Catch bonds hold tighter as more force is applied, useful for binding in the tumbling and pulsing conditions of blood flow.
“It finally clarified to us why all of these cells are down-regulating their adhesives so that they require force,” Dr. Thomas says. “If you have one that’s always weak, it’s not strong enough to bind, and if you have one that’s always strong you can’t bind rapidly enough to capture in flow.” Their research suggests mechanical forces drive the switch in the adhesion protein called FimH during changing conditions, allowing it to hit a sweet spot for binding.
Dr. Thomas and her team are applying lessons learned from this bacterial adhesion protein to understanding problems with blood clotting and endocarditis, both major problems in cardiovascular disease.
She and her team study von Willebrand factor, the clotting protein that helps blood platelets bind and begin clumping together at high flow, a critical part of both arterial wound healing and unwanted blood clots. Normally platelets and vWF circulate in the body without binding to each other. The platelets have a receptor that’s always activated or at least always ready to bind, Dr. Thomas says, but something about the vWF is not ready to bind when it circulates.
Giving the protein a surface to grab onto however, seems to activate a change. If vWF binds to exposed collagen – what happens if the protective layer of endothelial cells lining a blood vessel is damaged – or if it binds to the surface of biomaterials placed into the body, then the platelets suddenly bind to vWF much more easily. They still bind better at higher flow, most of the time, but they stick to each other more readily if the vWF is on a surface.
That’s one of ways the protein helps support healing, but in some conditions, such as an artery narrowed by atherosclerosis, it can cause a blood clot, or particularly, problems on biomaterial implants.
Dr. Thomas and David Castner, joint professor of bioengineering and chemical engineering, recently submitted a paper revealing their understanding of some of the changes that occur when the domain of vWF that’s recognized by platelets binds to different surfaces. When it binds to some surfaces it seems to be activated in a certain way so that it’s prepared to bind to platelets even without high flow, Dr. Thomas says.
The team is also working to understand how — and why — vWF activity is typically reduced when it’s circulating. Researchers know that the domain of vWF that’s recognized by platelets forms catch bonds, but Dr. Thomas wants to better understand why it needs mechanical force or surface immobilization in order to activate the binding to platelets.
In her von Willebrand factor work, Dr. Thomas collaborates with BloodWorks Research Institute to understand the structural basis for the mechanical activation of clotting. The long-term goal of their projects is to try to understand the changes that are involved in the vWF regulation process so that researchers can develop clinically useful ways to help when clotting goes awry. “The clinicians are always dealing with how to walk the balance between bleeding and clotting,” Dr. Thomas says. “We want tools that will specifically control that balance, but it’s a long path, and we’re at the beginning of it.”