by Angela Spivey

ou’re walking down the street, and a few blood vessels break in, say, your knees. Within minutes, tiny blood clots form—but only in the precise area of those breaks. This process happens many times a day.

If your body doesn’t continuously make these tiny clots, you have hemophilia and bleed uncontrollably. Even more common is thrombosis—when clots spread too far or occur in the wrong places—which often leads to heart attacks.

How does your blood know when to flow and when to clot? The answer, say some researchers, is cells.

"Cells talk to one another," says Harold Roberts, professor of medicine. "It’s like they’ve got a telephone line between them." The cells do their "talking" through receptors, which are proteins that will bind only to another specific protein. When that binding happens, a change occurs in the cell. That change is known as a signal.

Roberts and his collaborators, Mac Monroe and Maureane Hoffman, have developed a textbook-changing model of how cells control blood clotting. Other Carolina researchers are studying the receptors involved in that control.

Cells haven’t always gotten this much attention. For 50 years, blood clotting has been thought to be controlled by 12 proteins called clotting factors. (For simplicity’s sake, most of the factors are referred to by a roman numeral.) The factors have been studied intensely, and researchers know for example, that if you’re missing factor VIII or IX, you have hemophilia.

Cells, on the other hand, have been widely thought of as just "bags of lipid," says Monroe, assistant professor of medicine. Lipids, which make up the membranes of cells, are molecules made of a water-soluble part and chains of fat. One lipid in particular, phosphatidylserine (PS), regulates one of the last steps in clotting. Some coagulation researchers still believe that cells are good for only one thing: to provide a surface containing PS where the clotting factors can assemble. And many researchers don’t use whole cells in their experiments. Instead they use synthetic lipid vesicles (small liquid-filled sacs) that contain PS.

"Cells are really messy," Monroe says. "You have to grow them or isolate them from someone." The thinking has often been if the synthetic vesicles serve the same purpose, then why bother with cells?

Monroe can understand that reasoning because he’s a biochemist, which means he is, in his own words, a control freak—he likes a nice, clean experiment that gives reliable results. But he also knows that in our bodies things aren’t always that simple. And if Monroe forgets, Roberts, a physician who regularly sees hemophilic and thrombotic patients, will remind him. And then there’s Maureane Hoffman. Now director of the Coagulation Laboratories and blood bank at the Durham Veterans Affairs Medical Center, Hoffman used to do research at Carolina and first got to know Roberts and Monroe when she began giving them platelets that were a waste product of her work. Of the three researchers, she knows the most about how cells work, and she makes sure the group's experiments take cells’ properties into account.

The three believe that the traditional model of blood clotting tells us a lot about how the clotting factors react with each other but that it downplays the role of cells too much. For one thing, the traditional model of coagulation doesn’t always jibe with what happens in our bodies. It doesn’t explain how clotting occurs in only the tiny place where a break occurs. Nor does it explain why the lack of factor IX causes hemophilia in humans. In a test tube with synthetic lipid vesicles, blood will clot without factor IX.

oberts, Hoffman, and Monroe work to design experiments that combine the control of biochemistry with the complexity of the human body. In their test tubes, they use whole cells such as human platelets, as well as the clotting factors. But not just one or two in isolation—a whole bunch together. "We know some of the important players, but biochemistry hasn’t looked at them in a complex," Hoffman says.

After nine years of research, the team has developed a model of blood coagulation that has begun appearing in new editions of Williams Hematology and the Oxford Textbook of Medicine. Instead of depicting coagulation as a "cascade" of reactions among the clotting factors, the new model shows clotting happening in three stages, all controlled by cells.

Next: "stick down here"

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