Jan. 14, 2003 DALLAS, Jan. 10 – A potent clot-busting substance originally extracted from the saliva of vampire bats may be used up to three times longer than the current stroke treatment window – without increasing the risk for additional brain damage, according to research reported in today's rapid access issue of Stroke: Journal of the American Heart Association.
The vampire bat saliva-derived clot buster is called Desmodus rotundus salivary plasminogen activator (DSPA) or desmoteplase. DSPA targets and destroys fibrin, the structural scaffold of blood clots, says senior author Robert Medcalf, Ph.D. NH & MRC senior research fellow at Monash University Department of Medicine at Box Hill Hospital in Victoria, Australia.
"When the vampire bat bites its victim, it secretes this powerful clot-dissolving (fibrinolytic) substance so that the victim's blood will keep flowing, allowing the bat to feed," Medcalf explains.
In the mid-1980s, Wolf-Dieter Schleuning, M.D., Ph.D., now chief scientific officer of the German biotechnological company PAION GmbH, found that the vampire bat enzyme was genetically related to the clot buster tissue plasminogen activator (t-PA) but was more potent. Medcalf and Schleuning were pioneers in the cloning and the study of gene expression of t-PA and were among the first scientists to spot its potential use for heart attack.
The only Food and Drug Administration-approved clot buster for treating ischemic stroke is intravenous recombinant tissue plasminogen activator, (rt-PA). Ischemic strokes are caused when a blood clot or series of clots block blood supply to the brain. rt-PA is administered to a small percentage of stroke patients because current protocols allow treatment only within three hours of stroke onset. Also, rt-PA has been shown to promote brain cell death in some animal studies.
The clot-busting activity of DSPA increases about 13,000-fold when exposed to fibrin. The activity of rt-PA increases only 72-fold when exposed to fibrin.
Researchers injected either DSPA or rt-PA into the brains of mice, then tracked the survival of brain cells. They discovered that while DSPA zeros in on fibrin, it had no affect on two brain receptors that can promote brain damage, Medcalf says. In contrast, rt-PA greatly enhanced the degree of brain cell death following receptor activation and may therefore be detrimental if it's delivered too long after stroke onset.
The highly fibrin-specific activity demonstrated by DSPA may be an important advantage over rt-PA. It is this single-minded clot-busting action that has stroke researchers especially intrigued because while rt-PA is effective at breaking up and dissolving clots, it must be given quickly – within just three hours of the onset of stroke symptoms. By contrast, Medcalf says DSPA could be a safe treatment option for a longer period since it has no detrimental effect on brain cells. The three-hour time window often allows insufficient time for patients to undergo imaging tests to determine that they have a true ischemic stroke before rt-PA can initiated, he says.
"This report provides data suggesting a potential advantage of a type of plasminogen activator derived from bat saliva over t-PA, the only FDA-approved treatment for selected patients with acute ischemic stroke," says Larry Goldstein, M.D., chairperson of the American Stroke Association Advisory Committee. "It needs to be understood that this study is limited to mice without stroke and focused only on toxicity. Whether this approach will prove either safe or efficacious in improving stroke outcomes requires further testing."
Goldstein is director of the Center for Cerebrovascular Disease at Duke University in Durham, N.C.
DSPA is being tested up to nine hours after stroke onset in human stroke patients in Europe, Asia and Australia. A U.S. study could begin this year, Schleuning says. Other co-authors are Gabriel T. Liberatore, Ph.D, André Samson; and Christopher Bladin, M.D.
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