We are normally born with a highly sophisticated array of molecules that act as "sentries," constantly scanning our bodies for injuries such as cuts and bruises. One such molecular sentry, known as von Willebrand factor (VWF), plays a critical role in our body's ability to stop bleeding.
To prevent hemorrhage or life-threatening blood clots, VWF must strike a delicate balance between clotting too little or too much. Researchers have long suspected that the mechanical forces and shear stress of blood flow could be closely-related to VWF's function.
It has not been possible to witness exactly how VWF senses and harnesses these mechanical forces -- until now.
A team of researchers has revealed exactly how VWF does its job. Cutting-edge fluorescence imaging and microfluidic tools, developed by the team, allowed them to capture images of individual VWF molecules on camera while manipulating the molecules with life-like mechanical forces emulating natural blood flow.
The team's findings, published in Nature Communications, reveal that VWF undergoes a two-step, shape shifting transformation to activate blood clotting. This transformation is triggered when VWF senses certain changes in blood flow that are indicative of injury.
"Under normal circumstances, VWF molecules are compact and globular in shape," says a co-first author on the paper. "But we found that when blood flow rate increases, VWF rapidly elongates, stretching out more and more in response to higher shear stress."
However, elongating is not sufficient on its own to activate blood clotting. To safeguard against unnecessary -- and potentially life threatening -- blood clots, it's only when the tensile forces generated in the elongated VWF hit critical levels that the shapeshifter's transformation becomes complete.
The tensile forces activate"sticky" sites along VWF, allowing it to adhere to circulating platelets, the cells that work in conjunction with VWF to clump up and stop blood loss.
Normally, the rush of blood needed to reach these critically-high tensile forces can only occur at sites of injury inside blood vessels. This specificity enables VWF to sense blood loss and activate rapidly and locally, without activating elsewhere in the body.
Revealing how VWF responds to changes in flow in the highly dynamic bloodstream is a critical step to understanding the interplay between mechanical force and biology in clotting-related diseases and developing novel therapeutics.
"This experiment really represents a new platform for seeing and measuring what's happening in the blood on a molecular level," says the author. "Through the use of novel microfluidic technologies that allow us to mimic the body's vasculature in combination with single-molecule imaging techniques, we are finally able to capture striking images that uncover the mystery of nature's forces at work in our bodies."