Stop that clot: proteins uncovered.

Two proteins with previously unknown roles in the complex series of chemical reactions that result in blood clotting are slowly revealing their workings to researchers. Deficiencies in these proteins have now been found to cause excess clotting, and further work with them may result in a way to prevent blood clots where they're not wanted, Charles T. Esmon of the University of Oklahoma in Oklahoma City said at last week's American Heart Association Science Writers Forum in Monterey, Calif.

The body suffers minute internal rips and tears on a daily basis, and usually seals them up quietly with small clots. But in some people an out-of-kilter clotting mechanism forms clots that break off. A wandering clot can cause great pain if it lodges in a leg, and it can cause death if it lodges in the lung. Esmon and Oklahoma co-worker Philip C. Comp have identified a series of such patients--about 50 so far--who are deficient in one of the two recently identified proteins, called protein C. And they have described another six people whose blood also clots too readily with a deficiency in a necessary cofactor of protein C called protein S.

Discovery of the functions of proteins C and S by observing their activity in animal organs explains a curious but vital phenomenon: While blood in a test tube becomes a solid clot within a few minutes, injured people form only enough of a clot to squelch bleeding. The reason, it turns out, lies in a factor missing in the test tube --the blood vessel wall.

"When the blood is in contact with the blood vessel, part of the emphasis to form a clot is switched off," explains Esmon. The circulatory system uses its own complicated feedback system to shut down a long sequence of events called the clotting cascade that is set off when a blood vessel wall breaks. The last step in the cascade, the final "on switch," is the protein thrombin. And while thrombin causes clotting, it also flips on a second cascade that halts the process.

"Thrombin has a role in clotting but also serves as an anticoagulant," Esmon explains. It activates thrombomodulin, a protein on the blood vessel wall that turns on protein C, which, with the help of protein S, then shuts off clotting by interfering with previous steps in the process. Since without the blood vessel-linked thrombomodulin there is primarily inactive protein C in the test tube, that blood continues to clot unfettered, whereas it would be halted in the body.

Esmon isn't willing to predict how many unexplained cases of thrombosis are due to a deficiency in protein C or protein S, but he believes that the problem is "not uncommon." Blood drawn from healthy individuals contains no thrombomodulin and thus little or no activated protein C, making it appear no different from deficient blood. But knowing how the system works, the researchers can not test for the inactive form and thus identify people with anomalies.

Understanding the two proteins may have implications for people with normal levels of the substances as well. The tendency to "throw" blood clots is a common and occasionally fatal postsurgical problem, and the blood-thinning methods currently used to prevent it carry the threat of excessive bleeding. The clotting tendency may be due to the average reduction in protein C to 60 percent of normal, a level similar to that in people with disease-related deficiencies. As a result of surgery the protein may be used up faster than it is produced, or surgery may slow synthesis of the molecule. Whatever the cause, providing protein C postoperatively may safely prevent clot formation, Esmon says.

The gene for the protein has recently been cloned via genetic engineering, a feat that should speed up research. As for therapy, Esmon and Comp are working out a way to provide protein C to deficient pateints; they expect to report on its use within three years. If all works out, Esmon says, "it may eventually provide a unique and much more specific approach to controlling coagulation." But, he says, given human-activated protein C's failure to disolve clots in monkeys, the protein holds more promise as a clot preventer than as a clot buster.