Too much clot  pg. 6

In the meantime, drugs that specifically inhibit PAI-1 are being developed. Vaughan predicts that patients at risk of heart attack in the future may have their PAI-1 levels checked, just as they are currently screened for high levels of cholesterol.

The peroxide connection

The anti-coagulant system also is a delicate balance that can easily get out of whack.

Prostacyclin’s ability to prevent platelet clumping, for example, is matched by thromboxane, which does exactly the opposite—it stimulates platelet aggregation and constricts blood vessels, thereby limiting blood flow.

Prostacyclin and thromboxane are members of a family of lipid molecules that include the prostaglandins, and which are involved in everything from inflammation to smooth muscle constriction and blood pressure regulation. They are generated by the cyclooxygenase (COX) enzymes.

Thromboxane is produced in platelets by the COX-1 enzyme, while prostacyclin is a product of the COX-2 enzyme acting in the blood vessel lining. Both COX enzymes are inhibited by aspirin. During the past 30 years, John Oates, M.D., founding director of Vanderbilt’s Division of Clinical Pharmacology, has helped define the role of these critical compounds in high blood pressure, cancer and other disorders.

In the mid-1980s, for example, Oates and Garret FitzGerald, M.D., currently chair of Pharmacology at the University of Pennsylvania, found that low doses of aspirin inhibited thromboxane production without unduly lowering levels of prostacyclin. Their work helped form the basis for the use of low-dose aspirin to reduce clotting risk in heart patients.

People with diabetes, however, seem to be “resistant” to aspirin’s protective effect. Oates, who is leading a fourth major project in the SCCOR, believes this may have something to do with peroxide.

The COX enzymes actually have two binding sites: one for arachidonic acid, the fatty acid precursor to prostacyclin, thromboxane and the like; and the other for peroxide.

Peroxide is a ubiquitous cellular messenger that in this case activates the COX enzymes like the starter of a car. It is produced when fats in the body are exposed to oxygen (lipid peroxidation)—the same thing that causes butter to go rancid.

Too much peroxide, however, will overcome aspirin’s ability to block COX activity. “We’ve found that when the enzyme is exposed to peroxide, aspirin binds less readily,” Oates says.

In 1990, Jason Morrow, M.D., Jackson Roberts, M.D., and their colleagues at Vanderbilt discovered a series of bioactive prostaglandin-like compounds they called isoprostanes.

Produced by lipid peroxidation, isoprostanes are now recognized as the gold standard to measure oxidative stress. Smokers have high levels of isoprostanes. So do people who are obese or who have high levels of low-density lipoprotein, the “bad” form of cholesterol, in their bloodstream.

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