To prevent blood clots during therapeutic hypothermia, researchers have developed what may be the first drug activated by cool temperatures and turned off by warm ones, according to research presented April 9 at the American Heart Association's 2010 Arteriosclerosis, Thrombosis and Vascular Biology annual conference in San Fransisco.
"We used biotechnology to create a modern intelligent drug," said lead author Karlheinz Peter, MD, PhD, associate director of Baker IDI Heart & Diabetes Institute in Melbourne, Australia. "This drug is tailored for preventing clots during therapeutic hypothermia and for minimizing bleeding problems especially after re-warming."
According to the researchers, the new drug works only at cooler temperatures by inhibiting the activity of platelets. In mouse and human blood samples, researchers said they demonstrated that the experimental drug bound to platelets and prevented them from clumping together at cool temperatures (71.6º F). When they raised the temperature to normal (98.6º F), the anti-platelet action stopped.
"Our idea was to develop a reagent that is highly active at the moment it is really needed when patients are at low temperature, and that loses its function when it is no longer needed, when patients are re-warmed," Peter said.
Peter and his collaborators at Baker, along with colleagues at Emory University in Atlanta, used recombinant DNA technology to fuse a temperature-dependent protein with a protein that inhibits platelet activity. The first part of the new protein is similar to the protein elastin, which gives skin and other organs their flexibility and is known to change shape in response to temperature changes. The second, antibody portion of this combined protein inhibits platelet activity by blocking the receptors that normally enable these cells to clot together to heal an injury.
The researchers noted that cardiac hypothermic surgery is associated with a substantial risk of clotting. To prevent this complication, anti-clotting medication is a standard part of therapeutic hypothermia. The drawback, according to the presenters, is that the effects of current anti-clotting medicines continue even after body temperature is raised to a normal level, which sometimes leads to excessive post-surgical bleeding, researchers said. In contrast, Peter reported the new combined protein not only inhibited blood clot formation during cooling but also prevented bleeding problems after rewarming.
To assure that the novel temperature-dependent drug also protects patients subjected to this type of therapeutic hypothermia used for the protection of the brain in patients after cardiocirculatory arrest, further studies are needed to determine the extent of platelet inhibition at temperatures such as 89.6 º F to 93.2 º F, Peter said.