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Surprising Find with Blood Platelets Opens Avenues for Developing Drugs to Prevent Blood Clots

Oct. 23, 2006 — In a finding with significant ramifications for developing drugs to prevent dangerous blood clots, University of Utah School of Medicine researchers have identified an unsuspected mechanism that triggers key blood cells to form clots.

Platelets are blood cells the body uses to form clots and stop blood loss when veins and arteries are injured. University researchers examined human blood platelets and discovered the cells make tissue factor (TF), a key protein in clot formation. The process is regulated by an enzyme found in blood platelets called cdc2-like kinase 1 (Clk1). Before this study, it was not known that blood platelets possess Clk1 and use this critical factor to make tissue factor.

Now that the role of Clk1 has been identified, it’s possible to develop drugs that prevent the enzyme from making tissue factor and inducing blood clots. These medications could help many people at risk for stroke, heart attack, sepsis (general infection), and other life-threatening disorders and diseases related to blood clots, according to Andrew S. Weyrich, Ph.D., associate professor of internal medicine and senior author of the just-published study.

“This discovery could be really important therapeutically,” Weyrich said. “Well-known anti-platelet or anticoagulant drugs do not target the Clk1 pathway.”

The study was led by Hansjörg Schwertz, M.D., a postdoctoral fellow at the University”s Eccles Institute of Human Genetics, and is published online today in the Journal of Experimental Medicine. The research appears as a Brief Definitive Report, an article the journal features that is expected to have a high impact in its field.

Tissue factor, which is expressed in blood platelets only after they are activated, is required for clot formation.

Weyrich, Schwertz, and other members of the Utah team found the Clk1 enzyme controls the expression of tissue factor protein through a process called splicing. Circulating human blood platelets, it turns out, possess tissue factor pre-messenger RNA, a type of messenger RNA that does not generate functional protein. Using their Clk1 pathway, platelets change the pre-messenger RNA into mature messenger RNA, a decoding process referred to as splicing. The mature RNA is subsequently used to make biologically functional tissue factor protein that forms clots.

The researchers found splicing occurs only in blood platelets that have been activated; splicing can occur within five minutes of platelet activation. But when Clk1 splices the pre-messenger RNA at the wrong time, tissue factor is made and blood clots can form.

Drugs that target Clk1 probably wouldn’t help once a clot has formed; but if given before a clot forms, medications aimed at Clk1 might prevent clots related to a number of serious illnesses and diseases.

“A lot of (pharmaceutical) companies are trying to come up with anticoagulants after TF is made,” Weyrich said. “But I don’t know of anything that targets an intracellular pathway before tissue factor is made.”

The study follows groundbreaking work last year by Weyrich and Guy A. Zimmerman, M.D., professor of internal medicine and director of the medical school’s Program in Human Molecular Biology and Genetics, in which they discovered blood platelets regulate genes through splicing. That finding upended a long-held biological tenet, because blood platelets don’t have a nucleus, which scientists thought was essential for regulating genes.

Weyrich’s group is now analyzing blood platelets from University Hospital patients to see if tissue factor splicing is prevalent in patients with sepsis. Preliminary results indicate tissue factor splicing does occur in blood platelets in septic patients, according to Weyrich.

University of Utah co-authors on the study include Zimmerman, Larry W. Kraiss, M.D., associate professor of vascular surgery; Estelle M. Harris, M.D., assistant professor of internal medicine; Neal D. Tolley, Jason M. Foulks, and Ben W. Risenmay, all of the Eccles Institute of Human Genetics; Matthew T. Rondina, Department of Internal Medicine; and, posthumously, Melvin M. Denis, a University of Utah medical student who died in 2004.