The association between obesity and pathologic coagulation has been well established. In the current work with mice, investigators believe they have found the link between obesity and blood clot formation-- leptin.

"Our results suggest that clot formation begins with some type of interaction between leptin and the leptin receptor on platelets" says Daniel T. Eitzman, M.D., a coauthor of the study.

Learning how to block this leptin-receptor interaction could help prevent myocardial infarctions and ischemic strokes in people who are either obese or overweight, conditions that affect half of all American adults.

Although leptin certainly plays a major role, Eitzman emphasizes that leptin may not be the only factor involved. "The link between obesity and cardiovascular disease is very complex, and there is much we don't know about how other blood clotting factors are regulated in obesity," he says.

Eitzman's original research goal was to study how obesity affects blood clot formation. He decided to use the fattest laboratory mice he could find -- a strain of mice that do not have the gene required to produce leptin.

When Eitzman began his experiments, the first results were surprising. Contrary to his expectations, leptin-deficient obese mice took nearly twice as long to form blood clots as normal mice (average of 75.2 minutes and 42.2 minutes, respectively). Eitzman repeated the experiment with a strain of obese mice that did not have the gene for the leptin receptor. These mice also took an abnormally long time to clot (68.6 minutes).

"Finally we tried injecting the mice with leptin, and that's when clotting times in the leptin-deficient mice dropped to normal [41.8 minutes]," said Eitzman. "That's when we first knew that leptin was the critical factor. To confirm our results, we transplanted bone marrow from leptin-deficient to normal mice. When the transplanted bone marrow began producing platelets without the leptin receptor, clotting time in the normal mice was prolonged significantly."

Recent research by other scientists found evidence for leptin's role in human blood clotting. Results from the West of Scotland Coronary Prevention Study, published in the December 2001 issue of Circulation, showed that high levels of leptin were an independent risk factor for cardiovascular thrombotic events, such as myocardial infarctions and ischemic strokes, in 1,160 men enrolled in the prospective study.

"We suspect that the more leptin in blood plasma, the higher the risk of forming blood clots, but we haven't quantified the relationship yet," Eitzman says. "We know that losing weight lowers the amount of leptin in your bloodstream, however. So for now diet and exercise remain the best way to prevent blood clots and the strokes and heart attacks they cause."

Eitzman and his research team also are studying the relation between leptin and insulin sensitivity to try to discover why diabetics have a higher-than-normal risk of blood clots.