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These new findings, led by investigators at Beth Israel DeaconessMedical Center (BIDMC) and published in online in The Journal of Clinical Investigation (JCI), identify a novel strategy for preventing thrombosis, and help pavethe way for clinical testing of this popular flavonoid as a therapyfor the prevention and treatment of stroke and heart attack, aswell as deep venous thrombosis (DVT) and pulmonary embolism. "It's not always fully appreciated that the majority ofAmericans will die as the result of a blood clot in either theirheart or their brain," says senior author Robert Flaumenhaft,MD, PhD, an investigator in the Division of HemostasisandThrombosis at BIDMC and Associate Professor of Medicine atHarvard Medical School. "Approximately half of all morbidityand mortality in the United States can be attributed to heartattack or stroke." The study focused on protein disulfide isomerase (PDI) which isfound in all cells. Investigators in BIDMC's Division of Hemostasisand Thrombosis had previously shown that PDI is rapidly secretedfrom both platelets and endothelial cells during thrombosis, when aclot forms in a blood vessel, and that inhibition of PDI couldblock thrombosis in a mouse model. "This was a transformative and unanticipated finding becauseit identified, for the first time, that PDI is secreted from cellsin a live animal and is a potential target for preventingthrombosis," says Flaumenhaft. However, because intracellularPDI is necessary for the proper synthesis of proteins, thescientists had to identify a specific compound that could block thethrombosis-causing extracellular PDI -- without inhibiting theintracellular PDI. They began by conducting a high-throughput screen of a wide arrayof compounds to identify PDI inhibitors. Among the more than 5,000compounds that were screened, quercetin-3-rutinoside (rutin)emerged as the most potent agent. "Rutin was essentially thechampion compound," says Flaumenhaft. A bioflavonoid that is naturally found in many fruits, vegetablesand teas including onions, apples and citrus fruits, rutin is alsosold as an herbal supplement, having received a special designationfor safety from the U.S. Food and Drug Administration (FDA).Surprisingly, studies of the rutin molecule demonstrated that thesame part of the molecule that provides rutin with its ability toinhibit PDI also prevents the compound from enteringcells."That finding explained how this compound can be both apotent inhibitor of PDI and a safe food supplement," saysFlaumenhaft. "Our next questions were, 'Is this compoundanti-thrombotic? Can it prevent blood clots?'" The team went on to test rutin in a mouse model of thrombosis.Because they knew that humans would be taking rutin in pill form,they included studies in which the compound was administered orallyand determined that it successfully retained its anti-thromboticproperties when it was metabolized following oral ingestion. "Rutin proved to be the most potently anti-thrombotic compoundthat we ever tested in this model," says Flaumenhaft. Ofparticular note, rutin was shown to inhibit both plateletaccumulation and fibrin generation during thrombus formation."Clots occur in both arteries and in veins," explainsFlaumenhaft. "Clots in arteries are platelet-rich, while thosein veins are fibrin-rich. This discovery suggests that a singleagent can treat and prevent both types of clots." Even with the use of existing anti-clotting therapies, such asaspirin, clopidogrel (Plavix) and warfarin (Coumadin), each yearthere are approximately 400,000 recurrent episodes among patientswho previously experienced a stroke or heart attack, saysFlaumenhaft. "A safe and inexpensive drug that could reduce recurrent clotscould help save thousands of lives," he adds. "Thesepre-clinical trials provide proof-of-principle that PDI is animportant therapeutic target for anti-thrombotic therapy, andbecause the FDA has already established that rutin is safe, we arepoised to expeditiously test this idea in a clinical trial, withoutthe time and expense required to establish the safety of a newdrug." The original research that identified this mechanism as well as theidentification of PDI as a drug target of rutin was supportedprimarily by grants from the National Heart, Lung and BloodInstitute of the National Institutes of Health (NIH) and also fromthe American Heart Association. Additional support came from theEuropean Hematology Association-American Society of Hematology andthe Foundation for Women's Wellness. Study coauthors include BIDMC investigators Reema Jasuja (firstauthor), Freda H. Passam, Daniel R. Kennedy, Sarah H. Kim, Lottevan Hessem, Lin Lin, Sheryl R. Bowley, Sucharit S. Joshi, James R.Dilks, Bruce Furie and Barbara C. Furie, all of the Division ofHemostasis and Thrombosis. I am an expert from hydropower-turbine.com, while we provides the quality product, such as Axial Flow Pump Manufacturer , China Natural Gas Powered Generators, Francis Hydro Turbine,and more.
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