New evidence links inflammation to venous disease

November 18, 2003

ANN ARBOR, MI - For a medical disorder affecting more than 250,000 Americans each year, researchers don't know much more today about what causes blood clots in veins than they did over 100 years ago. But deep vein thromboses or DVTs are a serious health problem, especially in the elderly. When blood clots form in deep leg veins, they can permanently damage the venous system or even be fatal, if a blood clot, or pulmonary embolism, travels to the lungs.

Until recently, DVT was thought to be solely a blood or vascular disorder. Now, scientists from the University of Michigan Medical School have discovered intriguing new evidence to support the idea that the development of blood clots in veins - just like blocked arteries in atherosclerosis - is an inflammatory process.

"When a blood clot develops in superficial veins of the leg - a condition called phlebitis - the redness and swelling associated with inflammation are visible," says Thomas W. Wakefield, M.D., a scientist and vascular surgeon in the U-M's Cardiovascular Center. "When a clot forms deep inside the leg, these signs are hidden, so physicians have rarely associated DVTs with inflammation."

Working with Daniel D. Myers, DVM, MPH, an assistant professor of vascular surgery and animal medicine in the U-M Medical School, Wakefield is trying to figure out exactly what happens inside veins when a blood clot develops. In a study published in the November 2003 issue of The Journal of Vascular Surgery, he and Myers report that inflammatory molecules and immune system cells play a major role in the process.

The U-M scientists used four types of mice in the study. The first was a strain of genetically engineered mice developed by co-author Denisa D. Wagner, Ph.D, a professor of pathology at Harvard Medical School. A genetic mutation in these mice causes them to have abnormally high levels of a pro-inflammatory molecule called P-selectin circulating in their blood plasma. In previous studies, Wakefield has found that large amounts of P-selectin are expressed in the vein wall shortly after a blood clot starts to form.

A second group of mice lacked the gene required to produce P-selectin. A third group was unable to express either P-selectin or a related molecule called E-selectin. The fourth group consisted of normal controls. In all, 659 mice were involved in the research study.

Mice were surgically treated to induce thrombosis in the IVC - the major vein carrying blood from the lower body back to the heart. On the second and sixth day after surgery, U-M scientists measured the size and weight of blood clots in the IVC, examined the vein walls and took blood samples from mice in all four groups.

U-M scientists found that mice with the highest levels of P-selectin in their blood developed the largest venous blood clots and had more inflammatory cells in their vein walls. Blood from mice with high levels of P-selectin also contained microparticles - small fragments of cell membrane from degraded cells. Most of these microparticles came from immune system cells called leukocytes, but some were derived from blood platelets, which are responsible for clot initiation. Additionally, some may have come from endothelial cells lining vein walls.

"Our laboratory is the first to evaluate microparticle formation in a mouse model of DVT," Myers says. "We found that when P-selectin binds to its receptor, it seems to release these pro-coagulant microparticles, which accelerate the clot-forming process. Mice with more leukocyte-derived microparticles developed larger blood clots than mice with microparticles derived primarily from blood platelets."

Wakefield says the ultimate goal of his research is finding new ways to inhibit clot formation in his patients by using an anti-inflammatory approach, instead of relying on anticoagulants to treat DVT after it develops.

"All current blood-thinning medications can cause serious bleeding problems in patients, so there's a need for new treatment options," he says. "The more we understand about the mechanism of DVT formation, the better our chances of finding safer ways to treat it. Just stopping inflammation alone will not inhibit thrombosis. You have to target the interaction between inflammation and thrombosis, which is why we think P-selectin or leukocyte-derived microparticles would make good therapeutic targets."

In addition to research designed to understand the complex relationship between inflammation and thrombosis, Wakefield also is conducting clinical studies to see whether microparticles or P-selectin could be used as a diagnostic marker for DVT formation in patients.

"Right now, the gold standard for diagnosis of DVT is ultrasound," Wakefield says. "We have other diagnostic tests, but none of them are accurate enough to use on their own. You have to combine them with a test such as ultrasound, which is expensive and labor-intensive. Better markers would allow us to detect the early stages of DVT development and intervene before problems develop."

The study was funded by the National Institutes of Health and Wyeth Research of Cambridge, Mass. In addition to Denisa Wagner, Ph.D., a professor of pathology and member of the Center for Blood Research at Harvard University, other research collaborators included Robert G. Schaub, Ph.D., assistant vice president of cardiovascular and metabolic diseases, Wyeth Research; Anjali Kumar, Ph.D., director of pharmacology, Critical Therapeutics in Cambridge, Mass.; U-M research associates Angela Hawley, Diana Farris, Shirley Wrobleski; and Porama Thanaporn, a U-M medical student.
-end-
Reference: The Journal of Vascular Surgery: 38 (5), pp.1075-1089 (November 2003)

University of Michigan Health System

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