Olfactory Receptor as a Therapeutic Target in Thrombosis?

A Cleveland Clinic-led research team has identified a novel therapeutic pathway that could reshape antiplatelet therapy. They found that targeting a specific olfactory receptor located on the surface of platelets may suppress dangerous clot formation without raising the risk of life-threatening bleeds.

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“This approach directly addresses the need to reduce the high residual platelet reactivity that persists in some patients despite use of dual antiplatelet therapy,” says Scott Cameron, MD, PhD, Section Head of Vascular Medicine at Cleveland Clinic and senior author of the research, which was published in Circulation (2026;153[23]:1827-1844).

Backdrop: An olfaction-clotting connection?

The role of platelets is the focus of a laboratory directed by Dr. Cameron in the Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Research. In a 2022 publication in the Journal of Clinical Investigation, he and colleagues reported their discovery of olfactory receptors in platelets, which revised the previous assumption that such receptors were present only in nerve pathways from the nose to the brain.

Dr. Cameron’s research interest in potential connections between the sense of smell and blood clots stems from an encounter with a patient in 2018 who was using cleaning chemicals with a strong odor just before the onset of myocardial infarction symptoms. “That made me start to think differently about clotting,” he explains.

Dr. Cameron and colleagues also knew from prior work that odor molecules — such as carvone, the active compound in spearmint — could activate platelets. Since odors are not usable as drugs, they wanted to instead find stable, modifiable chemical compounds that could be used as therapeutics. Building on their prior research on ectopic olfactory receptors in the vasculature, they focused on OR2L13, the most prevalent olfactory receptor identified in human platelets.

Essentials of the new study

In their current study, the researchers conducted a high-throughput screen of 8,000 bioactive, nonodorant compounds to identify potential agonists for the OR2L13 receptor. The most promising candidate, a chemical probe designated CCF0054500, was evaluated in a series of ex vivo human studies and in vivo murine models. The human studies involved tested the compound using platelets isolated from patients with established coronary artery disease (CAD) and peripheral artery disease (PAD).

Several key findings emerged:

Broad inhibition. CCF0054500 inhibited platelet activation triggered by multiple receptors, including PAR1, P2Y₁₂, glycoprotein VI and thromboxane receptors. “We found that it inhibited both biochemical and biomechanical activation of platelets,” Dr. Cameron notes. “This represents a broader effect compared with standard antiplatelet therapies like aspirin and clopidogrel, which target specific biochemical pathways but fail to mitigate biomechanical activation of platelets.”
Ability to overcome resistance to standard antiplatelets. CCF0054500 effectively suppressed high residual platelet reactivity in patients with CAD or PAD who had continued to show reactivity despite taking aspirin, clopidogrel or both.
Thrombus protection without increased bleeding. In a murine model of arterial injury, the compound reduced arterial thrombus formation by nearly 90% without lengthening bleeding times or disrupting fibrin generation. “The preservation of normal clotting activity to stop bleeding, if confirmed in humans, could be a major advantage over current antiplatelet drugs,” Dr. Cameron says.
Post-MI benefits. In a murine model of myocardial infarction, treatment with CCF0054500 preserved left ventricular ejection fraction and significantly improved survival relative to controls.

Research and clinical implications

In addition to identifying CCF0054500 as a chemical probe that activates an olfactory receptor integral to hemostasis, the research team also discovered how it does so — by disrupting the actin cytoskeleton, the structure underneath the membrane of the platelet.

Briefly, unlike traditional agents, CCF0054500 triggers the phosphorylation of heat shock protein 27. This signaling event leads to depolymerization of the actin cytoskeleton, essentially preventing the platelet from spreading or changing shape to form a stable clot.

“This insight may benefit development of future antiplatelet therapy strategies,” Dr. Cameron observes.

side-by-side medical illustrations of cells and blood vessels — Illustration depicting the effects of activating the platelet olfactory receptor OR2L13 (shown as the red transmembrane protein in the left panel) with a compound identified by the Cameron lab (CCF0054500). The middle panel shows disruption of the platelet cytoskeleton accompanied by changes in membrane shape. In the paired images on the right, panel A demonstrates increased platelet reactivity within a narrowed vessel (stroke risk), while panel B shows reduced platelet activity following addition of the compound. Image created by Dave Schumick.

On the clinical front, the researchers note that further pharmacokinetic studies and human trials are needed to explore the practical potential of these findings. “With that essential caveat,” Dr. Cameron says, “targeting platelet OR2L13 appears to represent a promising new frontier in the prevention of arterial thrombosis, particularly for patients at risk despite standard-of-care therapy. By use of a signaling pathway that leaves the protective mechanisms of hemostasis intact, this approach could offer a safer alternative for high-risk populations, including the elderly and those with complex atherosclerotic disease.”

“This novel approach, meticulously characterized by Dr. Cameron and his team using an olfactory receptor agonist, is particularly compelling because it appears to act through a downstream mechanism common to all the pathways of platelet activation that have traditionally been targeted individually with antithrombotic medications,” notes interventional cardiologist A. Michael Lincoff, MD, who wasn’t involved in the study. “While the finding that this agent can inhibit thrombosis without compromising protective hemostasis in mouse models remains to be corroborated in humans, this therapy holds exciting potential as a means of achieving the sweet spot of suppressing residual high platelet reactivity in patients with cardiovascular disease without excessive bleeding risk.”