(RxWiki News) Scripps Research Institute scientists have discovered new elements of the blood clot formation process, a finding that could lead to new methods for preventing heart attacks and strokes.
The discovery was recently published in the Journal of Clinical Investigation.
The previous model suggested that an injury to the wall of blood vessels causes smooth muscle cells to expose a clot-organizing protein called tissue factor. But in the newer model, tissue factor exists on the surfaces of the smooth muscle cells, and also on circulating immune cells, only those immune cells are in an inactive state.
"The finding could lead to better drugs to prevent numerous clot-based diseases."
Scripps Research professor Wolfram Ruf said the team has demonstrated that cell-surface receptor P2X7, which was known to promote inflammation when stimulated, also plays a major role in the clot-forming process by activating tissue factor.
Scientists performed a set of experiments on cultured mouse cells and transgenic mouse models. The investigation began with the P2X7 receptor because of its known role in the inflammatory response that can lead to excessive clotting in sepsis, a severe illness in which the bloodstream is overpowered by bacteria.
Generally when cells are damaged, they release large amounts of energy-storage molecules known as adenosine triphosphate (ATP.) Previous research suggested that when this freed ATP encounters passing immune cells, it serves as a damage signal, stimulating the immune cells' P2X7 receptors and causing the release of "microparticles" exposing the clot-promoting tissue factor. Through the new study, researchers showed that ATP can affect P2X7 receptors on both immune cells and smooth muscle cells.
In order to be assured of the significance of the P2X7 receptor in the clot formation process, researchers bred transgenic mice that lacked functional P2X7 receptors, and discovered that these mice failed to form stable arterial blood clots when the vessel wall was exposed to a clot-inducing substance. They also discovered that these mice did not suffer from uncontrollable bleeding.
Ruf said that molecular events following P2X7 stimulation alter the activity of a thiol-targeting enzyme known as protein disulfide isomerase (PDI), which previous studies had suggested was a possible activator of tissue factor. The team was able to demonstrate the importance of PDI in this process by showing that they could block clot formation in normal mice with anti-PDI antibodies.
Targeting the top of the clot-formation pathway by blocking the P2X7 receptor could have even wider benefits since the activation of this receptor occurs in many inflammatory disorders.
