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Scientists’ Discovery Of Blood Clotting Mechanism Could Lead To New Antithrombotic Drugs

Discussion in 'Hematology' started by Mahmoud Abudeif, Apr 29, 2021.

  1. Mahmoud Abudeif

    Mahmoud Abudeif Golden Member

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    Under normal healthy circulation, the von Willebrand Factor (vWF) maintains itself. Large, mysterious glycoproteins move through the blood, swell tightly, and their reaction sites are not exposed. However, when severe bleeding occurs, it begins to move and begins the coagulation process.

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

    According to X. Frankchan, an associate professor of bioengineering at Lehigh University, there is only one FDA-approved drug to target vWF and treat thrombosis or excessive blood coagulation disorders. It works by binding to vWF and blocking the binding to platelets. But no one understands the specific mechanism behind how it achieves this.

    So far, Zhang and his colleagues at Emory University School of Medicine and the University of Nottingham have identified for the first time certain structural elements of vWF that allow them to bind to platelets and initiate coagulation. The team states that a particular unit, called the Discontinuous Automatic Suppression Module (AIM), is the main site for new drug development.This work is mentioned in an article published last week Nature Communications, “Activation of the von Will brand factor through the mechanical deployment of its discontinuous self-suppressing module.”

    “The AIM module keeps vWF molecules non-reactive in normal circulating blood and activates vWF as soon as it bleeds,” Zhang said. “In our study, coupleriszumab binds to the AIM region of vWF, raises the force threshold and mechanically removes the self-suppressing structure of vWF, leading to the development of antithrombotic drugs that target the AIM structure. I’ve confirmed that it works by opening a new path. “

    An essential feature of vWF is that it remains non-reactive to platelets most of the time in the cycle, says Zhang.However, at the site of bleeding, vWF can be activated and achieved almost instantly. platelet Adhesions and thrombus formation. In this study, the team identified the structural element AIM around a portion of vWF called the A1 domain that is involved in platelet binding.

    “In normal circulating blood, AIM wraps around A1 and prevents it from interacting with platelets, however. Binding site, blood The change in flow pattern provides enough fluid force to stretch the AIM and pull it away from the A1, allowing the A1 to grab the platelets at the bleeding site. “

    Zhang, who has been studying vWF for years, specializes in single molecular force spectroscopy and mechanical sensing, or how cells respond to mechanical stimuli.He uses a special tool called Optical tweezers, Focusing laser beam is used to apply force to a small object as small as a single molecule.

    “Optical tweezers can grab small objects,” explains Zhang. “At the same time as grabbing vWF, we will see how the shape of the protein changes by applying force, and how the protein is activated when mechanical perturbation or mechanical force is generated. I will. “

    Prior to conducting the investigation, Zhang said the team suspected that they would find a self-restraint module based on a previous investigation by Emory University co-author Renhao Li.

    “But I didn’t expect this inhibitory module to play such an important role in vWF,” says Zhang. “It not only regulates vWF activation for platelet interactions, but also plays a role in causing several types of von Willebrand disease, a hereditary hemorrhagic disease that affects 1 percent of the population.”

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