Too much clot  pg. 7

Another unhealthy consequence of too much fat thus may be aspirin resistance.

Genetics also may play a role. “It’s conceivable there may be a polymorphism (mutation) in the COX 1 gene related to aspirin resistance,” Oates says. “Once we identify groups of people who are susceptible to aspirin resistance we can devise all kinds of strategies” to reverse it.

Paradoxical effects

People with high levels of fats and glucose in their bloodstream are not the only ones at increased risk of dying from a clot—so are people with hypoglycemia—not enough glucose to satisfy the body’s energy needs.

Hypoglycemia is the complication most feared by patients with diabetes who must inject insulin periodically to lower their blood glucose levels, Davis says. Unless recognized and treated immediately, severe hypoglycemia can lead to convulsions, unconsciousness and, occasionally, death.

Several reports have linked severe hypoglycemia to serious cardiac and cerebral thrombotic events—heart attacks and strokes. Corticosteroids—hormones that regulate carbohydrate and fat metabolism—may be involved.

Davis and his colleagues helped pioneer methods for teasing out the complex interactions between insulin, corticosteroids and other factors that regulate the supply and delivery of glucose and other fuels required by body tissues.

Recently they found that experimentally induced hypoglycemia resulted in significantly increased levels of PAI-1 in normal subjects. So did administration of drugs that mimic the actions of corticosteroids.

One of those hormones, cortisol, is secreted by the adrenal glands in response to psychological or physical stress, including hypoglycemia. Acting through corticosteroid receptors, it stimulates release of glucose by the liver. But it may also increase the risk of clotting.

Davis and his colleagues will try to find out whether activation of a specific corticosteroid receptor is responsible for hypoglycemia’s pro-thrombotic effect.

“This information is urgently needed,” he says, “bearing in mind… that increasing numbers of (people with) type 2 diabetes are experiencing hypoglycemia due to the move towards intensive metabolic control.”

While the Vanderbilt researchers say they are not out to discover new drugs, their work could lead to new avenues for drug discovery.

For example, Hamm’s research could lead to a more effective way to block thrombin.

There is already a thrombin blocker on the market, bivalirudin, which binds directly to the circulating enzyme. The drug is given intravenously to patients undergoing coronary procedures such as angioplasty. The goal is to prevent clotting without thinning the blood too much.

Bivalirudin is superior to the classic blood thinner heparin in preventing bleeding complications during coronary procedures, but it is no better in preventing subsequent heart attacks or deaths. That may be because the drug also inhibits the paradoxical anti-coagulant properties that thrombin exhibits at low concentrations.

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