Plant Flavonoids May Yield a New Generation of Drugs to Prevent Blood Clots

Chemical compounds that block the activity of the enzyme protein disulfide isomerase (PDI) are being considered for development into drugs to prevent the formation of blood clots (thrombosis).

Investigators at Harvard Medical School (Boston, MA, USA) have been searching for compounds with antithrombotic potential for use in therapy for medical disorders caused by blood clots such as stroke, heart attack, deep venous thrombosis, and pulmonary embolism.

The investigators used high-throughput screening techniques to search for compounds able to block PDI’s oxidoreductase enzyme activity, since PDI had recently been shown to participate in thrombus formation.

Results published in the May 8, 2012, online edition of the Journal of Clinical Investigation revealed that after screening more than 5,000 compounds, they had identified quercetin-3-rutinoside (rutin) as having significant anti-PDI properties. Rutin, which is a bioflavonoid found in a wide range of fruits and vegetables and is sold as an over-the-counter dietary supplement, was shown in cellular assays to inhibit aggregation of human and mouse platelets and endothelial cell–mediated fibrin generation in human endothelial cells. That rutin blocked thrombus formation in vivo by inhibiting PDI was confirmed by experiments that showed that infusion of recombinant PDI reversed its antithrombotic effect. Rutin’s antithrombotic activity was found to be due to blocking of extracellular (secreted) PDI and not the enzyme located in cellular cytoplasm.

“This was a transformative and unanticipated finding because it identified, for the first time, that PDI is secreted from cells in a live animal and is a potential target for preventing thrombosis,” said senior author Dr. Robert Flaumenhaft, associate professor of medicine at Harvard Medical School. “Rutin proved to be the most potently antithrombotic compound that we ever tested in this model. Clots occur in both arteries and in veins. Clots in arteries are platelet-rich, while those in veins are fibrin-rich. This discovery suggests that a single agent can treat and prevent both types of clots.”

“A safe and inexpensive drug that could reduce recurrent clots could help save thousands of lives,” said Dr. Flaumenhaft. “These preclinical trials provide proof of principle that PDI is an important therapeutic target for antithrombotic therapy, and because the FDA has already established that rutin is safe, we are poised to expeditiously test this idea in a clinical trial, without the time and expense required to establish the safety of a new drug.”

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