New drug blocks formation of killer clots to prevent strokes and heart attacks

Four of the co-authors on the paper, L-R: Ms Natasha Setiabakti,
Associate Professor Justin Hamilton,(senior author)
Ms Nurul Aisha Zainal Abidin, Dr Mitch Moon

Monash researchers have found a potential drug that can be given as a preventive against heart attack.

The drug – which has been studied in human cells and animal models – literally blocks the minute changes in blood flow that precede a heart attack and acts on the platelets preventing the platelet-triggered clot from forming before it can kill or cause damage.

One-third of all deaths globally – 18 million a year - are caused by cardiovascular disease, largely heart attack or stroke, both of which are triggered by clots blocking the vessels in the brain or heart.

While drugs such as aspirin, given at the time of the attack, can prevent further clots forming, they only work in 25 per cent of cases, and these drugs can cause serious side effects from bleeding.  The paper describing the new drug is published in the prestigious journal, Science Translational Medicine. According to the lead scientist, Associate Professor Justin Hamilton, from Monash University's Australian Centre of Blood Diseases, “There have been no new drugs to treat, let alone prevent, heart attack or stroke in more than 15 years."

Anatomy of a platelet, showing 

internal components of the cell

including membrane (light blue),

storage granules (blue and yellow), 

and mitochondria (black) 

Associate Professor Hamilton said that the researchers stumbled across the potential drug by accident. They were looking at changes within platelets that occur around the time of what is called a pathological setting, i.e., a heart attack or stroke. They found an enzyme of interest, isolated the gene responsible for producing the enzyme and developed a mouse that was missing just that gene.

The mice – to their surprise – were completely protected against heart attack.   But why silencing this enzyme provided protection remained a mystery for two years. “It drove us mad,” Associate Professor Hamilton recalls.

The researchers used electron microscopy to cut ultra-thin “slices” of the platelets from these mice to see what was going on. What they saw was a slightly modified membrane, which appears to prevent these platelets from attaching to each other or to blood vessel walls, the minute that there is a change in blood flow. “It is this blood flow perturbation which is a hallmark and predictor of a heart attack,” Associate Professor Hamilton said.

“This particular enzyme allows the platelets to respond to the blood flow change and to 'gear up' their capacity to clot, causing an attack.”

Once the researchers were aware of the importance of the enzyme, they developed a drug that could shut this process down, in animal models and in laboratory models using human blood. This drug has the potential to be given to patients at risk of heart attack and stroke, to prevent blood clots forming when there is a risk of attack.

The next step is to develop a more suitable drug candidate that could be taken into a clinical trial, according to Associate Professor Hamilton. Initially, he is hoping to test the drug on patients who have a higher risk of cardiovascular disease such as those with diabetes.

These same clots - targeted by the Monash drug - have recently been linked to COVID-19 as a key cause of death from the disease. Associate Professor Hamilton says that, while it is early days, “the possibility of using our newly developed anti-thrombotic to improve the treatment of COVID-19 patients is an appealing idea we would like to explore."

See more in A/Prof Hamilton's explainer videos & follow the group on Twitter:

• New compound to prevent bad blood clots
• New thrombosis prevention compound of interest for treating clotting in COVID-19 patients
• @lab_hamilton

 Reference

Selvadurai MV, Moon MJ, Mountford SJ, Ma X, Zheng Z, Jennings IG, Setiabakti NM, Iman RP, Brazilek RJ, Abidin NAZ, Chicanne G, Severin S, Nicholls AJ, Wong CHY, Rinckel J-Y, Eckly A, Gachet C, Nesbitt WS, Thompson PE, Hamilton JR.  Disrupting the platelet internal membrane via PI3KC2 inhibition impairs thrombosis independently of canonical platelet activation. Science Translation Medicine.Vol. 12, Issue 553, eaar8430 DOI: 10.1126/scitranslmed.aar8430
stm.sciencemag.org/content/12/553/eaar8430.editor-summary

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