Stenosis of the Inferior Vena Cava: A Murine Model of Deep Vein Thrombosis

Payne, Holly; Brill, A.B.

doi:10.3791/56697-v

Cited by 5 publications

(6 citation statements)

References 12 publications

(13 reference statements)

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“…The flow restriction model of DVT in the IVC is commonly used and is described as reproducing the kinetics and the clinical features of DVT in humans by reducing venous flow (14). Using this model, in combination with intravital imaging, von Brühl et al characterized the thrombus by a successive layer of red blood cells and fibrin, called “red clot”, associated with a large number of leukocytes and activated platelets (3).…”

Section: Discussionmentioning

confidence: 99%

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ADP-dependent platelet activation is required for thrombus formation during a long-distance flight

Tourn,

Carminita,

Crescence

et al. 2024

Preprint

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The association between venous thromboembolism (VTE) and air travel is well documented.Prolonged exposure to reduced atmospheric pressure and low oxygen levels during flights triggers coagulation disorders, representing the primary risk factor for Deep Vein Thrombosis (DVT), surpassing immobility. In our study, we investigated how long-distance flight conditions affect VTE development in mice exposed to 6h of hypobaric hypoxia or normobaric normoxia after inferior vena cava (IVC) ligation. We observed a pro-thrombotic profile under flight-simulated conditions, characterized by larger thrombi with higher neutrophil and fibrin densities. However, no difference was observed in neutrophil extracellular traps (NETs) or fibrin-positive neutrophils in thrombi between groups, indicating that neutrophils/NETs may not be involved in DVT development during flight. Considering the elevated ADP levels observed at high altitudes, we further assessed thrombus formation in wild-type and P2RY12 -deficient mice. Remarkably, thrombus formation was no longer affected by aircraft conditions in P2RY12-deficient or wild type mice treated with clopidogrel. We conclude that ADP-induced platelet activation is involved in the development of DVT during flight, suggesting that the use of P2RY12 inhibitors may be of interest to prevent DVT in susceptible patients.

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Section: Discussionmentioning

confidence: 99%

“…Stenosis in the IVC was created using the DVT model as described by Holly Payne and Alexander Brill (14) and adapted to our specific condition (hypobaric and hypoxia). 24 hours before the stenosis procedure, the animals were acclimatized to the water intake with a gel.…”

Section: Mouse Model Of Flow Restriction In the Ivcmentioning

confidence: 99%

ADP-dependent platelet activation is required for thrombus formation during a long-distance flight

Tourn,

Carminita,

Crescence

et al. 2024

Preprint

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“…The mouse inferior vena cava (IVC) stenosis model of DVT was performed, as previously reported. 48 , 49 , 50 , 51 Only male mice were used for this model, because ligation in female mice may result in necrosis of the reproductive organs. 50 , 52 Briefly, a midline laparotomy was made, and IVC side branches were ligated.…”

Section: Methodsmentioning

confidence: 99%

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Pandey,

Kaur,

Chorawala

et al. 2024

Blood Advances

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Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein, highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in post-stroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of post-stroke DVT. Neutrophil-specific integrin α9 deficient mice (α9fl/flMrp8Cre+/−) exhibited a significant reduction in post-stroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase (ERK), and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/− mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.-

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“…All side and back branches of the IVC (usually 1–2), were completely ligated with a 7-0 silk suture before the main ligation. 24–27 This modified technique resulted in thrombus formation in 98% of the ligated animals, those without thrombus were excluded from subsequent analyses. Endothelial denudation with a neurosurgical vascular clip 28 was not performed because of a high rate of rupture of the IVC wall.…”

Section: Methodsmentioning

confidence: 99%

“…All side and back branches of the IVC (usually 1-2), were completely ligated with a 7-0 silk suture before the main ligation. [24][25][26][27] 11,17,29,30 We ascertained by Western blots that Bβ 15-42 was detectable in mouse thrombus (data not shown).…”

Section: Murine Models Of Ivc Thrombosismentioning

confidence: 96%

Synthetic Fibrin-Derived Bβ _15-42 Peptide Delays Thrombus Resolution in a Mouse Model

Chausheva

Redwan

Sharma

et al. 2021

ATVB

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Objective: Thrombus resolution is driven by leukocyte recruitment and thrombus angiogenesis. An effective inhibition of leukocyte transmigration in vitro is mediated by naturally occurring peptide Bβ 15-42 , which is a competitive inhibitor of the interaction between the N-terminus of the fibrin beta chain and vascular endothelial cadherin. We investigated the effect of Bβ 15-42 on thrombus resolution in a murine stagnant flow venous thrombosis model and studied Bβ 15-42 levels in venous thrombus of human patients. Approach and Results: We investigated 2 mouse models of subtotal inferior vena cava ligation. In the first model, we ligated the inferior vena cava. In the second model, we additionally ligated all visible inferior vena cava side and back branches. Study groups of 8 to 12 weeks old BALB/c mice were then injected intraperitoneal twice daily with 2.4 mg/kg of Bβ 15-42 , unrelated control peptide or saline. Bβ 15-42 attenuated thrombus resolution after inferior vena cava ligation. We observed decreased numbers of thrombus macrophages and microvessels and less urokinase-type plasminogen activator expression in mice that were injected with Bβ 15-42 . Mechanistic experiments demonstrated that Bβ 15-42 blocks monocyte transmigration through an endothelial cell monolayer. Measurements of Bβ 15-42 in red clot and plasma of chronic thromboembolic pulmonary hypertension cases indicated high concentrations compared with controls. Conclusions: Our data suggest that excess of the fibrin fragment Bβ 15-42 misguides thrombus resolution, presumably by inhibiting vascular endothelial cadherin-mediated leukocyte migration during early thrombus organization.

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Stenosis of the Inferior Vena Cava: A Murine Model of Deep Vein Thrombosis

Cited by 5 publications

References 12 publications

ADP-dependent platelet activation is required for thrombus formation during a long-distance flight

ADP-dependent platelet activation is required for thrombus formation during a long-distance flight

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Synthetic Fibrin-Derived Bβ _15-42 Peptide Delays Thrombus Resolution in a Mouse Model

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Stenosis of the Inferior Vena Cava: A Murine Model of Deep Vein Thrombosis

Cited by 5 publications

References 12 publications

ADP-dependent platelet activation is required for thrombus formation during a long-distance flight

ADP-dependent platelet activation is required for thrombus formation during a long-distance flight

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Synthetic Fibrin-Derived Bβ 15-42 Peptide Delays Thrombus Resolution in a Mouse Model

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Synthetic Fibrin-Derived Bβ _15-42 Peptide Delays Thrombus Resolution in a Mouse Model