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Sepsis buster

Receptor helps clears blood-clotting factors

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3:22pm, May 18, 2008
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For years the Ashwell receptor has been the Paris Hilton of the liver — famous for being famous — but now researchers have discovered that the receptor has talent.

Ashwell receptors are important for clearing blood-clotting factors, including platelets and von Willebrand factor, during sepsis, an infection of the blood, a team of researchers report in the May 18 Nature Medicine. The discovery solves a decades-old mystery about the receptor’s function and may dramatically change treatment for life-threatening sepsis cases.

“People have been wondering for almost 40 years ‘what does this receptor do?’” says Ajit Varki, a physician-scientist specializing in glycobiology at the University of California, San Diego.

Biochemist Gilbert Ashwell discovered the receptor in the 1970s. It is the first sugar-binding receptor ever discovered. Scientists call such sugar-binders lectins.

Most proteins in the body have sugar chains, called glycans, attached to them. Ashwell showed that the receptor bearing his name could latch onto proteins that lack a component of the sugar chain called sialic acid — termed asialoglycoproteins — and clear them from the body.

But to everyone’s great surprise, mice genetically engineered to lack the receptor were perfectly healthy, says Varki, who was not involved in the new research. UC San Diego researchers Jamey Marth and Victor Nizet led the research and discovered that the Ashwell receptor helps mice survive a serious complication of sepsis. Mice lacking the receptor die of sepsis more often than mice with the receptor.

Sepsis results when bacteria or other organisms infect the blood. The immune system spirals out of control, setting off a storm of inflammation, which can damage organs.

One sign that a patient in sepsis is likely to have a poor prognosis is a drop in the number of platelets, blood cells that help coagulate and clot the blood. Platelets are necessary for wound healing. Clotting blocks the blood supply to organs and uses up coagulation factors so that patients are susceptible to internal bleeding. About 20 to 50 percent of people who die of sepsis are killed by complications caused by overactive coagulation.

Doctors have always assumed that platelets and another clotting protein called von Willebrand factor were consumed by clots caused by bacteria. “One of the only treatments we have for sepsis, other than antibiotics, is to replace clotting factors,” says Nizet, an infectious disease expert.

But the new research shows that the Ashwell receptor clears the coagulation factors as a sepsis defense mechanism. The receptor drops platelet levels to a third of normal levels when an animal has a septic infection with Streptococcus pneumoniae, one of the leading causes of pneumonia, ear infections, sinus infections and sepsis worldwide.

The bacteria produce an enzyme called neuraminidase or sialidase, which clips sialic acid off of proteins. The enzyme helps the bacterium slip in and out of host cells, but the new results indicate that the enzyme might also help the bacterium keep its host alive, says Marth, a Howard Hughes investigator specializing in glycobiology.

The receptor is likely to be important in dealing with sepsis from several different kinds of bacteria, especially those that make sialic acid–clipping enzymes, Varki says.

These results call into question whether giving platelets in response to the low platelet count of sepsis, known as thrombocytopenia, is a good idea. “The data that would suggest it is advantageous should be looked at carefully,” Marth says.

Marth and Nizet’s group is exploring whether giving people with sepsis infusions of sialidase early in the infection could improve outcomes.

“If we can induce, engage and enhance the Ashwell receptor, we may be able to improve survival of people with sepsis,” Marth says.

The new study is “provocative,” says J. Perren Cobb, a trauma expert who directs the Center for Critical Illness and Health Engineering at WashingtonUniversity in St. Louis. But therapies that work well for mice translate to human treatments about only half the time, he points out. Doctors must also get better at classifying sepsis patients to learn who has the best chance of benefiting from the new approaches that Marth and his colleagues propose.

And patients who are critically injured or have septic infection typically don’t get platelets until signs of bleeding appear, Cobb says. “Our clinical practice is in line already with what the authors suggest.”


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