For the first time, researchers have identified the specific mechanism of von Willebrand Factor (vWF)―an essential blood clotting protein―that enables it to bind to platelets and initiate clotting

Under normal, healthy circulatory conditions, the von Willebrand Factor (vWF) keeps to itself. The large and mysterious 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, according to the Centers for Disease Control and Prevention (CDC), about 60,000 to 100,000 Americans die each year from thrombosis, a disorder characterized by too much clotting. Blood clots can trigger a stroke or heart attack.

According to X. Frank Zhang, an associate professor of bioengineering, only one drug, Caplacizumab, has been FDA-approved to target vWF and treat thrombosis, or excessive blood clotting disorders. It works by binding to vWF and blocking it from binding to platelets. However, no one has understood the specific mechanism behind how it accomplishes this.

human circulatory system illustration by iStock/magicmine
Credit: iStock/magicmine

Zhang and his colleagues from Emory University School of Medicine and the University of Nottingham have identified, for the first time, the specific structural element of vWF that allows it to bind with platelets and initiate clotting. The team says that the specific unit, which they call the discontinuous auto-inhibitory module, or AIM, is a prime site for new drug development. The work is described in an article published last week in Nature Communications. The study was co-led by Lehigh bioengineering graduate student Wenpeng Cao.

“The AIM module allows the vWF molecule to remain non-reactive in normal circulating blood, and activates the vWF instantly upon bleeding,” says Zhang. “In our research, we identified that Caplacizumab works by binding the AIM region of vWF and enhancing the force threshold to mechanically remove vWF's auto-inhibitory structures, opening up a new avenue to the development of antithrombotic drugs targeting the AIM structures.”

Read the full story in the Lehigh University News Center.

Story by Lori Friedman

X. Frank Zhang

X. Frank Zhang, associate professor, Department of Bioengineering