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.”