Too much clot  pg. 3

Powerful platelets

In the early 1960s, the landmark epidemiological study conducted in Framingham, Mass., pinpointed high blood pressure, smoking and high cholesterol as major risk factors for cardiovascular disease. Within a decade, coronary care units, angioplasty and open heart surgery had become the standard of care, and drugs had been developed to lower blood pressure and cholesterol levels.

But while blood pressure drugs and cholesterol-lowering statins remain a pharmaceutical cornerstone in the effort to prevent heart attacks and strokes, “non-traditional” treatments may be equally as important among people with diabetes and obesity. Vaughan believes these people may have “a special environment in their arterial vasculature that promotes cardiovascular complications.”

One of the key players is the platelet—the disc-shaped element produced by the bone marrow that promotes blood clotting. While it does not have a nucleus, and therefore is not a cell, it is bristling with receptors, enzymes and other factors that allow it respond to—and powerfully influence—its environment.

Among them:

-- Collagen receptors, notably alpha 2, beta 1 integrin and glycoprotein VI, which enable platelets to attach to exposed collagen at the site of a tear in the blood vessel lining; and

-- Protease activated receptors (PARs), which, when activated by thrombin, trigger the aggregation or clumping of other platelets into the clot.

“When platelets encounter collagen, they don’t just stick to it; they are stimulated to form aggregates,” says Santoro, whose lab at Washington University in St. Louis discovered the alpha 2, beta 1 integrin collagen receptor in 1990. “It is the first component of blood clotting.”

The platelets of patients with type 2 diabetes have been found to “over-express” the integrin receptor. As a result, they may bind more readily to exposed collagen, thereby increasing the clotting risk.

This idea is supported by a mouse model engineered by Santoro, Mary Zutter, M.D., and their colleagues in 2002, the year before they moved their lab to Vanderbilt. The animals, which lack the integrin gene, exhibit a “profound deficit” in platelet adhesion to collagen.

Zutter, who directs the Vanderbilt Division of Hematopathology, is continuing her efforts to model the mechanism of collagen binding, while Santoro and others in his lab are conducting studies in humans to better understand the genetics of receptor over-expression.

Meanwhile, Heidi Hamm, Ph.D., chair of Pharmacology at Vanderbilt, is trying to understand why the platelets of people with type 2 diabetes seem to be “hypersensitive” to other clotting stimuli, including thrombin. She is focusing on the thrombin receptors, G protein-coupled PAR1 and PAR4.

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