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New Grant Awarded to Study Mechanisms of Clotting

Published on December 21, 2018 in Cornerstone Blog · Last updated 4 months 2 weeks ago


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Thrombosis — the abnormal, life-threatening blood clots that form in the artery or vein — does not discriminate. Young. Old. Rich. Poor. Gender. Race. Ethnicity. We’re all in this together. We’re all susceptible. Some more so than others.

Up to 900,000 people in the U.S. are affected by blood clots each year; 100,000 will die, which is greater than the total number of people who lose their lives each year to AIDS, breast cancer, and motor vehicle crashes combined.

Enter Sriram Krishnaswamy, PhD, a researcher at Children’s Hospital of Philadelphia and professor of Pediatrics at the Perelman School of Medicine of University of Pennsylvania, with his recently awarded five-year Program Project Grant “Hemostasis and Thrombosis: Chemistry, Biology and Physiology” from the National Heart, Lung, and Blood Institute (NHLBI). He and his multidisciplinary group of researchers will use this grant to investigate how blood coagulates.

Mechanistic Aspects of Coagulation

“The problem with too much clotting is by far one of the most staggering medical issues in the Western world,” Dr. Krishnaswamy said. “It’s the largest cost — related to hospitalization and loss of life — of any disease out there. Like any biological process that actually contributes to disease, you need to understand what’s going on before you can potentially treat it. And treating it is a multi-billion dollar market for drug makers. Our goal is to use innovative approaches — multidisciplinary approaches — to try to understand the basic mechanisms by which blood clots.”

Thrombosis affects so many other diseases, which in turn affects so many people. For example, too much clotting is a major cause of morbidity and mortality in cancer patients, and it can cause life-threatening problems for coronary care patients treated with cardiac assist devices.

This condition is often thought of as an old person’s disease, but not necessarily so, Dr. Krishnaswamy said. With a variety of childhood disorders requiring the use of catheters or central lines for infusion therapy, thrombosis is problematic among the younger population too. So understanding thrombosis and ultimately finding a safe treatment for it, will have a major impact on healthcare.

Many of today’s drug approaches used to modulate or reduce excessive clotting require careful monitoring, according to Dr. Krishnaswamy. If the medication is dosed incorrectly, excessive bleeding may occur, or the drug may not inhibit thrombosis effectively.

“It’s a critical balancing act between clotting and bleeding,” Dr. Krishnaswamy said. “The newer drugs are supposedly less problematic, but they have not been developed in an imaginative way.”

The goals of Dr. Krishnaswamy and colleagues is to use a multidisciplinary approach to look at the mechanisms of clotting, figure out how to modulate it in a better way than current drugs, and, ultimately, reveal new approaches for the treatment of human diseases.

The A Team

His team of investigators, including Rodney Camire, PhD, professor of Pediatrics in the Perelman School of Medicine at Penn and member of the Division of Hematology and Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP; Valder Arruda, MD, PhD, researcher in CHOP’s Division of Hematology and associate professor of Pediatrics at Penn; Timothy Stalker, PhD, research assistant professor of Medicine at Penn: and Bruce Sullenger, PhD, of Duke University, has been working together since 2003.

“This is one of the most concerted group efforts, perhaps in the world but certainly in the United States, where there are so many investigators working together on mechanistic aspects of coagulation,” Dr.  Krishnaswamy said.

The new grant builds on a study his group conducted and published results in the June 2018 issue of Nature Biotechnology. The paper “Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass” explains how they were looking to improve the activity of an alternative anticoagulant to the standard one used for cardiopulmonary bypass (CPB) surgery. The standard, unfractionated heparin (UFH), carries a risk of postoperative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated (decrease or low number of platelets) antibodies. By combining the protein (aptamer) that binds to a specific target molecule with the existing catalytic-site directed small molecule drugs, clot formation was prevented as effectively as UFH in human blood that was circulated in a model that mimicked CPB, while avoiding life-threatening side effects of UFH.

“We also developed an approach to instantly reverse the anticoagulant effects,” he said with the snap of his fingers. “Our results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone — and we accidentally revealed the strategy for creating a novel compound along the way.”

Research under the new grant is focused on using “X-ray structures of these proteins to make novel findings related to function,” Dr. Krishnaswamy said. “So the structural biology is new. It also has a component of trying to understand the enzymes and cofactor that are involved in hemophilia. We’re really only interested in how these things work. For us, that’s what the interest is — and ultimately to develop new approaches for treating human diseases.”

World Thrombosis Day

One in four people worldwide are dying from conditions caused by thrombosis, but despite its prevalence, the life-threatening disease isn’t on most people’s radar. Get to know the signs and symptoms, and be sure to mark your 2019 calendars for Oct. 13, World Thrombosis Day.