RNA proposed as mystery 'foreign surface' that mediates blood clotting in damaged tissue
Researchers in Germany and Japan say they may have solved one of biochemistry’s bloodier conundrums - the physiological reason why blood coagulates in the presence of ’foreign’ surfaces such as glass. The finding could open the way to the development of new clot-preventing drugs or ways of curbing excessive bleeding.
For centuries it has been observed that fresh blood spontaneously clots in a glass vessel or in the presence of the clay mineral kaolin. This phenomenon has been termed the contact-phase system of the biochemical cascade that leads to the formation of blood clots. It involves the activation of a number of blood proteins but its physiological significance has remained obscure.
Klaus Preissner, of the Justus-Liebig-Universit?t, Germany, led a team that has shown that RNA could be the naturally occurring ’foreign surface’ in the body that promotes blood clotting after tissues have become damaged.
The researchers showed that isolated samples of blood coagulated in the presence of RNA, with only the contact-phase proteins being activated - the same ones that are activated in the presence of glass or kaolin. The team then induced a clot in a blood vessel in a mouse and showed that large concentrations of RNA were present in the vicinity of the clot. When the scientists pre-injected the mouse with the enzyme RNase, which degrades RNA, they found that the clot took around four times as long to develop.
’When cells are damaged material from within the cells becomes exposed and could play a part in the wound-healing process,’ Preissner told Chemistry World. ’In severe injury when millions of cells might be damaged, the release of RNA locally would be sufficient to trigger or enhance blood clotting.’
It appears to be the highly polyanionic nature of RNA that is responsible for its activity in triggering the clotting process - in the same way that foreign surfaces such as glass are polyanionic. DNA has similar activity in isolated samples of blood, but seems to be relatively insignificant in vivo. ’We think there is less DNA released when tissue is damaged because it remains tightly packaged within the nuclei of the cells, whereas the RNA is floating freely in the cell cytoplasm,’ Preissner said.
The finding could open the way to new methods to prevent blood clots from forming by targeting RNA. It could also provide a means to trigger blood coagulation in wound healing or for people who bleed easily by using polyanionic analogues of the nucleic acids.
Michael Greaves, professor of haematology at the University of Aberdeen, UK, said that the work had uncovered ’a potentially clinically important mechanism of blood coagulation.’ Furthermore, extracellular RNA might now be implicated in certain diseases, such as disseminated intravascular coagulation, a potentially fatal condition in which there is unregulated activation of blood coagulation. ’If such a mechanism applies in man, these novel observations could potentially lead to the development of new therapeutic strategies,’ Greaves told Chemistry World.
C Kannemeier et al, Proc. Nat. Acad. Sci. (2007), 104, 6388