Update on the electrolytic IVC model for pre‐clinical studies of venous thrombosis

EssentialsThree key updates are provided on the electrolytic inferior vena cava model (EIM).The originally described stimulator equipment has been discontinued; we developed an alternative.The fibrinolytic system and the current and time dependency of the EIM was characterized.EIM allows the investigation of the fibrinolytic system, critical for endovascular therapies.BackgroundThe electrolytic inferior vena cava model (EIM) is a murine venous thrombosis (VT) model that produces a non‐occlusive thrombus. The thrombus forms in the direction of blood flow, as observed in patients. The EIM is valuable for investigations of therapeutics due to the presence of continuous blood flow. However, the equipment used to induce thrombosis in the original model description was expensive and has since been discontinued. Further, the fibrinolytic system had not been previously studied in the EIM.ObjectivesWe aimed to provide an equipment alternative. Additionally, we further characterized the model through mapping the current and time dependency of thrombus resolution dynamics, and investigated the fibrinolytic system from acute to chronic VT.ResultsA voltage to current converter powered by a direct current power supply was constructed and validated, providing an added benefit of significantly reducing costs. The current and time dependency of thrombus volume dynamics was assessed by MRI, demonstrating the flexibility of the EIM to investigate both pro‐thrombotic and anti‐thrombotic conditions. Additionally, the fibrinolytic system was characterized in EIM. Centripetal distribution of plasminogen was observed over time, with peak staining at day 6 post thrombus induction. Both active circulating plasminogen activator inhibitor‐1 (PAI‐1) and vein wall gene expression of PAI‐1 peaked at day 2, coinciding with a relative decrease in tissue plasminogen activator and urokinase plasminogen activator.ConclusionsThe EIM is a valuable model of VT that can now be performed at low cost and may be beneficial in investigations of the fibrinolytic system.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143801/1/rth212074.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143801/2/rth212074_am.pd

Dual-reporter high-throughput screen for small-molecule in vivo inhibitors of plasminogen activator inhibitor type-1 yields a clinical lead candidate

Plasminogen activator inhibitor type-1 (PAI-1) is a serine prote-ase inhibitor (serpin) implicated in numerous pathological processes, including coronary heart disease, arterial and venous thrombosis, and chronic fibrotic diseases. These associations have made PAI-1 an attractive pharmaceutical target. However, the complexity of the serpin inhibitory mechanism, the inherent metastability of serpins, and the high-affinity association of PAI-1 with vitronectin in vivo have made it difficult to identify pharmacologi-cally effective small-molecule inhibitors. Moreover, the majority of current small-molecule PAI-1 inhibitors are poor pharmaceutical candidates. To this end and to find leads that can be efficiently applied to in vivo settings, we developed a dual-reporter high-throughput screen (HTS) that reduced the rate of nonspecific and promiscuous hits and identified leads that inhibit human PAI-1 in the high-protein environments present in vivo. Using this system, we screened \u3e152,000 pure compounds and 27,000 natural product extracts (NPEs), reducing the apparent hit rate by almost 10-fold compared with previous screening approaches. Furthermore, screening in a high-protein environment permitted the identification of compounds that retained activity in both ex vivo plasma and in vivo. Following lead identification, subsequent medicinal chemistry and structure–activity relationship (SAR) studies identified a lead clinical candidate, MDI-2268, having excellent pharmacokinetics, potent activity against vitronectin-bound PAI-1 in vivo, and efficacy in a murine model of venous thrombosis. This rigorous HTS approach eliminates promiscuous candidate leads, significantly accelerates the process of identifying PAI-1 inhibitors that can be rapidly deployed in vivo, and has enabled identification of a potent lead compound

Extended anticoagulation for venous thromboembolism : A survey of the American Venous Forum and the European Venous Forum

Objective: Extended anticoagulation therapy should always be considered after standard treatment of an unprovoked episode of venous thromboembolism (VTE). It can also be considered for selected patients with provoked VTE. However, the evidence-based protocols suggested by some clinical guidelines and risk assessment tools to guide this practice are limited and ambiguous. The goal of the present survey research was to analyze current practices in applying extended anticoagulation therapy for patients with VTE among members of the American Venous Forum (AVF) and European Venous Forum (EVF). Methods: An online survey was created by the AVF Research Committee. The survey consisted of 16 questions to identify the country of practice, specialty, experience of the participating physicians, and their clinical practice patterns in applying extended anticoagulation therapy for VTE patients. The survey was distributed via e-mail to the members of the AVF and EVF. Results: A total of 144 practitioners, 48 AVF members (33%) and 96 EVF members (66%), participated in the survey. Most of the respondents identified themselves as vascular specialists with primary certification in vascular surgery (70%), vascular medicine or angiology (9%), and venous disease or phlebology (3%). Of the 144 respondents, 72% believed that the risk of VTE recurrence will generally overweigh the risk of bleeding for patients with unprovoked VTE. Extended anticoagulation therapy might be used by 97% of providers. Different patterns in real world clinical practice were identified. More than one half of the practitioners estimated the VTE recurrence and bleeding risk subjectively. The antithrombotic drugs most commonly used for secondary prophylaxis were rivaroxaban, apixaban, warfarin, dabigatran, and aspirin, in decreasing order of frequency. Among the reasons selected for not regularly considering extended anticoagulation therapy were the lack of specific clinical practice guidelines (24%), lack of reported evidence (9%), and absence of valid VTE and/or bleeding risk prediction calculators (8%). Twelve participants (8%) stated that extended anticoagulation therapy would not be beneficial for most patients with VTE. Ten participants (7%) indicated that prescribing extended anticoagulation therapy was outside the scope of their specialty. Conclusions: Different practice patterns exist regarding extending anticoagulation therapy beyond the standard treatment for patients with VTE. Major gaps in knowledge remain a serious challenge at least partially explaining the inaccuracy and inconsistency in long-term VTE management. Appropriately designed studies are needed to evaluate risk stratification tools when contemporary best medical therapy is used, accurately predict VTE recurrence and its long-term outcomes, and tailor safe and effective secondary prophylaxis

Extended anticoagulation for venous thromboembolism: A survey of the American Venous Forum and the European Venous Forum

Objective: Extended anticoagulation therapy should always be considered after standard treatment of an unprovoked episode of venous thromboembolism (VTE). It can also be considered for selected patients with provoked VTE. However, the evidence-based protocols suggested by some clinical guidelines and risk assessment tools to guide this practice are limited and ambiguous. The goal of the present survey research was to analyze current practices in applying extended anticoagulation therapy for patients with VTE among members of the American Venous Forum (AVF) and European Venous Forum (EVF). Methods: An online survey was created by the AVF Research Committee. The survey consisted of 16 questions to identify the country of practice, specialty, experience of the participating physicians, and their clinical practice patterns in applying extended anticoagulation therapy for VTE patients. The survey was distributed via e-mail to the members of the AVF and EVF. Results: A total of 144 practitioners, 48 AVF members (33%) and 96 EVF members (66%), participated in the survey. Most of the respondents identified themselves as vascular specialists with primary certification in vascular surgery (70%), vascular medicine or angiology (9%), and venous disease or phlebology (3%). Of the 144 respondents, 72% believed that the risk of VTE recurrence will generally overweigh the risk of bleeding for patients with unprovoked VTE. Extended anticoagulation therapy might be used by 97% of providers. Different patterns in real world clinical practice were identified. More than one half of the practitioners estimated the VTE recurrence and bleeding risk subjectively. The antithrombotic drugs most commonly used for secondary prophylaxis were rivaroxaban, apixaban, warfarin, dabigatran, and aspirin, in decreasing order of frequency. Among the reasons selected for not regularly considering extended anticoagulation therapy were the lack of specific clinical practice guidelines (24%), lack of reported evidence (9%), and absence of valid VTE and/or bleeding risk prediction calculators (8%). Twelve participants (8%) stated that extended anticoagulation therapy would not be beneficial for most patients with VTE. Ten participants (7%) indicated that prescribing extended anticoagulation therapy was outside the scope of their specialty. Conclusions: Different practice patterns exist regarding extending anticoagulation therapy beyond the standard treatment for patients with VTE. Major gaps in knowledge remain a serious challenge at least partially explaining the inaccuracy and inconsistency in long-term VTE management. Appropriately designed studies are needed to evaluate risk stratification tools when contemporary best medical therapy is used, accurately predict VTE recurrence and its long-term outcomes, and tailor safe and effective secondary prophylaxis

Global guidelines trends and controversies in lower limb venous and lymphatic disease Narrative literature revision and experts' opinions following the vWINter international meeting in Phlebology, Lymphology & Aesthetics, 23-25 January 2019

Guidelines are fundamental in addressing everyday clinical indications and in reporting the current evidence-based data of related scientific investigations. At the same time, a spatial and temporal issue can limit their value. Indeed, variability in the recommendations can be found both among the same nation different scientific societies and among different nations/continents. On the other side, Garcia already published in 2014 data showing how, after three years in average, one out of five recommendations gets outdated (Martinez Garcia LM, Sanabria AJ, Garcia Alvarez E, et al. The validity of recommendations from clinical guidelines: a survival analysis. CMAJ 2014;186(16):1211–1219). The present document reports a narrative literature revision on the major international recommendations in lower limb venous and lymphatic disease management, focusing on the different countries’ guidelines, trends and controversies from all the continents, while identifying new evidence-based data potentially influencing future guidelines. World renowned experts’ opinions are also provided. The document has been written following the recorded round tables scientific discussions held at the vWINter international meeting (22–26 January 2019; Cortina d’Ampezzo, Italy) and the pre- and post-meeting literature search performed by the leading experts

Fake-news-free evidence-based communication for proper vein-lymphatic disease management

Published scientific evidence demonstrate the current spread of healthcare misinformation in the most popular social networks and unofficial communication channels. Up to 40% of the medical websites were identified reporting inappropriate information, moreover being shared more than 450,000 times in a 5-year-time frame. The phenomenon is particularly spread in infective diseases medicine, oncology and cardiovascular medicine. The present document is the result of a scientific and educational endeavor by a worldwide group of top experts who selected and analyzed the major issues and related evidence-based facts on vein and lymphatic management. A section of this work is entirely dedicated to the patients and therefore written in layman terms, with the aim of improving public vein-lymphatic awareness. The part dedicated to the medical professionals includes a revision of the current literature, summing up the statements that are fully evidence-based in venous and lymphatic disease management, and suggesting future lines of research to fulfill the still unmet needs. The document has been written following an intense digital interaction among dedicated working groups, leading to an institutional project presentation during the Universal Expo in Dubai, in the occasion of the v-WINter 2022 meeting