Choosing a Mouse Model of Venous Thrombosis

Díaz, José; Saha, Prakash; Cooley, Brian C.; Palmer, Olivia R.; Grover, Steven P.; Mackman, Nigel; Wakefield, Thomas W.; Henke, Peter K.; Smith, Alberto; Lal, Brajesh K.

doi:10.1161/atvbaha.118.311818

Cited by 50 publications

(36 citation statements)

References 51 publications

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“…4,5 None of these murine models precisely replicates human thrombosis and most experts agree that use of more than a single model should be used in evaluating genetically modified animals or new therapeutic interventions. [6][7][8] The cremaster arteriole laser injury model of thrombosis has been adopted by investigators worldwide. 5 The cremaster arteriole laser injury model uses a focused laser pulse to cause a localized injury to the vessel wall in cremaster arterioles that serves as a nidus for accumulation of platelets and fibrin.…”

Section: Introductionmentioning

confidence: 99%

Injury measurements improve interpretation of thrombus formation data in the cremaster arteriole laser‐induced injury model of thrombosis

Grover

Bendapudi

Yang

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: The cremaster arteriole laser-induced injury model is a powerful technique with which to investigate the molecular mechanisms that drive thrombus formation. This model is capable of direct visualization and quantification of accumulation of thrombus constituents, including both platelets and fibrin. However, a large degree of variability in platelet accumulation and fibrin formation is observed between thrombi. Strategies to understand this variability will enhance performance and standardization of the model. We determined whether ablation injury size contributes to variation in platelet accumulation and fibrin formation and, if so, whether incorporating ablation injury size into measurements reduces variation. Methods: Thrombus formation was initiated by laser-induced injury of cremaster arterioles of mice (n = 59 injuries). Ablation injuries within the vessel wall were consistently identified and quantified by measuring the length of vessel wall injury observed immediately following laser-induced disruption. Platelet accumulation and fibrin formation as detected by fluorescently labeled antibodies were captured by digital intravital microscopy. Results: Laser-induced disruption of the vessel wall resulted in ablation injuries of variable length (18-95 µm) enabling interrogation of the relationship between injury severity and thrombus dynamics. Strong positive correlations were observed between vessel injury length and both platelet accumulation and fibrin formation when the data are transformed as area under the curve (Spearman r = .80 and .76, respectively). Normalization of area under the curve measurements by injury length reduced intraclass coefficients of variation among thrombi and improved hypothesis testing when comparing different data sets. Conclusions: Measurement of vessel wall injury length provides a reliable and robust marker of injury severity. Injury length can effectively normalize measurements | 3079 GROVER Et al.

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Section: Introductionmentioning

confidence: 99%

Injury measurements improve interpretation of thrombus formation data in the cremaster arteriole laser‐induced injury model of thrombosis

Grover

Bendapudi

Yang

et al. 2020

Journal of Thrombosis and Haemostasis

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“…Due to the logistical difficulty of directly investigating DVT in humans, several experimental murine models of DVT have been used extensively as critically reviewed by Diaz et al [24,25]. The two most common models involve surgical complete ligation or partial ligation (stenosis) of the mouse inferior vena cava (IVC).…”

Section: Dependence On Murine Modelsmentioning

confidence: 99%

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Nicklas

Gordon

Henke

2020

IJMS

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Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy. already progressed past the point of anticoagulant efficacy [12,13]. Thus, there is potential clinical utility in investigating and controlling the process by which DVTs resolve in order to provide better care to these later-stage patients, with less bleeding risk. Overview of Venous Thrombus Development in HumansThe time sequence of DVT development and resolution was correctly suggested as early as 1962, based on empirical stains that detected changes in the nanoscopic roughness of clotted material [14]. As Lendrum et. al. remarked, "we consider that the intracytoplasmic granules, which we think are engulfed fibrin, seen in pulmonary phagocytes and in the endothelium of arteries and veins containing thrombus, are better shown by this (methyl-scarlet-blue) method than by any of the others." In fresh clot (whether in deep veins or in diabetic kidneys), platelets and erythrocytes are initially linked in a fine mesh yielding a relatively smooth surface (stage 1). A mat of the medium-textured fibrin replaces the initial thrombus (stage 2), which is gradually replaced by much coarser collagen (stage 3). This staging of clot development quickly became the basis of a pathological guide to grade thrombi [15]. The current three-stage refinement of the DVT grading scheme indicates that the turnover of erythrocyte-rich to fibrin-rich clot in humans is complete approximately seven days after the initial thrombotic event [16], whereas fibrin deposition commences after one day [17]. Various leukocytes, initially neutrophils and later macrophages, are believed to control this progression of DVTs development from a mass of erythrocytes, to fibrin, and finally to collagen [18]. Infiltrating T-lymphocytes and macrophages conta...

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“…Reduction of the vessel lumen does not denude the endothelium; however, the endothelium is still activated, and releases the von Willebrand factor (vWF) and P-selectin from the Weibel-Palade bodies. Information regarding thrombus size and composition, thrombus resolution and eventual vessel recanalization is forthcoming, but the lack of valves in the IVC is a distinct disadvantage to studying DVT [ 3 , 29 ].…”

Section: Animal Models Of Disease Pathophysiologymentioning

confidence: 99%

Sickle Cell Disease: A Paradigm for Venous Thrombosis Pathophysiology

Lizarralde-Iragorri

Shet

2020

IJMS

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Venous thromboembolism (VTE) is an important cause of vascular morbidity and mortality. Many risk factors have been identified for venous thrombosis that lead to alterations in blood flow, activate the vascular endothelium, and increase the propensity for blood coagulation. However, the precise molecular and cellular mechanisms that cause blood clots in the venous vasculature have not been fully elucidated. Patients with sickle cell disease (SCD) demonstrate all the risk factors for venous stasis, activated endothelium, and blood hypercoagulability, making them particularly vulnerable to VTE. In this review, we will discuss how mouse models have elucidated the complex vascular pathobiology of SCD. We review the dysregulated pathways of inflammation and coagulation in SCD and how the resultant hypercoagulable state can potentiate thrombosis through down-regulation of vascular anticoagulants. Studies of VTE pathogenesis using SCD mouse models may provide insight into the intersection between the cellular and molecular processes involving inflammation and coagulation and help to identify novel mechanistic pathways.

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Choosing a Mouse Model of Venous Thrombosis

Cited by 50 publications

References 51 publications

Injury measurements improve interpretation of thrombus formation data in the cremaster arteriole laser‐induced injury model of thrombosis

Injury measurements improve interpretation of thrombus formation data in the cremaster arteriole laser‐induced injury model of thrombosis

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Sickle Cell Disease: A Paradigm for Venous Thrombosis Pathophysiology

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