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A Thrombus in 3D
This is a three-dimensional image of a mouse artery which has developed a
thrombus after laser-induced injury. The vessel wall is shown in blue, the
platelet thrombus is in red, and fibrin deposits are shown in green.
Platelets Activating at the site of Injury
Upon injury of a blood vessel, platelets (green) accumulate to repair the
damage. Platelets are recruited to the site of injury, and then begin to
display different receptors, such as P-selectin, on their outer surface.
These activated platelets are shown in yellow.
Thrombus Formation in Real Time
Using intravital microscopy, it is possible to visualize thrombus formation
in a live mouse in real time. A laser is used to damage the blood vessel of
an anesthetized mouse, and then fluorescent antibodies are used to
visualize the growing thrombus. The laser damages the vessel wall such that
the endothelial cell layer is exposed to the blood stream. The endothelial
cell layer expresses Tissue Factor (green) which, upon exposure to plasma,
begins the necessary steps to recruit platelets (red) to the site of
injury. Activated platelets release the necessary components to further
recruit more platelets, as well as begin to form a fibrin clot (blue) which
acts as a patch to repair the injury.
PDI Accumulating at the site of Injury
Protein Disulfide Isomerase (PDI) is a crucial enzyme in the proper folding
of proteins in the endoplasmic reticulum. More recently, however, PDI has
been shown to also play a crucial role in the early stages of thrombus
formation. This video shows that upon laser injury of the vessel wall,
endothelial cells and platelets are activated, and PDI (green) is released
from the inside of the cell and accumulates on the outside of the cell.
PDI Activity is Required for Thrombus Formation, and Removal of PDI
Activity Results in Loss of Thrombus Formation
PDI plays a crucial role in the early stages of thrombus formation.
Comparison of the two videos below show that in the video on the left, upon
injury PDI (green) is released and platelets (red) accumulate to form a
thrombus and repair the damage. However, the video on the right shows, that
when the mouse is injected with an antibody that binds and inactivates PDI,
this loss of enzymatic activity from PDI causes a complete abolishment of
any thrombus formation. While the exact mechanism of the role of PDI is
still unknown, it is the current hypothesis that PDI catalytically alters
the thiol redox state of other proteins involved in this cascade, and this
alteration is necessary for further downstream effects that lead to