How histones cause blood clotting in severe illness

The mechanisms of extracellular histone-induced immunothrombosis and its roles in microvascular circulatory failure during critical illnesses

Dr Guozheng Wang and his colleagues at the University of Liverpool are investigating what goes wrong in the circulation of people who are critically ill, for example, those with severe infection or after severe trauma. In critical illness, when large numbers of cells in the body die suddenly from infection or other severe illness, a group of proteins called histones are released into the blood stream from the dying cells. Histones are normally found in the central part of the cell that contains the DNA - the nucleus. But when they are released into the blood they cause inflammation and make the blood clot more easily. We don’t yet fully understand how this happens. Dr Wang has recently found that histones increase the levels of blood clotting molecules called thrombin, antithrombin and fibrin, which leads to clot formation. He has also found in preliminary work that clots containing histones make immune cells release net-like structures that can enlarge into clumps and can block the small blood vessels, especially in the lungs. In this project, Dr Wang will work out in more detail how high levels of circulating histones promote clotting and damage the small blood vessels in the lungs. He will also work out, using a mouse model of disease, which processes are the most important, to see which ones should be targeted using drugs. This research could identify new ways to treat and improve the outcome for critically ill patients, helping the very sick to survive.