Under normal, healthy circulatory conditions, the von Willebrand Factor (vWF) keeps to itself. The large and mysterious multimeric glycoprotein moves through the blood, balled up tightly, its reaction sites unexposed. But when significant bleeding occurs, it springs into action, initiating the clotting process.
When it works properly, vWF helps stop bleeding and saves lives. However, about one to two percent of the world’s population is affected by vWF mutations that result in bleeding disorders. For those with more rare, severe forms, a very expensive treatment in the form of blood plasma replacement may be required.
On the other hand, if vWF activates where it isn’t needed, it can trigger a stroke or heart attack.
A better understanding of how vWF functions could result in drugs that replace it in those who lack it. It could also lead to the development of new drugs or drug carriers that mimic the protein’s behavior for more effective drug delivery. With that in mind, a team of Lehigh researchers is working to characterize this mysterious protein.
The team, which includes Xuanhong Cheng, associate professor of materials science and engineering; Alparslan Oztekin, professor of mechanical engineering and mechanics; Edmund Webb III, associate professor of mechanical engineering and mechanics; and Frank Zhang, associate professor of bioengineering and mechanical engineering and mechanics (all of whom are affiliated with Lehigh's Institute for Functional Materials and Devices, or I-DISC); as well as doctoral students Chuqiao Dong, Sagar Kania, Michael Morabito and Yi Wang, is exploring vWF from a variety of angles, through both experiment and simulation.
vWF at Work
At the location of a minor wound, platelets adhere to the collagen-exposed sites near the hole in the blood vessel wall on their own and act as a plug, effectively stopping the bleeding. Rapid blood flow, however, makes it difficult for platelets to do this. Fortunately, the von Willebrand Factor recognizes this rapid blood flow and activates: “It’s a flow-mechanics-activated event, if you will,” explains Webb.
The globular molecule unfolds like a Slinky, stretching to 10 times its original size and exposing its reaction sites. It clings to the broken blood vessel wall, where exposed collagen—the structural protein of the blood vessel wall—attracts platelets. vWF then captures platelets from blood as they flow by, acting like a bridge between the collagen and the platelets.
Although the biological function of vWF has long been recognized by scientists, not much is known about the specifics of how vWF functions, particularly under flow conditions.
“Most proteins in blood functions are executed through biochemical reactions,” says Cheng. “This protein [vWF] also requires some biochemical reaction for its function, so it needs to grab onto platelets, grab onto collagen—those are biochemical reactions. At the same time, vWF relies on mechanical stimulation to execute the biochemical function, and that part is not very well known. That’s what we’re trying to study.”
Adds Webb: “Some of the data that’s coming out of our group but also from other groups indicates that those biochemical reactions are somehow abetted by there being some sort of a tension, a pulling force. So even the biochemical reactions appear to be somewhat mechanically mediated. Again, it was understood that there was this change from a compact, almost ball-like shape, if you will, to this long, stringy thing. But very recently people have been indicating it’s not just that. For this chemical site to be active, you have to be pulling it, you have to be in a bit of tension, locally. So it’s a really fascinating system.”
The von Willebrand Factor is a particularly large protein made up of many monomers, or molecules that can be bonded to other identical molecules to form a polymer. Within each monomer of vWF are different domains: A, C and D. Each domain and each of its respective subdomains has its own role, and many of these roles are yet unknown. The A1 domain, for example, binds vWF to platelets. A3 binds vWF to collagen. The A2 domain unfolds to expose the protein’s reaction sites, and, when fully opened, exposes a site that permits scission of the vWF molecule down to size. Members of the team have focused on the A2 domain, in particular.
“Understanding that domain and how it interacts with the flow, I think, is the best contribution from our group,” says Oztekin.
Each member of the team plays a particular role. Cheng, Zhang and their graduate students work on the experimental side of the project; Oztekin and Webb, who are both affiliated with the university's Institute for Data, Intelligent Systems, and Computation (I-DISC), and their graduate students focus on simulation. Each team’s results inform the work of the other.
Read the full story in the Lehigh University News Center.
Story by Kelly Hochbein
Illustration by Laurindo Feliciano
