Viagra deaths explained by new understanding of platelet clumping

Incidents of heart attack and stroke, some fatal, in a small number of men taking the drug Viagra have remained a puzzle. After all, Viagra, commonly prescribed for erectile dysfunction, was originally developed to prevent these conditions — not only by dilating blood vessels but also by stopping platelets in the blood from clumping.

In fact, the drug does just the opposite, according to researchers at the University of Illinois at Chicago College of Medicine. They found that Viagra, by elevating levels of a compound in cells called cyclic guanosine monophosphate, or cGMP, actually encourages platelets to aggregate.

The study, to be published in the Jan. 10 issue of the scientific journal Cell, amends 20 years of scientific claims that cGMP acts to prevent platelet aggregation.

While platelet aggregation helps minimize the loss of blood when injury occurs, it can also lead to clotting that blocks a blood vessel — a life-threatening condition called thrombosis that can cause heart attack and stroke.

“Viagra, by itself, probably is not sufficient to cause a heart attack in healthy people, but our research suggests that it may present a risk for patients with preexisting conditions such as atherosclerosis,” said Xiaoping Du, associate professor of pharmacology and the study’s lead author.

Du said he and his coworkers had not set out to investigate the cause of fatalities in Viagra patients when they began their research about five years ago. Rather, as a basic research scientist, he was hoping to illuminate the highly complex series of molecular steps that control platelet aggregation.

Platelets are disk-shaped cells that freely circulate in the blood. When a blood vessel is injured, the platelets form sticky surfaces, adhering to one another and to the damaged area to plug the hole.

Using recombinant DNA techniques, the researchers forced standard laboratory cells to manufacture two proteins key to platelet aggregation: one that helps the platelets clump together and stick to the surface of broken blood vessels, and another that activates the first. The genetic manipulation enabled the researchers to isolate and study the molecules that trigger these proteins.

Du focused on PKG, or cGMP-dependent protein kinase.

“It was accepted knowledge that cGMP, by stimulating PKG-catalyzed reactions in platelets, inhibits their clumping,” said Du. To his astonishment, he and his colleagues found otherwise.

“When we put PKG into the recombinant cells, we found that we actually made the cells more adherent,” Du said.

The results were so surprising that the researchers wondered whether there was something special about the laboratory cells that made them react differently. But tests in mouse and human platelets yielded the same results. Moreover, platelets from mice incapable of manufacturing PKG failed to aggregate as well as platelets from normal mice.

Reconciling their findings with earlier scientific evidence that cGMP inhibits platelet aggregation, the UIC researchers believe that cGMP initially causes platelets to clump to seal a wound, but later reverses to stop an excessive buildup of cells that might block a blood vessel. If a person were at risk of thrombosis — if, for instance, a damaged blood vessel were already narrowed — even the initial accumulation of platelets could be sufficient to cause a problem.

Since Viagra is known to work by inhibiting an enzyme that breaks down cGMP, and hence raises its level, Du and his colleagues tested the drug on platelets taken from normal donors. Alone, Viagra did not promote platelet aggregation, but it did so in the presence of a small amount of other compounds typically present when a blood vessel is damaged. In fact, Viagra caused the cells to clump at concentrations well below those achieved in patients prescribed the drug for erectile dysfunction.

An estimated 16 million men worldwide have taken Viagra. According to data in the Journal of the American Medical Association, 564 deaths were reported as of July 1999.

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In addition to Du, other UIC researchers involved in the study were Zhenyi Li, Xiaodong Xi, Minyi Gu and Richard Ye.

The study was supported by the National Institutes of Health and the American Heart Association.