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July 24, 2002
Contact: Sue Pondrom (619) 543-6163UCSD Researchers Discover Enzyme
Defective in Bleeding Abnormality
One of the key ingredients in the complex molecular mix of genes that control bleeding has been discovered by researchers at the University of California, San Diego (UCSD) School of Medicine.
In studies that included mice and humans, the researchers found that mutations in a naturally occurring enzyme called sialytransferase ST3Gal-IV greatly reduced levels of von Willebrand factor (VWF) in mice, by a mechanism also seen in some human patients with clinical signs of bleeding abnormalities and abnormally low levels of VWF.
The level of VWF, a blood element involved in clotting, is a major determinant of the severity of von Willebrand disease (VWD), which is the most prevalent bleeding disorder in humans, affecting more than 3 million Americans. VWD patients have such symptoms as easy bruising, heavy or prolonged menstrual periods, frequent nosebleeds or prolonged bleeding after injury, surgery, childbirth or dental work.
The UCSD results, published in the July 23, 2002 issue of the journal Proceedings of the National Academy of Sciences (PNAS), showed that mice bred with a mutated ST3Gal-IV enzyme had a substantially longer bleeding time than normal mice and had low levels of platelets and the blood clotting factor VWF.
The ST3Gal-IV enzyme normally acts by adding a sialic acid, a molecule found throughout the body, to certain blood factors that regulate clotting. The mutated version is unable to produce this sialic acid.
The study’s senior author, Jamey D. Marth, Ph.D., UCSD professor of cellular and molecular medicine and an investigator with the Howard Hughes Medical Institute, noted that the level of VWF in both mouse and human blood is highly variable, but must stay within a narrow range to avoid either excess bleeding or dangerous clotting that can lead to heart attack or stroke.
“One of the greatest mysteries for doctors and researchers studying in hematology is how the body regulates levels of von Willebrand factor,” Marth said. “Variability in VWF levels has been found to be a major determinant of VWD severity and abnormally high VWF level is reported as a risk factor for stroke and heart attack.”
“What we’ve identified is a new regulatory control point that modifies the level of clotting factors within blood,” Marth added.
The research team found that 30 mice with the mutated gene bled for more than four minutes following a small cut to the tail, as compared to 30 normal mice that bled only 50 seconds. The investigators also analyzed mouse blood samples for levels of VWF and Factor VIII, another blood component that regulates clotting. They determined that mice with mutated ST3Gal-IV had 30 percent of normal (or 70 percent fewer) blood platelets, and from 10-50 percent of normal VWF and Factor VIII levels. They manifested a syndrome that looked like human VWD.
“When VWF levels are too low in humans, blood doesn’t clot fast enough,” Marth said. “Many of these individuals will show up in hematology clinics to ask why they bleed excessively, bruise easily, or don’t heal quickly.”
The researchers utilized these clinic visits to study 136 UCSD Medical Center patients with complaints of bleeding abnormalities. They determined that 117 patients had normal VWF levels. Of 19 patients with low VWF levels, five were found to have the same deficiency in sialic acid on VWF as did the mutant mice. The researchers are conducting further tests with these patients to determine if they lack ST3Gal-IV, and if reduction in ST3Gal-IV may prevent arteriosclerosis, stroke and heart attack.
In addition to Marth, authors of the paper were first author Lesley G. Ellies, Ph.D., UCSD Department of Cellular and Molecular Medicine; and David Ditto, BSc, and Dzung T. Le, Ph.D., M.D., UCSD Department of Pathology; Gallia G. Levy, Ph.D., and David Ginsburg, M.D., a Howard Hughes Medical Institute investigator at the University of Michigan Medical School; Mark Wahrenbrock, BSc, and Ajit Varki, M.D., UCSD Department of Medicine.
The research was funded by the National Institutes of Health and the Howard Hughes Medical Institute.
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