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Redesigned protein accelerates blood clotting
Date:12/22/2008

and heart attacks in otherwise healthy people. In patients with hemophilia, however, enhanced clotting is desirable. On the other hand, we have sought to change the protein's structure as little as possible, because the immune system is more likely to react the more we change it."

More Effective Without Drawing Notice

Blood clotting involves more than a dozen proteins known to take part in a cascade of chemical reactions inside blood vessels following injury, with each factor, or complex of factors, activating the next in the chain. Named for roman numerals, these clotting factors include factor VIII, which is modified slightly to form an active cofactor, VIIIa, and partners with factor IX to activate factor X. Factor X creates a burst of thrombin, which in turn generates fibrin, the sticky protein strands that form a web-like clot over damaged tissue.

As Fay's team gained a deeper understanding of Factor VIII's structure over 20 years, it gradually became clear how they could change it to make the protein more likely to drive clotting. In 2005, he and Wakabayashi published work showing that swapping out a naturally occurring glutamic acid with an alanine at a specific spot in the calcium binding site on factor VIII doubled its ability to bind with factor IX and increased clotting. Factor VIII has on its surface pocket-like chains of amino acids shaped to hold calcium, a metallic element that makes factor VIII better able to bind to factor IX.

While the past work increased the protein's activity (binding with factor IX), the current work dramatically increased the stability of factor VIII. In this context, stability is the ability of the protein to withstand the rigors of manufacturing and of exposure to the human blood stream. It must resist forces that would unravel it, or tear it apart, before it can have its therapeutic effect. Standard stability tests include exposing a protein to increased temperature (thermal
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Contact: Greg Williams
Greg_Williams@urmc.rochester.edu
585-275-3676
University of Rochester Medical Center
Source:Eurekalert

Page: 1 2 3 4

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