The standard of care for treating strokes caused by blood clots involves the therapeutic infusion of tissue plasminogen activator (tPA), which can help dissolve the clots and restore blood flow. This thrombolytic treatment carries the risk of bleeding and swelling in the brain and must be administered within three hours from the start of the stroke, which sharply limits its clinical benefits.
Researchers at Joslin Diabetes Center have now demonstrated in animal models the potential of giving a drug that targets a coagulation factor in combination with tPA. The combination might improve stroke outcomes and increase the window of opportunity for the therapy. The study was reported online on January 27 in the journal Blood.
Drugs that target the proteins plasma kallikrein and factor XII, which promote coagulation, “may provide the opportunity to make tPA safer by reducing these complications and increasing its efficacy in opening blood vessels,” says Edward Feener, an HMS associate professor of medicine at Joslin and study co-author. About 800,000 people in the United States suffer a stroke each year, and about 87 percent of those strokes are ischemic, in which blood flow is blocked by a clot.
The research team first demonstrated that tPA boosts the activity of plasma kallikrein in both human and mouse plasma. They then looked at mouse models in which blood clots had been induced in the brain and then treated with tPA and a plasma kallikrein inhibitor. The animals that were genetically modified to produce lower amounts of plasma kallikrein showed significantly less bleeding, brain swelling, and damaged brain areas than control animals without a plasma kallikrein blockade.
The researchers traced the biological mechanisms by which tPA activates plasma kallikrein via factor XII. Plasma kallikrein is known to activate the kallikrein-kinin system, a pathway that has been implicated in stroke complications including brain swelling and the breakdown of the blood-brain barrier.
The U.S. Food and Drug Administration has approved a plasma kallikrein inhibitor for the treatment of hereditary angioedema. These new findings suggest additional potential therapeutic opportunities for plasma kallikrein inhibitors in thrombolytic therapy.
Image: Science Source