Shedding light on venous thromboembolism

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Science Translational Medicine  13 May 2020:
Vol. 12, Issue 543, eabb7098
DOI: 10.1126/scitranslmed.abb7098


A preclinical deep vein thrombosis model was developed in mice using blood flow restriction and illumination.

Thromboembolic events occur when a blood clot becomes dislodged from the site of formation and embolizes or travels in the bloodstream to another site, where it can have adverse implications. Elucidating the pathophysiology of venous thromboembolism has been challenging, and visualizing these events has been limited by their infrequent and rapid occurrence. Current preclinical models of deep vein thrombosis (DVT) include ferric chloride–induced thrombosis and ligation of the inferior vena cava. Although delivery of ferric chloride is not surgically complex, resulting thrombi are platelet-rich, which is not representative of the composition of deep vein thrombi. Conversely, tying off the inferior vena cava creates clots that are rich in fibrin, platelets, and red blood cells, but the large clots do not embolize to the lungs.

Now, Okano et al. have established a preclinical deep venous thrombosis model that enables the formation of fibrin- and erythrocyte-rich thrombi in the femoral and saphenous veins of a mouse. This was achieved using a combination of blood flow restriction and light illumination. Simultaneously, the authors could visualize the thrombus using high-resolution, fluorescent imaging. Thrombus size was positively correlated with irradiance but was independent of wavelength.

Interestingly, the authors were able to induce DVT in the pocket formed by venous valve leaflets and image it with high resolution. Further, by deligating the suture that created the initial flow restriction, they enabled spontaneous embolization of a thrombus from the leg vein to the lungs, mimicking a pulmonary embolism. Imaging of the development and organization of a DVT was achieved using two-photon microscopy. The authors showed the initial formation of a fibrin- and erythrocyte-rich thrombus and the subsequent migration of platelets and leukocytes into the thrombus.

Limitations include the low penetration depth of two-photon imaging from the upper surface of the vein, preventing three-dimensional volume measurements of thrombus, and the lack of understanding of the precise mechanism of thrombus formation in this model. Imaging of erythrocyte-rich DVT formation and embolization in vivo in real time has vast potential in elucidating pathophysiology of venous thromboembolic events.

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