Alireza "Ray" Rezaie, Ph.D., professor of biochemistry and molecular biology at Saint Louis University School of Medicine, has received a $1.52 million NIH grant to study how the key blood clotting inhibitor antithrombin might be exploited to prevent premature death from heart disease.
The National Heart Lung and Blood Institute awarded the four-year grant, which will allow Rezaie to continue studying how to maintain the delicate balance between the life-preserving and life-threatening activity of blood clotting.
"Blood clotting factors must be turned on and off at exactly the right time so a person does not bleed to death or die of an episode such as a heart attack, which is triggered by a blood clot," said Rezaie, who has engineered molecules that impose equilibrium on the delicate system.
Rezaie recently discovered that antithrombin, which is a molecule produced by the liver that turns off several proteins in the coagulation system, can block inflammation in the blood vessel wall. This inflammation can lead to heart disease as well as a violent, life-threatening reaction to blood infections called acute sepsis.
Rezaie is working on harnessing the anti-inflammatory activity of antithrombin to reduce the incidence and severity of heart disease and to save the lives of those who suffer from acute sepsis. He has studied the control of blood clotting factors for 23 years.
Blood carries nutrients and oxygen to the body's organs and tissues as well as the ordnance of immunity—antibodies and white blood cells—that defend organs and tissues from infection. Given these critical functions, it is essential that bodies preserve blood against loss from bleeding injuries.
Imbedded in blood is the chemistry to stop bleeding before too much blood is lost. Whenever small cuts or bruises occur, the blood at the site of injury rapidly mobilizes clotting factors that build a plug at the breech in the blood vessel to prevent blood loss.
However, the ability to make blood clot is also the cause of vascular disease and sudden death for some when it is not controlled properly.
Efficient blood clotting can be a double-edged sword when clots appear at the wrong places and times. Heart attack, stroke and pulmonary embolism are life-threatening conditions stemming from clots that block blood circulation to the heart, brain or lung.
Currently, a patient who suffers a heart attack, stroke or pulmonary embolism is treated with heparin, a medication that prevents the formation of additional life-threatening blood clots. At the same time, heparin treatment puts patients at risk of uncontrolled bleeding by inhibiting antithrombin, which upsets the body's normal response to injury and infections.
"The blood clotting cascade has to be maintained in a balanced state - not too much of one and not too little of the other," Rezaie said.
In parallel with his pioneering work on antithrombin, Rezaie is also working to improve the anticoagulant activated protein C. This FDA-approved vitamin K-dependent blood clotting factor has been used to treat acute sepsis in adults, which affects nearly 750,000 Americans annually and results in at least 225,000 deaths.
His ongoing studies on activated protein C are funded by another $1.5 million grant from the National Institutes of Health, given in 2010. They aim to improve the ability of the protein to prevent organ failure while reducing its anti-clotting activity, so that bleeding complications can be avoided.
Rezaie's work builds on the legacy of Edward A. Doisy, Ph.D., the first chair of SLU's department of biochemistry and molecular biology, who received a Nobel prize in 1943 for determining the chemical nature of vitamin K, which is an essential component in blood coagulation.
"I am working with the blood clotting factors that are activated by Dr. Doisy's vitamin K, which does something to these molecules so they can physiologically function," Rezaie said.
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