Viagra Deaths Explained by New Understanding of Platelet Clumping

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Viagra Deaths Explained by New Understanding of Platelet Clumping

Thu Jan 9, 7:00 PM ET

 

Source: University of Illinois at Chicago

 

 

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 (news - web

sites), 564 deaths were reported as of July 1999.

 

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 (news -

web sites) and the American Heart Association (news - web sites).

 

 

2003 Acurian Inc. .

 

 

 

 

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