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February 16, 2009
Blocking toxic effects boosts clot-buster safety

By Quinn Eastman

Since the introduction of the life-saving clot-busting drug tPA more than a decade ago, evidence has been accumulating that it can be a double-edged sword. Although tPA (tissue-type plasminogen activator) remains the only FDA-approved treatment for acute stroke, it can also contribute to inflammation and brain cell damage.

“tPA is a protein released naturally by the body in response to a blood clot,” neurologist Manuel Yepes says. “But it’s clearly not just dissolving the clot.”

Research by Yepes and his colleagues suggests that blocking tPA’s toxic effects could make it safer and allow doctors to use it more often on patients experiencing a stroke. The results were published online Jan. 15 by the American Journal of Pathology.

Yepes’ team is testing strategies for blocking LRP1, a molecule that transmits inflammation signals triggered by tPA. They have shown that in mice, genetically removing LRP1 from brain cells called microglia softens tPA’s impact on the brain.

They are now testing a natural inhibitor of LRP1 called RAP in the laboratory. Co-treating or even pre-treating stroke patients with RAP might soften tPA’s effects.

Doctors in community hospitals can often be reluctant to administer tPA to patients who appear to be having a stroke, because tPA has been shown to increase the risk of bleeding in the brain, Yepes said.