Key found to breakthrough drug for clot victims

The researchers contemplate that, if it is approved for use in humans, WE thrombin – which the research team has demonstrated is effective and safe in large primates – could safely be injected by paramedics or others, whenever someone displays the first symptoms and signs of a stroke or heart attack without fear of causing harm if the symptoms prove to be a false alarm.

Aronora LLC, a startup biotechnology company, has been formed by Gruber along with the primary co-investigators and others, to seek financial support for preclinical and early clinical development of WE-thrombin as a safe alternative to existing antithrombotic drugs. The market for such drugs is estimated to exceed $20 billion per year worldwide. The patents on WE-thrombin are currently co-owned by the investigators’ parent institutions, OHSU, Emory University and Washington University.

“WE-thrombin is the most potent antithrombotic agent that ever has been described,” said Gruber. “And that’s because of its specificity. It effectively utilizes a natural “drug delivery system” of circulating blood platelets and white blood cells that accumulate in the clot formation process to deliver its punch directly to a blood clot. The process parallels that of targeted drug delivery. It’s effective inside a blood vessel, but not at all effective outside the blood stream, which is exactly what you want from an antithrombotic agent.”

“What we’ve done recently,” added coinvestigator Owen J.T. McCarty, Ph.D., “is located the exact point where the catalytic reaction takes place in vivo that makes this molecule work as a superior antithrombotic agent.” McCarty, an expert in platelet biology, is assistant professor of biomedical engineering in the department of cell and developmental biology, OHSU School of Medicine.

Blood platelets are small cells that sense an injury and rush to form a clot to reduce bleeding. They do so by binding thrombin, which cuts fibrinogen into strands of fibrin to form the “glue” of a clot. The process becomes self sustaining, or autocatalytic, which means that the glue is produced and reproduced in a rapid chain reaction. Thrombin subsequently counterbalances the process by activating protein C inside the blood vessel, which shuts down the autocatalytic reaction in the blood stream.

WE-thrombin, the mutant form of thrombin, lacks the ability to create the glue but still can produce activated protein C (APC) inside the blood vessels, which makes it a unique, locally acting anticoagulant. The molecule enhances this ability, the research team discovered, by attaching itself to a receptor, or sticking point, called glycoprotein Ib (GPIb), located on the surface of platelets. In doing so, WE-thrombin shoulders aside – and thus inhibits – the protein (the von Willebrand factor) that promotes coagulation, which now has to compete for the same receptor on the platelets.