Model‐dependent contributions of FXII and FXI to venous thrombosis in mice

Grover, Steven P.; Olson, Tatianna M.; Cooley, Brian C.; Mackman, Nigel

doi:10.1111/jth.15037

Cited by 16 publications

(12 citation statements)

References 58 publications

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“…Finally, we recognize that the influence of neutrophils in murine models of venous thrombosis is variable. The strongest evidence to date has been observed in the IVC stenosis model, while some models do not demonstrate a significant contribution of leukocytes to venous thrombosis in otherwise healthy animals 22,24,51,64–67 . However, of importance, several studies have now shown that neutrophilia or elevated NET release contribute to the pathogenesis of venous thrombosis in the IVC stasis, jugular vein Rose Bengal, and lung model of spontaneous thrombosis in the presence of solid or blood cancers 47,68,69 .…”

Section: Discussionmentioning

confidence: 99%

Stabilin‐2 deficiency increases thrombotic burden and alters the composition of venous thrombi in a mouse model

Michels

Swystun

Dwyer

et al. 2021

Journal of Thrombosis and Haemostasis

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Background Stabilin‐2 is an endocytic scavenger receptor that mediates the clearance of glycosaminoglycans, phosphatidylserine‐expressing cells, and the von Willebrand factor‐factor VIII (FVIII) complex. In a genome‐wide screening study, pathogenic loss‐of‐function variants in the human STAB2 gene associated with an increased incidence of unprovoked venous thromboembolism (VTE). However, the specific mechanism(s) by which stabilin‐2 deficiency influences the pathogenesis of VTE is unknown. Objectives The aim of this study was to assess the influence of stabilin‐2 on deep vein thrombosis (DVT) and to characterize the underlying prothrombotic phenotype of stabilin‐2 deficiency in a mouse model. Methods DVT was induced using the inferior vena cava (IVC) stenosis model in two independent cohorts (littermates and non‐littermates) of wild‐type (Stab2+/+) and stabilin‐2 (Stab2−/−)–deficient mice. Thrombus structure and contents were quantified by immunohistochemistry. Plasma procoagulant activity was assessed and complete blood counts were performed. Results Incidence of thrombus formation was not altered between Stab2+/+ and Stab2−/− mice. When thrombi were formed, Stab2−/− mice developed significantly larger thrombi than Stab2+/+ controls. Thrombi from Stab2−/− mice contained significantly more leukocytes and citrullinated histone H3 than Stab2+/+ thrombi. Stab2−/− mice had increased FVIII activity. Circulating levels of monocytes and granulocytes were significantly elevated in Stab2−/− mice, and Stab2−/− mice had elevated plasma cell‐free DNA 24 hours post‐IVC stenosis compared to their Stab2+/+ counterparts. Conclusions These data suggest that stabilin‐2 deficiency associates with a prothrombotic phenotype involving elevated levels of neutrophil extracellular trap‐releasing leukocytes coupled with endogenous procoagulant activity, resulting in larger and qualitatively distinct venous thrombi.

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Section: Discussionmentioning

confidence: 99%

Stabilin‐2 deficiency increases thrombotic burden and alters the composition of venous thrombi in a mouse model

Michels

Swystun

Dwyer

et al. 2021

Journal of Thrombosis and Haemostasis

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“…The abdomen was opened by midline laparotomy and the bowel externalized and wrapped in wetted gauze. The inferior vena cava (IVC) was stenosed as previously described 23 . At 48 h post‐stenosis induction, the IVC was inspected for the presence of thrombus with any resultant thrombus removed from the IVC and weighed using a microbalance.…”

Section: Methodsmentioning

confidence: 99%

Genetic deletion of platelet PAR4 results in reduced thrombosis and impaired hemostatic plug stability

Lee

Kawano

Grover

et al. 2022

Journal of Thrombosis and Haemostasis

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Background: Protease-activated receptor 4 (PAR4) is expressed by a wide variety of cells, including megakaryocytes/platelets, immune cells, cardiomyocytes, and lung epithelial cells. It is the only functional thrombin receptor on murine platelets. A global deficiency of PAR4 is associated with impaired hemostasis and reduced thrombosis. Objective: We aimed to generate a mouse line with a megakaryocyte/platelet-specific deletion of PAR4 (PAR4 fl/fl ;PF4 Cre+ ) and use the mouse line to investigate the role of platelet PAR4 in hemostasis and thrombosis in mice. Methods: Platelets from PAR4 fl/fl ;PF4 Cre+ were characterized in vitro. Arterial and venous thrombosis was analyzed. Hemostatic plug formation was analyzed using a saphenous vein laser injury model in mice with global or megakaryocyte/plateletspecific deletion of PAR4 or wild-type mice treated with thrombin or glycoprotein VI (GPVI) inhibitors.Results: PAR4 fl/fl ;PF4 Cre+ platelets were unresponsive to thrombin or specific PAR4 stimulation but not to other agonists. PAR4 −/− and PAR4 fl/fl ;PF4 Cre+ mice both exhibited a similar reduction in arterial thrombosis compared to their respective controls.More importantly, we show for the first time that platelet PAR4 is critical for venous thrombosis in mice. In addition, PAR4 −/− mice and PAR4 fl/fl ;PF4 Cre+ mice exhibited a similar impairment in hemostatic plug stability in a saphenous vein laser injury model. Inhibition of thrombin in wild-type mice gave a similar phenotype. Combined PAR4 deficiency on platelets with GPVI inhibition did not impair hemostatic plug formation but further reduced plug stability. Conclusion:We generated a novel PAR4 fl/fl ;PF4 Cre+ mouse line. We used this mouse line to show that PAR4 signaling in platelets is critical for arterial and venous thrombosis and hemostatic plug stability.

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“…In FV Leiden carriers, high FXI levels were suggested to contribute to the risk for VTE [52]. Furthermore, animal models al-so suggest that the activation of FXI by FXIIa promotes pathological thrombus formation [53]. FXI inhibition has been proposed as an innovative therapeutic tool to reduce the risk for VTE [54].…”

Section: Factor VII (Fvii) Deficiencymentioning

confidence: 99%

Rare Defects: Looking at the Dark Face of the Thrombosis

D’Andrea

Margaglione

2021

IJERPH

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Venous thromboembolism (VTE) constitutes a serious and potentially fatal disease, often complicated by pulmonary embolism and is associated with inherited or acquired factors risk. A series of risk factors are known to predispose to venous thrombosis, and these include mutations in the genes that encode anticoagulant proteins as antithrombin, protein C and protein S, and variants in genes that encode instead pro-coagulant factors as factor V (FV Leiden) and factor II (FII G20210A). However, the molecular causes responsible for thrombotic events in some individuals with evident inherited thrombosis remain unknown. An improved knowledge of risk factors, as well as a clear understanding of their role in the pathophysiology of VTE, are crucial to achieve a better identification of patients at higher risk. Moreover, the identification of genes with rare variants but a large effect size may pave the way for studies addressing new antithrombotic agents in order to improve the management of VTE patients. Over the past 20 years, qualitative or quantitative genetic risk factors such as inhibitor proteins of the hemostasis and of the fibrinolytic system, including fibrinogen, thrombomodulin, plasminogen activator inhibitor-1, and elevated concentrations of factors II, FV, VIII, IX, XI, have been associated with thrombotic events, often with conflicting results. The aim of this review is to evaluate available data in literature on these genetic variations to give a contribution to our understanding of the complex molecular mechanisms involved in physiologic and pathophysiologic clot formation and their role in clinical practice.

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Model‐dependent contributions of FXII and FXI to venous thrombosis in mice

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 16 publications

References 58 publications

Stabilin‐2 deficiency increases thrombotic burden and alters the composition of venous thrombi in a mouse model

Stabilin‐2 deficiency increases thrombotic burden and alters the composition of venous thrombi in a mouse model

Genetic deletion of platelet PAR4 results in reduced thrombosis and impaired hemostatic plug stability

Rare Defects: Looking at the Dark Face of the Thrombosis

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