New targets ID'd in hunt for clotting reduction drugs

Monash University scientists have identified potential new targets for the development of drugs to reduce blood clotting in patients at risk of heart attack or stroke.

The research is centred on the regulatory mechanism controlling the size of blood clots formed in patients with atherosclerosis, and the roles played by structural protein collagen and calcium signalling between the cells in the blood vessel and the platelets recruited to form clots after blood vessels are damaged.

"From a clinical perspective, what we are trying to work out is what regulates the size of blood clots," said Dr Shaun Jackson, who leads the team of researchers working on the problem. "The link between collagen and large clots has been established but not well defined."

Jackson and his team have determined that the amount of collagen contained within artery walls plays a key role in initiating the chain of events that result in blood clots. Collagen from atherosclerotic plaques is released when the blood vessels are damaged, and this has an effect on the calcium signalling between platelets.

"The platelets clump together by sending calcium signals to each other," Jackson said. "When there is collagen present, as there is in patients with atherosclerosis, the calcium signalling between the platelets is much more efficient and larger clots form."

And the larger the clot, the greater its potential for blocking vital blood vessels, leading to heart attack or stroke, he said.

The research suggests that two new approaches can be taken to develop new anti-clotting drugs. Existing drugs act on the adhesion molecules cross-linking platelets together within clots, but the drugs are very potent and can only be used in a hospital setting.

"We can now look for methods of impeding the calcium signalling so the clots don't grow as large. Another approach could be to block the collagen and make the blood vessels less responsive to the blood clotting mechanism," said Jackson.

"You want to damp down the clotting, not block it altogether as that increases the potential for bleeding."

Jackson's team, which is located in the Australian Centre for Blood Diseases at Monash Department of Medicine's Box Hill Hospital campus, works closely with Melbourne-based biotechnology company Kinacia, which was founded by Jackson and has previously licensed other targets identified by the Monash researchers.

The Monash researchers use a biorheology laboratory to enable them to study blood flow under conditions mimicking those occurring in arteries, allowing them to model the effects of potential therapeutic molecules developed by Kinacia's scientists.

The research was published last month in the Journal of Cell Biology.

Reference: Warwick S Nesbitt, Simon Giuliano, Suhasini Kulkarni, Sacha M Dopheide, Ian S Harper, and Shaun P Jackson (2003). Intercellular calcium communication regulates platelet aggregation and thrombus growth. J Cell Biol 2003 160: 1151-1161.