Research News

A new publication in Circulation from the lab of Scott Cameron, MD, PhD, illustrates the impact of a collaborative effort behind a key finding: the compound that activates the olfactory receptor in platelets.

The article builds on research published in 2022 that first identified the presence of the olfactory receptor in platelets. The research team not only identified the compound that activates the receptor, but also how it does so—which could shape future treatment strategies for antiplatelet drugs and clotting.

The connection between smell and clotting

Platelets are tiny cell fragments in the blood whose main job is to stop bleeding. When a blood vessel is injured, platelets change shape, stick to the damaged area and form clots.

The same process can also lead to serious problems like heart attack and stroke, especially if blood clots form inside arteries. Physicians occasionally prescribe antiplatelet drugs, like aspirin or clopidogrel, to prevent platelet activation and blood clot formation. These same drugs may also be prescribed after a patient has suffered a heart attack or stroke. However, some patients do not respond well to these medications, which can also increase the risk of bleeding.

The Cameron Lab focuses on the role of platelets. In 2022, the same research team discovered olfactory receptors in platelets, previously thought to only be present in nerve pathways from the nose to the brain (the olfactory nerve), which relay information about the sense of smell, As it turns out, those same receptors in the nose are also chemical sensors embedded in the surface of cells that travel throughout the body—including platelets.

Pieces of a puzzle

In 2018, a patient encounter sparked Dr. Cameron’s investigation into the connections between smell and blood clots.

“A patient experiencing a heart attack was cleaning an old house prior to the onset of their symptoms, using chemicals that had a strong odor,” he explains. “That made me think differently about clotting.”

Although there was no convincing link between odor and heart attack at the time, the patient’s anecdote was the start of piecing together a larger puzzle that formulated this research.

The other pieces include Dr. Cameron’s previous research, his knowledge of pathways and other receptors, and even an article in Science that explains why hibernating bears don’t get blood clots: heat shock proteins (HSPs). With the help of Naseer Sangwan, PhD, director of the Microbial Sequencing & Analytics Resource Center, the team found that HSP-27—which Dr. Cameron noticed in earlier work—was the missing downstream link in this research, from the upstream olfactory receptor.

The research team also knew from prior work that odor molecules (including carvone, the active compound in spearmint), could activate platelets. Since odors are not usable as drugs, they wanted to find stable, modifiable chemical compounds that could become therapeutics instead.

So the team, led by Anu Aggarwal, PhD, a postdoctoral fellow in Dr. Cameron’s lab and first author of the paper, tested around 8,000 compounds before finding one that strongly activated the receptor.

“This compound reduced platelet activity, meaning platelets were less likely to clump and released fewer clot-promoting chemicals,” says Dr. Aggarwal, who won the Elaine W. Raines Early Career Award from the American Heart Association for her work on olfactory receptors. “More importantly, the normal clotting activity needed to stop bleeding was not impaired. This is a potentially major advantage over current antiplatelet drugs.”

Solving complex problems through collaboration

In addition to identifying the compound that activates the receptor, the team also discovered how it does so: by disrupting the actin cytoskeleton—the structure underneath the membrane of the platelet. This knowledge may benefit future antiplatelet therapy strategies. Dr. Cameron credits the impact of the Circulation article to the perspectives and expertise of the authors: 23 Cleveland Clinic researchers across six departments, including Shaun Stauffer, PhD, who directs the Cleveland Clinic Center for Therapeutics Discovery (C3TD).

“Modern discoveries require multidisciplinary teams and many contributors because the questions are getting harder to figure out,” he says. “The breadth and depth of this work truly required that level of expertise in technology and multidisciplinary input as we get narrower down the funnel of scientific research.”