The bile acid receptor TGR5 inhibits platelet activation and thrombus formation.

Liver failure and cirrhosis are characterized by abnormal hemostasis with aberrant platelet activation. In particular, the consequences of cholestatic liver disease and molecular mechanisms, including the role of bile acids leading to impaired platelet responses, are not well understood. Here, we demonstrate that bile acids inhibit human and murine platelet activation, adhesion and spreading, leading to reduced thrombus formation under flow conditions. We identified the G-protein coupled receptor TGR5 in platelets and provide support for its role as mediator of bile acid-induced impairment of platelet activation. In the liver, TGR5 couples to Gαs proteins, activates the adenylate cyclase to induce a transient cAMP rise and stimulates the MAPK signaling pathway to regulate cholangiocyte proliferation, hepatocyte survival and inflammation. In this report, we demonstrate that the genetic deficiency of TGR5 in mice led to enhanced platelet activation and thrombus formation, suggesting that TGR5 plays an important role in hemostasis. Mechanistically, platelet inhibition is achieved by TGR5 mediated PKA activation and modulation of AKT and ERK1/2 phosphorylation. Thus, this report provides evidence for the ability of TGR5 ligands to reduce platelet activation and identifies TGR5 agonism as a new target for the prevention of cardiovascular diseases.

What is the context? Liver failure or cirrhosis are related to impaired hemostasis and a role of bile acids in impaired platelet responses is known but only less understood.Platelets express the bile acid receptor FXR. Ligand binding to the FXR on platelets causes a shift in platelet reactivity and is atheroprotective suggesting that the FXR is a potential target for the prevention of atherothrombotic diseases.What is new? Treatment of murine and human blood with bile acids in low molecular quantity led to reduced platelet activation, adhesion and thrombus formation.The bile acid receptor TGR5 was identified on human and murine platelets.TGR5 plays an important role in hemostasis because TGR5 deficient mice showed elevated platelet reactivity and enhanced thrombus formation.Loss of TGR5 led to enhanced PKA activation and modulated the phosphorylation of MAPK such as AKT and ERK1/2.What is the impact? Impairment of platelet activation by bile acids is mediated by TGR5 via the protein kinase A signaling pathway.Our findings provide evidence for the modulation of TGR5 activation as a potential new target of both, anti-platelet therapy in cardiovascular diseases and the restoration of hemostasis upon liver injury.

Management of Extracorporeal Membrane Oxygenation Anticoagulation in the Perioperative Period: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic review-informed, modified Delphi consensus regarding the management of children on extracorporeal membrane oxygenation (ECMO) undergoing invasive procedures or interventions developed by the Pediatric Anticoagulation on ECMO CollaborativE (PEACE) Consensus Conference. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: ECMO anticoagulation and hemostasis management in the perioperative period and during procedures. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. Seventeen references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. Four good practice statements, 7 recommendations, and 18 consensus statements are presented. CONCLUSIONS: Although agreement among experts was strong, important future research is required in this population for evidence-informed recommendations.

Management of Bleeding and Thrombotic Complications During Pediatric Extracorporeal Membrane Oxygenation: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the management of bleeding and thrombotic complications during pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE Consensus Conference. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: The management of bleeding and thrombotic complications of ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Twelve references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. Two good practice statements, 5 weak recommendations, and 18 consensus statements are presented. CONCLUSIONS: Although bleeding and thrombotic complications during pediatric ECMO remain common, limited definitive data exist to support an evidence-based approach to treating these complications. Research is needed to improve hemostatic management of children supported with ECMO.

Effect of COVID-19 on Thrombosis Incidence and Patient Prognosis in Kidney Transplant Recipients.

BACKGROUND Thrombosis poses a grave threat to patients undergoing kidney transplants, with a heightened risk of mortality. While previous studies have established a link between COVID-19 and thrombosis, the specific association between COVID-19 and thrombosis in this patient population remains unexplored. MATERIAL AND METHODS We conducted a retrospective analysis utilizing data from 394 individuals who underwent kidney transplantation within the period of September 1, 2015, to April 1, 2023. To evaluate overall survival, we employed Kaplan-Meier analysis and utilized a logistic regression model for risk analysis. Furthermore, we developed a prediction model and assessed its accuracy through calibration curves. RESULTS Out of the 394 patients included in our study, a total of 51 individuals experienced thrombosis, resulting in 2 deaths. Our analysis revealed that COVID-19 infection significantly increased the risk of thrombosis (odds ratio [OR] 8.60, 95% confidence interval 3.13-24.74, P<0.01). Additionally, the use of cyclosporine was found to elevate the risk of death (OR 20.86, 95% CI 7.93-59.24, P<0.01) according to multifactorial analysis. Logistic models were employed to screen variables, and predictive models were constructed based on the presence of COVID-19 infection and the usage of cyclosporine. A nomogram was developed, demonstrating promising accuracy in estimating the risk of thrombosis during internal validation, with a corrected C-index of 0.869. CONCLUSIONS Our study suggests that both COVID-19 infection and the use of cyclosporine can serve as reliable predictors of thrombosis risk in patients undergoing renal transplantation. Furthermore, we developed a mortality risk prediction model based on COVID-19 in assessing thrombosis.

A rare case of giant left sinus of Valsalva aneurysm complicated by thrombus formation.

A rare transthoracic echocardiographic image of left sinus of Valsalva aneurysm complicated by thrombus formation.

[Coagulation and complement crosstalk: molecular mechanisms of complement-mediated diseases].

The complement and coagulation systems are ancestrally related mechanisms of serine protease-induced protein activation. Recent studies have shown that the complement system enhances platelet aggregation by activating platelets and vascular endothelial cells. This system is also involved in the expression of tissue factor, which induces the coagulation reaction. Activated platelets and coagulation factors are also known to activate the complement system. In diseases involving the complement system, such as paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, and atypical hemolytic uremic syndrome, excessive activation of this system contributes to complement-mediated thrombosis. The anti-C5 antibody eculizumab has shown a remarkable thromboprophylactic effect in these complement diseases. The recent surge in development of new anti-complement agents has raised expectations for the advancement of treatments and preventive measures for thrombosis associated with complement disorders. This review outlines the crosstalk between these two systems, and describes the mechanisms of several diseases featuring both thrombosis and complement activation.

Machine Learning-based Framework Develops a Tumor Thrombus Coagulation Signature in Multicenter Cohorts for Renal Cancer.

Background: Renal cell carcinoma (RCC) is frequently accompanied by tumor thrombus in the venous system with an extremely dismal prognosis. The current Tumor Node Metastasis (TNM) stage and Mayo clinical classification do not appropriately identify preference-sensitive treatment. Therefore, there is an urgent need to develop a better ideal model for precision medicine. Methods: In this study, we developed a coagulation tumor thrombus signature for RCC with 10 machine-learning algorithms (101 combinations) based on a novel computational framework using multiple independent cohorts. Results: The established tumor thrombus coagulation-related risk stratification (TTCRRS) signature comprises 10 prognostic coagulation-related genes (CRGs). This signature could predict survival outcomes in public and in-house protein cohorts and showed high performance compared to 129 published signatures. Additionally, the TTCRRS signature was significantly related to some immune landscapes, immunotherapy response, and chemotherapy. Furthermore, we also screened out hub genes, transcription factors, and small compounds based on the TTCRRS signature. Meanwhile, CYP51A1 can regulate the proliferation and migration properties of RCC. Conclusions: The TTCRRS signature can complement the traditional anatomic TNM staging system and Mayo clinical stratification and provide clinicians with more therapeutic options.

Comparison of embolic risk in left ventricular thrombus between nonischemic and ischemic cardiomyopathy: A nationwide database analysis.

BACKGROUND: Left ventricular (LV) thrombus is not common but poses significant risks of embolic stroke or systemic embolism. However, the distinction in embolic risk between nonischemic cardiomyopathy (NICM) and ischemic cardiomyopathy (ICM) remains unclear. METHODS AND RESULTS: In total, 2738 LV thrombus patients from the JROAD-DPC (Japanese Registry of All Cardiac and Vascular Diseases Diagnosis Procedure Combination) database were included. Among these patients, 1037 patients were analyzed, with 826 (79.7%) having ICM and 211 with NICM (20.3%). Within the NICM group, the distribution was as follows: dilated cardiomyopathy (DCM; 41.2%), takotsubo cardiomyopathy (27.0%), hypertrophic cardiomyopathy (18.0%), and other causes (13.8%). The primary outcome was a composite of embolic stroke or systemic embolism (SSE) during hospitalization. The ICM and NICM groups showed no significant difference in the primary outcome (5.8% vs. 7.6%, p = 0.34). Among NICM, SSE occurred in 12.6% of patients with DCM, 7.0% with takotsubo cardiomyopathy, and 2.6% with hypertrophic cardiomyopathy. Multivariate logistic regression analysis for SSE revealed an odds ratio of 1.4 (95% confidence interval [CI], 0.7-2.7, p = 0.37) for NICM compared to ICM. However, DCM exhibited a higher adjusted odds ratio for SSE compared to ICM (2.6, 95% CI 1.2-6.0, p = 0.022). CONCLUSIONS: This nationwide shows comparable rates of embolic events between ICM and NICM in LV thrombus patients, with DCM posing a greater risk of SSE than ICM. The findings emphasize the importance of assessing the specific cause of heart disease in NICM, within LV thrombus management strategies.

Antiplatelet and Antithrombotic Properties of Compound L-36, a 6H-1,3,4-Thiadiazine Derivative.

Compound L-36, a new derivative of 6H-1,3,4-thiadiazine, was studied in in vitro and in vivo experiments. This compound exhibits high antiplatelet and antithrombogenic activity. In in vitro experiments, compound L-36 by its antiplatelet activity (by IC50) was superior to acetylsalicylic acid by 9.4 times. In in vivo experiments, compound L-36 by its ED50 value was close to the comparison drug. On the model of pulmonary artery thrombosis, compound L-36 ensured better survival of experimental animals than acetylsalicylic acid. Morphological studies showed that compound L-36 effectively attenuated the thrombosis processes in the pulmonary tissue induced by intravenous injection of a thrombogenic mixture (epinephrine and collagen).

Prognostic significance of refractory thrombus in STEMI patients and the role of red cell distribution width: A case-control study.

The high thrombus burden of the infarct-related artery (IRA) is associated with the adverse prognosis in ST-segment elevation myocardial infarction (STEMI) patients. Our objectives were to investigate the predictors and evaluate the prognosis of refractory thrombus in STEMI patients. A total of 1305 consecutive patients with STEMI who underwent primary percutaneous coronary intervention (pPCI) were screened. The refractory thrombus group (n = 15) was defined as IRA thrombolysis in myocardial infarction flow < grade 2 after multiple thrombus aspiration (TA). The control group (n = 45) was age- and sex-matched and was selected from the same batch of patients. Baseline hematologic indices were measured before the pPCI. The major adverse cardiovascular events (MACE) were recorded during follow-up. The refractory thrombus group had significantly higher red cell distribution width (RDW) at baseline compared with the control group (13.1 [12.4-13.7] vs 12.6 [12.3-12.8], P = .008). In multivariate logistic regression analysis, RDW was an independent predictor of refractory thrombus (odds ratio: 8.799, 95% CI: 1.240-62.454, P = .030). The area under the receiver-operating characteristic curve of the RDW was 0.730 (95%CI: 0.548-0.912, P = .008). During a mean period of 26 months follow-up, patients in the refractory thrombus group tended to have higher percent MACEs compared with patients in the control group (53.3% vs 6.7%, P < .001). In the present study, we found that the refractory thrombus in STEMI patients was associated with the worse prognosis and the increased RDW might be a potential independent predictor.

Impact of gender in patients with device-related thrombosis after left atrial appendage closure - A sub-analysis from the multicenter EUROC-DRT-registry.

BACKGROUND: Device-related thrombosis (DRT) is a common finding after left atrial appendage closure (LAAC) and is associated with worse outcomes. As women are underrepresented in clinical studies, further understanding of sex differences in DRT patients is warranted. METHODS AND RESULTS: This sub-analysis from the EUROC-DRT-registry compromises 176 patients with diagnosis of DRT after LAAC. Women, who accounted for 34.7% (61/176) of patients, were older (78.0 ± 6.7 vs. 74.9 ± 9.1 years, p = .06) with lower rates of comorbidities. While DRT was detected significantly later in women (173 ± 267 vs. 127 ± 192 days, p = .01), anticoagulation therapy was escalated similarly, mainly with initiation of novel oral anticoagulant (NOAC), vitamin K antagonist (VKA) or heparin. DRT resolution was achieved in 67.5% (27/40) of women and in 75.0% (54/72) of men (p = .40). In the remaining cases, an intensification/switch of anticoagulation was conducted in 50.% (9/18) of men and in 41.7% (5/12) of women. Final resolution was achieved in 72.5% (29/40) cases in women, and in 81.9% (59/72) cases in men (p = .24). Women were followed-up for a similar time as men (779 ± 520 vs. 908 ± 687 days, p = .51). Kaplan-Meier analysis revealed no difference in mortality rates in women (Hazard Ratio [HR]: 1.73, 95%-Confidence interval [95%-CI]: .68-4.37, p = .25) and no differences in stroke (HR: .83, 95%-CI: .30-2.32, p = .72) within 2 years after LAAC. CONCLUSION: Evaluation of risk factors and outcome revealed no differences between men and women, with DRT in women being diagnosed significantly later. Women should be monitored closely to assess for DRT formation/resolution. Treatment strategies appear to be equally effective.

Early Online.

BACKGROUND: Long-haul flights have been associated with a two- to four-fold increased risk of aviation-related thrombosis (ART). Several studies have investigated the extent to which hypoxic hypobaric exposure, dehydration and prolonged immobilisation during air travel induce changes in haemostasis. OBJECTIVE: To investigate the role of high altitude as a risk factor for ART. METHODS: Healthy volunteers aged ≥18 years (N=40), without risk factors for venous thromboembolism, were exposed to an exacerbated altitude of 18 000 feet (5 486 m) for 1 hour. During the flight, the oxygen (O2) levels of the participants, who received supplemental O2, were measured by pulse oximetry and maintained at >92%. Venous blood and urine samples were collected prior to departure and immediately after flying in an unpressurised twin-engine airplane. D-dimer levels, thromboelastography (TEG) parameters, von Willebrand factor (VWF) activity and urine osmolality were measured. RESULTS: The participants were 19 men and 21 women, with a mean (standard deviation) age of 46 (14) years. A significant difference in D-dimer levels, VWF activity, urine osmolality and TEG parameters (reaction (R) time, kinetic (K) time and maximum amplitude (MA)) before and after the 1-hour flight was observed (p<0.001). Urine osmolality correlated positively with VWF activity levels (r=0.469; p<0.002). CONCLUSION: Air travel at high altitude induced a hypercoagulable state in healthy volunteers. Future research should focus on whether thromboprophylaxis can significantly obviate the activation of coagulation in response to high altitude.

[Clinical diagnosis and treatment of renal angiomyolipoma with inferior vena cava tumor thrombus].

OBJECTIVE: To summarize the clinical characteristics of patients with renal angiomyolipoma (RAML) combined with inferior vena cava (IVC) tumor thrombus, and to explore the feasibility of partial nephrectomy and thrombectomy in this series of patients. METHODS: The clinical data of patients diagnosed with RAML combined with IVC tumor thrombus in the Department of Urology of the Peking University Third Hospital from April 2014 to March 2023 were retrospectively analyzed, and demographic and perioperative data of RAML patients with IVC tumor thrombus were recorded and collected from Electronic Medical Record System, including age, gender, surgical methods, and follow-up time, etc. The clinical characteristics between classic angiomyolipoma (CAML) patients with IVC tumor thrombus and epithelioid angiomyolipoma (EAML) patients with IVC tumor thrombus were compared to determine the clinical characteristics of these patients. RESULTS: A total of 11 patients were included in this study, including 7 patients with CAML with IVC tumor thrombus and 4 patients with EAML with IVC tumor thrombus. There were 9 females (9/11, 81.8%) and 2 males (2/11, 18.2%), with an average age of (44.0±17.1) years. 9 patients (9/11, 81.8%) experienced clinical symptoms, including local symptoms including abdominal pain, hematuria, abdominal masses, and systemic symptoms including weight loss and fever; 2 patients (2/11, 18.2%) with RAML and IVC tumor thrombus did not show clinical symptoms, which were discovered by physical examination. Among the 11 patients, 10 underwent radical nephrectomy with thrombectomy, of whom, 3 underwent open surgery (3/10, 30.0%), 2 underwent laparoscopic surgery (2/10, 20.0%), and 5 underwent robot-assisted laparoscopic surgery (5/10, 50.0%). In addition, 1 patient underwent open partial nephrectomy and thrombectomy. The patients with EAML combined with IVC tumor thrombus had a higher proportion of systemic clinical symptoms (100% vs. 0%, P=0.003), more intraoperative bleeding [400 (240, 3 050) mL vs. 50 (50, 300) mL, P =0.036], and a higher proportion of tumor necrosis (75% vs. 0%, P=0.024) compared to the patients with CAML combined with IVC tumor thrombus. However, there was no statistically significant difference in operation time [(415.8±201.2) min vs. (226.0±87.3) min, P=0.053] between the two groups. CONCLUSION: Compared with the patients with CAML and IVC tumor thrombus, the patients with EAML and IVC tumor thrombus had a higher rate of systemic symptoms and tumor necrosis. In addition, in the selected patients with CAML with IVC tumor thrombus, partial nephrectomy and tumor thrombectomy could be performed to better preserve renal function.

Analysis of rescue strategies for acute thrombosis during STA-MCA bypass surgery and the literature review.

BACKGROUND AND OBJECTIVES: STA-MCA bypass surgery is mainly used for Moyamoya disease, giant intracranial aneurysms, and resection of intracranial tumors requiring sacrifice of blood vessels. The intraoperative patency of the reconstructive vessels is critical to the efficacy of the procedure. This study aimed to evaluate the efficacy of intra-arterially infused tirofiban for the treatment of acute thrombosis during STA-MCA bypass surgery and countermeasures for acute thrombosis. METHODS: This study involved 209 patients (272 hemispheres) who underwent STA-MCA surgery between November 2020 and December 2023. Intraoperative acute thrombosis occurred in eight patients (3.83%,8 hemispheres). We retrospectively reviewed the clinical and imaging data, surgical procedure, and follow-up outcomes of eight patients. We implemented the different thrombolytic methods to evaluate the optimal thrombosis management during the bypass surgery. After three months, we assessed neurological functions using the modified Rankin Scale (mRS) and conducted a literature review using PubMed. RESULTS: Eight patients (four male patients and four female patients) developed acute thrombosis during the bypass surgery. Of the eight patients, two underwent re-anastomosis after thrombus removal, three received local injections of tirofiban into the anastomosis or the branches of the superficial temporal artery, and three underwent superselective intra-arterial tirofiban infusion using a microcatheter. Thrombosis were resolved, and arteries were recanalized in all patients. The mRS score was 0 in all patients. No major ischemic or hemorrhagic complications occurred. CONCLUSION: Our treatment methods were efficacious in the management of acute thrombosis. Intra-arterial tirofiban administration seems to be a simple and effective treatment option for acute thrombosis during STA-MCA bypass surgery.

Hemodialysis patients have signs of a chronic thrombotic burden.

BACKGROUND: Cardiovascular diseases are the dominant cause of morbidity in hemodialysis (HD) patients. Unless sufficient anticoagulation is used during HD, clotting may appear. The objective was to investigate if levels of fibrin degradation products (D-dimer) were increased before and during HD. METHODS: The combined observational study included 20 patients performing a total of 60 hemodialysis divided into three sessions of low-flux dialysis. None of the patients suffered from any clinically evident thromboembolic event before or during the study. Median bolus anticoagulation (mainly tinzaparin) doses were 84 Units/kg bow. Blood samples were drawn before HD (predialysis), and at 30min and 180min during HD with focus on analyzing D-dimer levels and its relation to interdialytic weight gain (IDWG) and speed of fluid elimination by HD (UF-rate). RESULTS: Predialysis, D-dimer levels (mean 0.767 ±0.821, min 0.136mg/L) were above the upper reference value in 95% of the sessions. D-dimer levels were lowered at 30min (p<0.001) and returned to predialysis levels at 180min. Predialysis D-dimer correlated with NT-pro-BNP, Troponin T, IDWG and UF-rate. Multiple regression analysis revealed that the D-dimer levels were significantly related to IDWG and the UF-rate. CONCLUSIONS: D-dimer levels were elevated in a high proportion predialysis and during HD and related to the IDWG and the UF-rate. Awareness of D-dimer levels and future studies will help clarify if optimization of those variables, besides anticoagulation and biocompatibility measures, will eradicate the repeated subclinical thromboembolic events related to each HD; one reason that may explain organ damage and shortened life span of these patients.

Preventing adverse events during paediatric cancer treatment: protocol for a multi-site hybrid randomised controlled trial of catheter lock solutions (the CLOCK trial).

INTRODUCTION: Central venous access devices (CVADs) are commonly used for the treatment of paediatric cancer patients. Catheter locking is a routine intervention that prevents CVAD-associated adverse events, such as infection, occlusion and thrombosis. While laboratory and clinical data are promising, tetra-EDTA (T-EDTA) has yet to be rigorously evaluated or introduced in cancer care as a catheter lock. METHODS AND ANALYSIS: This is a protocol for a two-arm, superiority type 1 hybrid effectiveness-implementation randomised controlled trial conducted at seven hospitals across Australia and New Zealand. Randomisation will be in a 3:2 ratio between the saline (heparinised saline and normal saline) and T-EDTA groups, with randomly varied blocks of size 10 or 20 and stratification by (1) healthcare facility; (2) CVAD type and (3) duration of dwell since insertion. Within the saline group, there will be a random allocation between normal and heparin saline. Participants can be re-recruited and randomised on insertion of a new CVAD. Primary outcome for effectiveness will be a composite of CVAD-associated bloodstream infections (CABSI), CVAD-associated thrombosis or CVAD occlusion during CVAD dwell or at removal. Secondary outcomes will include CABSI, CVAD-associated-thrombosis, CVAD failure, incidental asymptomatic CVAD-associated-thrombosis, other adverse events, health-related quality of life, healthcare costs and mortality. To achieve 90% power (alpha=0.05) for the primary outcome, data from 720 recruitments are required. A mixed-methods approach will be employed to explore implementation contexts from the perspective of clinicians and healthcare purchasers. ETHICS AND DISSEMINATION: Ethics approval has been provided by Children's Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC) (HREC/22/QCHQ/81744) and the University of Queensland HREC (2022/HE000196) with subsequent governance approval at all sites. Informed consent is required from the substitute decision-maker or legal guardian prior to participation. In addition, consent may also be obtained from mature minors, depending on the legislative requirements of the study site. The primary trial and substudies will be written by the investigators and published in peer-reviewed journals. The findings will also be disseminated through local health and clinical trial networks by investigators and presented at conferences. TRIAL REGISTRATION NUMBER: ACTRN12622000499785.

Stent coating containing a charged silane coupling agent that regulates protein adsorption to confer antithrombotic and cell-adhesion properties.

The evolution of endovascular therapies, particularly in the field of intracranial aneurysm treatment, has been truly remarkable and is characterized by the development of various stents. However, ischemic complications related to thrombosis or downstream emboli pose a challenge for the broader clinical application of such stents. Despite advancements in surface modification technologies, an ideal coating that fulfills all the desired requirements, including anti-thrombogenicity and swift endothelialization, has not been available. To address these issues, we investigated a new coating comprising 3-aminopropyltriethoxysilane (APTES) with both anti-thrombogenic and cell-adhesion properties. We assessed the anti-thrombogenic property of the coating using an in vitro blood loop model by evaluating the platelet count and the level of the thrombin-antithrombin (TAT) complex, and investigating thrombus formation on the surface using scanning electron microscopy (SEM). We then assessed endothelial cell adhesion on the metal surfaces. In vitro blood tests revealed that, compared to a bare stent, the coating significantly inhibited platelet reduction and thrombus formation; more human serum albumin spontaneously adhered to the coated surface to block thrombogenic activation in the blood. Cell adhesion tests also indicated a significant increase in the number of cells adhering to the APTES-coated surfaces compared to the numbers adhering to either the bare stent or the stent coated with an anti-fouling phospholipid polymer. Finally, we performed an in vivo safety test by implanting coated stents into the internal thoracic arteries and ascending pharyngeal arteries of minipigs, and subsequently assessing the health status and vessel patency of the arteries by angiography over the course of 1 week. We found that there were no adverse effects on the pigs and the vascular lumens of their vessels were well maintained in the group with APTES-coated stents. Therefore, our new coating exhibited both high anti-thrombogenicity and cell-adhesion properties, which fulfill the requirements of an implantable stent.