WU researchers to study blood-clotting disorders

Researchers at Washington University School of Medicine in St. Louis have received a $9 million grant to investigate blood-clotting disorders. From heart attacks and strokes to uncontrolled bleeding, clotting disorders cause more deaths each year in the United States than all types of cancer combined.

"Blood clots in veins and arteries remain one of the great killers," says principal investigator J. Evan Sadler, MD, PhD, professor of medicine and chief of the Division of Hematology. "The goal of this grant is to shorten the time between a new discovery in blood clotting or bleeding disorders, and the application of that knowledge to help patients."

Washington University is one of only five universities across the country receiving funding from the National Heart, Lung, and Blood Institute (NHLBI) to support a new Translational Research Center in Thrombotic and Hemostatic Disorders. The other institutions are Duke University, Emory University, the University of Utah and Beth-Israel Deaconess Medical Center at Harvard University.

At Washington University, researchers are focusing on five projects that look at bleeding disorders, including some that are rare, and clot formation in both large and small blood vessels. Sadler emphasizes the value of studying uncommon bleeding disorders.

"Many discoveries in this field have been made by the careful investigation of unique patients with inherited disorders that are quite rare," Sadler says. "But the knowledge gained from studying those patients has provided a foothold into understanding thrombosis or bleeding in humans generally."

The projects are:

Sadler and his group are investigating the role of a protein called ADAMTS13 in conditions that cause blood clots to form in capillaries and small arteries. The researchers will also evaluate treatments to prevent recurrence of a rare and sometimes deadly clotting disorder called thrombotic thrombocytopenic purpura. TTP causes tiny blood clots to form in small blood vessels throughout the body and can damage vital organs including the kidney, brain and heart.

John P. Atkinson, MD, the Samuel Grant Professor of Medicine, and his team are using genomic sequencing to identify DNA defects in the way the body regulates bleeding and clotting, focusing on genes for complement proteins. This project will also evaluate how these errors can lead to clotting disorders in small vessels, including conditions like preeclampsia in pregnant women.

Enrico Di Cera, MD, professor and chairman of biochemistry at Saint Louis University, has collaborated with Washington University researchers in the past and will share in the grant. He is leading an effort to develop an improved variant of a protein called thrombin, which plays an important role in blood clotting. The investigators plan to optimize the variant's anti-inflammatory and anticoagulant activity to better treat blood clots.

George J. Broze, MD, professor of medicine, and his colleagues are developing ways to inhibit tissue factors that control blood clotting. Tissue factor inhibitors also may reduce inflammation and metastasis of tumors, making them particularly important to study, according to the investigators.

Samuel A. Wickline, MD, professor of medicine, and his team are engineering nanoparticles that can both image blood clots and deliver anticoagulant therapy directly to a clot. These nanoparticles would be useful for finding and imaging the tiny clots that form throughout the body in patients with TTP (investigated by Sadler), and delivering anticoagulant thrombin and tissue factor inhibitors developed as part of the projects led by Di Cera and Broze.

The grant also supports several core resources. A tissue banking core is led by Elaine Majerus, MD, PhD, assistant professor of medicine. For genome sequencing, the grant's investigators are working closely with The Genome Institute at Washington University. Education for clinical faculty in translational research is supervised by Brian Gage, MD, professor of medicine. DNA analysis of patient samples will be directed by Atkinson. The education component is also supported through the Washington University Institute of Clinical and Translational Sciences (ICTS).

Suresh Vedantham, MD, professor of radiology and surgery, is helping to coordinate these resources and projects as the leader of the grant's Administrative Core at Washington University. This core will ensure collaboration locally and among the other four universities and help to accelerate clinical trials investigating clotting and bleeding disorders.