Essentials
Three 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.
Introduction:
Conventional treatment of deep vein thrombosis is suboptimal, requiring continuous improvement in knowledge about the disease and a search for new therapeutic approaches.
Hypothesis:
Blood flow affects the composition of an acute venous thrombus (VT).
Aim 1:
Compare VT composition under flow and stasis conditions.
Aim 2:
Evaluate the antithrombotic properties of the novel PAI-1 inhibitor MDI-2268 in-vivo.
Methods:
C57BL/6 mice, 10-12w, 20-25g were used in electrolytic (EIM) and ligation (LM) models of venous thrombosis.
Aim 1:
The thrombus weight (TW) and the microstructure of an acute VT (Day 2) in the EIM (n=5) and the LM (n=5) were compared. Expression of PAI-1, tPA, and uPA in the vein wall and plasma levels of D-dimer were investigated.
Aim 2:
Five EIM groups (n=5) were studied: MDI-2268 1.5 mg/kg (Group 1), MDI-2268 3 mg/kg (Group 2), enoxaparin 7.3 mg/kg (Group 3), MDI-2268 3 mg/kg plus enoxaparin 1.8 mg/kg (Group 4), and DMSO controls (Group 5). TW and bleeding time (BT) on Day 2 were measured.
Results: Aim 1:
VT within the EIM was smaller compared to the LM (6.2.5±3.6 vs. 26.2±3.6, P<0.05). VT formed within the EIM had a significantly higher amount of plasminogen. The level of D-dimer was 23.4±12.5 and 4.5±1.3 ng/mL/mg in the EIM and LM, respectively (p<0.05).
Aim 2:
TW was 6.9±3.3 (p>.05), 5.5±1.6 (p=.035), 3.8±1.3 (p=.005), and 4.8±2.4 mg (p=.035) for groups 1,2,3, and 4; compared to 12.7±5.7 mg in the controls. BT was not affected by the MDI-2268.
Conclusions:
Blood flow pattern significantly affects VT composition. Non-occlusive thrombus has a higher potential to be targeted by the fibrinolytic system due to a higher plasminogen content. MDI-2268 demonstrates strong antithrombotic properties in-vivo and may be associated with a lower risk of bleeding compared to enoxaparin. This data may contribute to a better understanding of the disease process, different outcomes after venous thrombosis, and new therapeutic targets.
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