Novel selective antithrombotic agents may avoid bleeding complications


By Manuela Callari

4 Aug 2020

Associate Professor Justin Hamilton (back left) and team

Victorian researchers are working on a novel class of antithrombotic agent that promises the best of both worlds: by selectively acting on platelets they inhibit thrombosis and yet avoid bleeding complications.

Associate Professor Justin Hamilton and colleagues at the Australian Centre for Blood Diseases, Monash University, have developed a series of ‘PI3KC2a inhibitors’ that act on the class II phosphoinositide 3-kinase enzyme in platelet membranes to exert a potent antithrombotic effect, but without affecting haemostasis.

The researchers, who report their findings in Science Translational Medicine, say the novel mechanism of action promises to overcome the key limitation of current antithrombotic therapies that block global platelet activation and indiscriminately prevent impair platelet function in both haemostasis and thrombosis.

In animal and human blood in vitro studies they showed that PI3KC2a inhibitors dilated the internal membrane reserve of platelets but did not affect activation-dependent platelet function.

Mechanistic studies showed the antithrombotic effect to be the result of impaired platelet adhesion driven by pronounced haemodynamic shear stress gradients.

Associate Professor Hamilton told the limbic that the Monash team started looking into PI3KC2α because of the well-known function of PI3KC1 in thrombosis. They had some preliminary evidence that PI3KC2α might also play a role in thrombi formation, “but we really had no idea of what to expect,“ he said.

“It was genuinely a combination of dogged determination and a little bit of dumb luck.”

The research group noticed that when the alpha-isoform of PI3KC2 was knocked out, mice were protected against thrombosis and, at the same time, they didn’t bleed. And when they looked at the mice platelets, their global function was preserved.

“At the time, that drove us crazy … but in hindsight, that was a really key finding that allowed us to provide this separation between preventing thrombosis and causing bleeding.”

The team then identified a series of seven compounds of ‘Class II PI3Ks’ that specifically target PI3KC2α ,reproducing the platelet phenotypes observed in PI3KC2α-deficient mice.

“When we use these compounds and look for platelet function they behave completely normally. And yet, when we pump the blood through an artificial blood vessel and look at thrombus formation, it’s significantly impaired,” says Associate Professor Hamilton.

He said many research groups have been looking at targeted therapies to overcome  the limitations of current antithrombotic drugs such aspirin and clopidogrel that prevent fewer than 25% of lethal cardiovascular events. But to date, very little work has been done on the PI3KC2α pathway.

However he cautioned that while the preliminary results were promising, the compounds were still some way off from human clinical trials. The next challenge  is to improve the solubility of the ‘Class II PI3K’ compounds necessary to develop an oral formulation.

“Furthermore, a direct mechanism by which PI3KC2α inhibition alters [platelet membrane channel] structure, and how this in turn inhibits thrombosis remains to be elucidated,” the researchers say.

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