchand), and eucalyptus (Eucalyptus sp.). Terpenes are widely studied molecules pharmacologically active on the cardiovascular system, hemostasis, and antioxidant actions. Herein, it was investigated the cytotoxic and antiplatelet activity of γ-TPN using different non-clinical laboratory models. For in silico evaluation, the PreADMET, SwissADME, and SwissTargetPrediction softwares were used. Molecular docking was performed using the AutoDockVina and BIOVIA Discovery Studio databases. The cytotoxicity of γ-TPN was analyzed by the MTT assay upon normal murine endothelial SVEC4-10 and fibroblast L-929 cells. Platelet aggregation was evaluated with platelet-rich (PRP) and platelet-poor (PPP) plasma from spontaneously hypertensive rats (SHR), in addition to SVEC4-10 cells pre-incubated with γ-TPN (50, 100, and 200 µM) for 24 h. SHR animals were pre-treated by gavage with γ-TPN for 7 days and divided into four groups (negative control, 25, 50, and 100 mg/kg). Blood samples were collected to measure nitrite using the Griess reagent. Gamma-TPN proved to be quite lipid-soluble (Log P = +4.50), with a qualified profile of similarity to the drug, good bioavailability, and adequate pharmacokinetics. It exhibited affinity mainly for the P2Y12 receptor (6.450 ± 0.232 Kcal/mol), moderate cytotoxicity for L-929 (CC50 = 333.3 µM) and SVEC 4-10 (CC50 = 366.7 µM)cells. The presence of γ-TPN in SVEC 4-10 cells was also able to reduce platelet aggregation by 51.57 and 44.20% at lower concentrations (50 and 100 µM, respectively). Then, γ-TPN has good affinity with purinergic receptors and an effect on the reversal of platelet aggregation and oxidative stress, being promising and safe for therapeutic targets and subsequent studies on the control of thromboembolic diseases.

Subdermal dissection technique for pure skin SCIA and ALT perforator flaps in burns and trauma defects: Clinical experience.

The pure skin perforator (PSP) flap is gaining popularity for its remarkable thinness. The subdermal dissection technique was recently introduced, allowing for a quicker elevation of a PSP flap. In this report, we present our two-year experience utilizing subdermal dissection for harvesting PSP flaps. All patients who had undergone PSP flap reconstruction at our hospital from February 2021 to February 2023 were included. Demographic data, intraoperative variables, flap characteristics, and postoperative outcomes were collected. Surgical planning involved locating the perforator using ultrasound and harvesting the flap using the subdermal dissection technique. A total of 26 PSP flap reconstructions were conducted on 24 patients aged between 15 and 86 years. The flaps were based on perforators issuing from the superficial circumflex iliac artery in 24 cases, and from the descending branch of the lateral circumflex femoral artery in 2 cases. Flap sizes ranged from 3 × 1.5 cm to 19 × 6 cm, with a mean thickness of 3.48 mm. The average time for flap harvest was 131.92 min. Postoperatively, we observed four cases of partial necrosis, 1 total flap loss, and 2 instances of vascular thrombosis at the anastomosis site. The flaps exhibited good pliability without contracture, and no debulking procedures were required during the follow-up period (minimum 6 months, range 6-24; mean 9.4615). The subdermal dissection technique is a safe and efficient approach for elevating PSP flaps. Our initial experience with this technique has been encouraging, and it currently serves as our preferred reconstructive option for defects requiring thin reconstruction.

Burden of atrial fibrillation risk and outcomes amongst patients attending cardiology and elderly medicine services: prospective in-hospital implementation of the FIND-AF algorithm

Abstract Background Screening for silent AF is becoming increasingly important (1, 2), and the FIND-AF algorithms can use routinely-collected data to identify individuals at higher risk for undiagnosed AF (3). There may be a much higher prevalence of patients at risk for AF and its complications in a hospital environment compared with the community (4). Purpose We prospectively implemented the FIND-AF algorithm within cardiology and geriatric services to quantify the burden of AF risk amongst all-comers, and to understand their outcomes over the next 6 months. Methods We prospectively implemented the FIND-AF algorithm in the cardiology and geriatric departments of three UK hospitals for consecutive inpatient or outpatient attendances from February 1 to July 13th 2023. We assessed the number of individuals attending each service eligible for an AF screening protocol (exclusion criteria: age &amp;lt;30 years, history of AF, on a palliative care pathway, use of oral anticoagulation), and calculated the burden of AF risk in each service. Patients were followed up for 6 months for the primary outcome of incident AF, heart failure (HF), stroke/transient ischaemic attack (TIA)/systemic embolism, and death. Incident diagnoses were the first record of that condition in primary or secondary care records. Rate ratios (RRs) with 95% confidence intervals (CIs) for combined incident cardiovascular outcomes or death were derived through Poisson regression for predicted higher versus lower AF risk. Results Of 467 consecutive patients, 364 were eligible for AF screening. 66 were excluded due to a previous diagnosis of AF, 25 were already prescribed a long-term oral anticoagulant, 5 were on a palliative care pathway and 7 were aged &amp;lt;30 years. Baseline characteristics of each cohort are summarised in Table 1. Of patients eligible for AF screening, those attending geriatrics were at higher risk of incident AF than patients attending cardiology (median FIND-AF score: geriatrics, 0.015, 95% CI 0.008 - 0.024; cardiology, 0.005, 95% CI 0.001-0.015; p&amp;lt;0.05; distributions of risk summarised in Figure 1) and had a higher stroke risk. Absolute risk of AF was greater than 5% within the next 6 months for 11.6% and 9.1% of geriatric and cardiology patients, respectively. Of the eligible cohort, 328 had follow up at 6 months, with 46 experiencing the primary outcome (9, 7, 3, and 27 recorded cases of AF, HF, stroke/TIA, and death, respectively). The higher predicted risk cohort, compared to lower predicted risk, had a higher risk of combined incident AF, heart failure, or stroke/TIA/systemic embolism (Rate ratio: 5.59, 95% CI 1.13-101.01) and death (RR 9.68, 2.06-172.85). Conclusions The FIND-AF algorithm can be prospectively implemented in hospital records to identify cardiology and geriatric patients at risk of incident AF, heart failure, thromboembolic disease and death. There is an opportunity to conduct risk-guided screening in the context of hospital attendances.