5 Aug 2016

Blood clot study points to new drug target

Shauna French and Dr Justin Hamilton analysing results
by Anne Crawford

Arterial thrombosis – blood clot in an artery – can lead to several serious conditions including heart attack and stroke, and is the most common cause of death and disability in Australia. A Monash PhD student at the Australian Centre for Blood Diseases (ACBD) has conducted research demonstrating a potential new solution to the clotting that causes the problem.

Existing drugs aiming to prevent arterial thrombosis by acting on the platelets that form blood clots have limitations in efficacy and/or safety, some causing excessive bleeding.

Shauna French and her colleagues at the ACBD investigated an alternative anti-platelet target. Supervised by Dr Justin Hamilton, Ms French conducted a study on PAR4 (protease-activated receptor) which activates platelets via the protease (enzyme) thrombin.

PAR4 is one of two PARs enlisted by thrombin to do this. Targets for the other one, PAR1, were taken to clinical trials and whilst effective had bleeding complications. Attention then turned to antagonists targeting PAR4, until recently regarded as a poor cousin to PAR1.

The study, published in the Journal of Thrombosis and Haemostasis, provides the first evidence that PAR4 is required for procoagulant function during thrombus formation in human blood.

Using an antibody previously developed by fellow researchers Ms Hannah Lee and Dr Hamilton, Ms French also showed that PAR4 could be inhibited, making it a possible anti-thrombotic drug target.

“When we started it was unknown as to what PAR4’s function was on platelets – it was thought that it did much the same thing but was not as good as PAR1,” Ms French said.

“We’ve developed one of the first inhibitors that works on PAR4 and found that it could reduce the amount of thrombin and fibrin – the major stabiliser of a blood clot – by about 50 per cent.”

Ms French recalls the excitement of looking down the microscope and seeing platelets, delineated by fluorescent markers, drop in number under the effect of the inhibitor.

Another highlight of her two years’ work was the special commentary by a senior scientist reviewing the paper that was published alongside the study in the journal.

Ms French’s work into blood clot prevention has a special resonance: she was hospitalised with a blood clot in her leg – deep vein thrombosis – when she was a 19-year-old-student. The clot was picked up thanks to her mother, a nurse, before it became more dangerous.
Then studying applied science in Queensland, she shifted focus to medical research and successfully gained a place at the ACBD.

Ms French said the antagonist used on the receptor in the study whilst not a therapeutic inhibitor itself was a good research tool. The researchers will now refine what they have found for clinical use.

“The end game is to stop the amount of people who die unnecessarily from heart attack and stroke,” she said. “PAR4 as an inhibitor could be really useful for a significant number of people.”

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