Scientists' discovery of blood clotting mechanism could lead to new antithrombotic drugs

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Under normal, healthy circulatory conditions, the von Willebrand factor (vWF) remains by itself. The large and mysterious glycoprotein moves tightly together through the blood, its reaction sites are not exposed. However, when significant bleeding occurs, it takes action and initiates the clotting process.

When it works properly, vWF helps stop bleeding and save lives. However, according to the Centers for Disease Control and Prevention (CDC), approximately 60,000 to 100,000 Americans die each year from thrombosis, a disorder characterized by too much clotting. Blood clots can cause a stroke or a heart attack.

According to X. Frank Zhang, associate professor in the Department of Bioengineering at Lehigh University, only one drug has been approved by the FDA to fight vWF and treat thrombosis or excessive blood clotting disorders, caplacizumab. It binds to vWF and blocks its binding to blood platelets. However, no one has understood the specific mechanism behind how this is achieved.

So far, Zhang and his colleagues at Emory University School of Medicine and the University of Nottingham have for the first time identified the specific structural element of vWF that enables it to attach to platelets and initiate clotting. The team says the specific unit they refer to as the discontinuous autoinhibitory module, or AIM, is a prime location for new drug development. The work is described in an article published last week in Nature Communications: “Activation of the von Willebrand factor by mechanical unfolding of its discontinuous autoinhibitory module.”

“The AIM module enables the vWF molecule to remain non-reactive in normally circulating blood and activates the vWF immediately after bleeding,” says Zhang. “In our research, we found that caplacizumab binds the AIM region of vWF and increases the force threshold to mechanically remove the autoinhibitory structures of vWF. This opens a new avenue for the development of antithrombotic drugs that target the AIM structures . “

A key characteristic of vWF is that it doesn’t respond to platelets most of the time in the bloodstream, says Zhang. At bleeding sites, however, vWF can be activated almost immediately to achieve platelet adhesion and blood clot formation. In this study, the team identified a structural element, AIM, that resides around the portion of the vWF, called the A1 domain, that is responsible for binding platelets.

“In normally circulating blood,” explains Zhang, “the AIM wraps around the A1, preventing the A1 from interacting with platelets. At the point of attachment, however, the change in blood flow pattern results in sufficient hydrodynamic force to stretch and pull the AIM away.” . ” from the A1 so that the A1 platelets can reach the bleeding site. “

Zhang, who has been working with vWF for years, specializes in single-molecule force spectroscopy and mechanosensors, or how cells react to mechanical stimuli. He uses a special tool called optical tweezers that uses a focused laser beam to apply force to objects as small as a single molecule.

“Optical tweezers can grip tiny objects,” explains Zhang. “We can grab the vWF and apply force at the same time to see how the protein changes shape, to see how the proteins are activated when there is a mechanical disturbance or a mechanical force.”

Zhang said that prior to conducting the study, the team suspected they had found an autoinhibitory module because co-author Renhao Li had previously conducted research at Emory.

“However, we did not expect this inhibition module to play such an important role in vWF,” says Zhang. “Not only does it control vWF activation for platelet interaction, but it also plays a role in causing some types of von Willebrand’s disease, an inherited bleeding disorder that affects one percent of the human population.”

A better understanding of the A2 domain of the von Willebrand factor

More information:
Nicholas A. Arce et al., Activation of the von Willebrand factor by mechanical unfolding of its discontinuous autoinhibitory module Nature Communications (2021). DOI: 10.1038 / s41467-021-22634-x Provided by Lehigh University

Quote: Scientists’ discovery of the mechanism of clotting could lead to new antithrombotic drugs (2021, April 28) on April 28, 2021 from .html

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