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

Abstract

Deep vein thrombosis (DVT) and its devastating complication, pulmonary embolism, are a severe health problem with high mortality. Mechanisms of thrombus formation in veins remain obscure. Lack of mobility (e.g., after surgery or long-haul flights) is one of the main factors leading to DVT. The pathophysiological consequence of the lack of mobility is blood flow stagnation in venous valves. Here, a model is described that mimics such flow disturbance as a thrombosis-driving factor. In this model, partial flow restriction (stenosis) in the inferior vena cava (IVC) is created. Closure of about 90% of the IVC lumen for 48 h results in development of thrombi structurally similar to those in humans. The similarities are: i) most of the thrombus volume is red, i.e., consists of red blood cells and fibrin, ii) presence of a white part (lines of Zahn), iii) non-denuded endothelial monolayer, iv) elevated plasma D-Dimer levels, and v) possibility to prevent thrombosis by low molecular weight heparin. Limitations include variable size of thrombi and the fact that a certain percentage of wild-type mice (0 - 35%) may not produce a thrombus. In addition to visual observation and measurement, thrombi may be visualized by non-invasive technologies, such as ultrasonography, which allows for monitoring the dynamics of thrombus development. At shorter time points (1 - 6 h), intravital microscopy may be applied to directly observe events (e.g., recruitment of cells to the vessel wall) preceding thrombus formation. Use of this method by several teams around the world has made it possible to uncover basic mechanisms of DVT initiation and identify potential targets that might be beneficial for its prevention.

IL-1β Blockade Attenuates Thrombosis in a Neutrophil Extracellular Trap-Dependent Breast Cancer Model

“…In the end, the needle was removed to avoid complete vessel occlusion. After the time indicated in each experiment, the thrombus that formed below the suture in the caudal direction was removed and weighed (14, 31).…”

“…Furthermore, treatment with a recombinant IL-1 receptor (IL-1R) antagonist alters the infiltrating immune cell composition of the tumor microenvironment (30). In the present study, we combined a well-established murine breast cancer model with a flow-restriction deep vein thrombosis (DVT) model (31) to interrogate whether the inhibition of IL-1β could attenuate cancer-associated thrombosis. Our data show that mice bearing tumors with elevated expression of G-CSF and IL-1β exhibit increased neutrophil counts and rely on the establishment of a NET-dependent prothrombotic state.…”

Immune Factors in Deep Vein Thrombosis Initiation

“…Animal models recapitulating complete [19] or partial 20 , 21 blood flow restriction by applying ligature on the inferior vena cava (IVC; stasis and stenosis DVT models, respectively; Table 1 ) have been developed and used to delineate mechanisms of venous thrombosis initiation and resolution. In addition to the experimental approach, the pivotal role of flow reduction in cell accrual in the valves has recently been demonstrated by a computer simulation approach [22] .…”

The role of valve stiffness in the insurgence of deep vein thrombosis

“…In vivo models of DVT include flow restriction in a major vein (usually the inferior vena cava, IVC) in rodents to induce thrombus formation [11][12][13] . These models have been useful for the development, for example, of drugs to treat DVT 12,14 , however, they do not allow for exploring the importance of physical parameters triggering thrombosis (blood flow, elasticity of the valve, etc.).…”