Researchers find a link between a liver receptor and blood clotting.

Platelets and red blood cells clump together to form a blood clot, one dangerous consequence of sepsis.

One of the most deadly consequences of an infection is sepsis—a drastic, full-body response characterized by inflammation and blood clotting.

A study led by HHMI investigator Jamey D. Marth of the University of California, San Diego, reveals that a protein whose function has mystified scientists for decades helps protect against this extreme response.

The protein—a receptor named after biochemist Gilbert Ashwell—coats liver cells in vertebrates (organisms with a backbone), and binds to a specific type of glycoprotein. But its role during health or illness had not been defined. Mice engineered to lack the receptor appeared healthy.

Marth's team traced the origin of the receptors' function by first showing that a change in that specific glycoprotein decreases platelets in the blood. Marth realized that the pathogen Streptococcus pneumonia also causes the same glycoprotein change, outside of the bloodstream, on its way to infecting cells.

To figure out whether there was a link between the Ashwell receptor and the pathogen, the researchers infected normal mice and those lacking the receptor with S. pneumonia. They saw that the bacteria caused glycoprotein alterations in two factors that lead to blood clotting—von Willebrand Factor and platelets. The Ashwell receptors then recognized the modified glycoproteins and signaled the liver to remove them from circulation.

Mice without Ashwell receptors could not remove these coagulation factors and underwent more severe clotting and tissue damage, which increased the likelihood of death.

Clinicians have assumed that a low platelet count during sepsis was the result of platelets being used up by the extreme blood clotting, but Marth's research suggests something different.

“It's an adaptive response by the liver,” he says, “enabled by the Ashwell receptors.”

The finding, published in the June 2008 issue of Nature Medicine, clears up many questions about the Ashwell receptor, but raises others, says Marth. “Does its protective response extend to other pathogens? Can it be employed to increase the chance of human survival in severe sepsis?”

Photo: Steve Gschmeissner / Photo Researchers, Inc.