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

Palmer, Olivia R.; Shaydakov, Maxim E.; Rainey, Joshua P.; Lawrence, Daniel A.; Greve, Joan M.; Díaz, José

doi:10.1002/rth2.12074

Cited by 16 publications

(27 citation statements)

References 15 publications

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“…A thrombus develops quickly in the direction of the blood flow and thrombus sizes are highly consistent. This venous thrombosis model is used to study pro-thrombotic, anti-thrombotic, and thrombolytic therapies (28)(29)(30). Moreover, this model can mimic the early and late stages of venous thrombosis.…”

Section: Electrolytic Inferior Vena Cava Thrombosis Modelmentioning

confidence: 99%

Extracellular DNA—A Danger Signal Triggering Immunothrombosis

et al. 2020

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Clotting and inflammation are effective danger response patterns positively selected by evolution to limit fatal bleeding and pathogen invasion upon traumatic injuries. As a trade-off, thrombotic, and thromboembolic events complicate severe forms of infectious and non-infectious states of acute and chronic inflammation, i.e., immunothrombosis. Factors linked to thrombosis and inflammation include mediators released by platelet granules, complement, and lipid mediators and certain integrins. Extracellular deoxyribonucleic acid (DNA) was a previously unrecognized cellular component in the blood, which elicits profound proinflammatory and prothrombotic effects. Pathogens trigger the release of extracellular DNA together with other pathogen-associated molecular patterns. Dying cells in the inflamed or infected tissue release extracellular DNA together with other danger associated molecular pattern (DAMPs). Neutrophils release DNA by forming neutrophil extracellular traps (NETs) during infection, trauma or other forms of vascular injury. Fluorescence tissue imaging localized extracellular DNA to sites of injury and to intravascular thrombi. Functional studies using deoxyribonuclease (DNase)-deficient mouse strains or recombinant DNase show that extracellular DNA contributes to the process of immunothrombosis. Here, we review rodent models of immunothrombosis and the evolving evidence for extracellular DNA as a driver of immunothrombosis and discuss challenges and prospects for extracellular DNA as a potential therapeutic target.

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Section: Electrolytic Inferior Vena Cava Thrombosis Modelmentioning

confidence: 99%

Extracellular DNA—A Danger Signal Triggering Immunothrombosis

et al. 2020

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“…Recently the EIM application was expanded for the study of pro‐thrombotic conditions . Further, imaging studies recently demonstrated the consistent thrombus size is both current and time dependent, enabling researchers to modify these parameters to create thrombi of consistent size to study both pro‐thrombotic and anti‐thrombotic phenotypes, supporting the modification introduced in 2015. Additionally, a new approach was recently introduced to address lack of equipment availability and high cost, following the same principles but significantly reducing equipment cost .…”

Section: Mouse Models Of Venous Thrombosismentioning

confidence: 99%

Choosing a mouse model of venous thrombosis: a consensus assessment of utility and application

Díaz

Saha

Cooley

et al. 2019

Journal of Thrombosis and Haemostasis

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Summary Murine models are widely used valuable tools to study deep vein thrombosis (VT). Leading experts in VT research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of VT. In this work, we provide an algorithm for model selection, with discussion of the advantages, disadvantages, and applications of the main mouse models of VT. Additionally, we provide a detailed surgical description of the models with guidelines to validate surgical technique.

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“…In contrast, stimulation of the fibrinolytic system could be a safer option for thrombosis treatment because the coagulation system will be unaffected, and PAI-1 is considered a potential therapeutic target in VT (24, 34 -36). For these studies, VT was induced via the electrolytic inferior vena cava model (EIM) as described (37). After induction, mice received either 3 mg/kg MDI-2268, or low-molecular weight heparin (LMWH), or vehicle alone three times/day by IP injection.…”

Section: Medicinal Chemistry and Structure-activity Relationship (Sarmentioning

confidence: 99%

“…The EIM is a murine model of venous thrombosis that has been described previously (37). Briefly, thrombosis is induced under flow conditions by a small current run through a copper wire applied to the anterior vein wall.…”

Section: Murine Model Of Venous Thrombosismentioning

confidence: 99%

“…This releases free radicals within the vessel, which in turn activate the endothelial cells, initiating coagulation. The EIM produces a thrombus that is highly consistent in size and develops in the presence of blood flow (37). After induction of the thrombus, mice received 3 mg/kg MDI-2268, 3 mg/kg LMWH, or vehicle by IP injection 3 times/day.…”

Section: Murine Model Of Venous Thrombosismentioning

confidence: 99%

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

Reinke

Warnock

et al. 2019

Journal of Biological Chemistry

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Edited by John M. DenuPlasminogen activator inhibitor type-1 (PAI-1) is a serine protease 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 pharmacologically 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 highthroughput 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 >152,000 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 vitronectinbound 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.

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

Cited by 16 publications

References 15 publications

Extracellular DNA—A Danger Signal Triggering Immunothrombosis

Extracellular DNA—A Danger Signal Triggering Immunothrombosis

Choosing a mouse model of venous thrombosis: a consensus assessment of utility and application

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

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