Antiplatelet drugs are one of the main tools used to prevent blood clots from forming in people who have had a heart attack or stroke or have cardiovascular disease that puts them at high risk for blood clots. These treatments work by reducing the ability of platelets to clump together and form blood clots that can block arteries. However, their use also increases the risk of bleeding, a common complication that limits their use to certain patients and remains one of the major challenges in cardiology today.
Now, research by researchers at the Saint Pau Institute (IR Saint Pau) and the Center for Cardiovascular Biomedicine (CIBERCV) has identified a new protein involved in platelet activation that could help advance safer antithrombotic therapy. Works published in magazines european heart journalshowed for the first time that the LRP5 protein, known for its role in the WNT signaling pathway, is directly involved in platelet aggregation and arterial thrombus formation. The relevance of this finding led the same journal to simultaneously publish an independent editorial on new antithrombotic strategies that could reduce bleeding risk.
We observed that both genetic deletion of LRP5 and its pharmacological inhibition highly significantly reduced platelet activation and thrombus formation in preclinical models, but the effect on bleeding was much lower than that of classical antiplatelet drugs such as aspirin and clopidogrel. ”
Dr. Maria Borrell-Pages, researcher in the Molecular Pathology and Treatment Group of Atherothrombotic and Ischemic Diseases at IR Sant Pau and CIBERCV, corresponding author of the study
New pathways involved in thrombus formation
To study the role of LRP5 in platelet activation, the researchers combined experiments with mouse models lacking the protein and human blood and platelets. The analysis showed that in the absence of LRP5, the ability of platelets to adhere to collagen and aggregate after stimulation with ADP and collagen, the two main mechanisms involved in clot formation, was significantly reduced.
One of the most relevant results was observed in an experimental model of arterial thrombosis. While normal animals developed complete occlusion of the carotid artery in approximately 21 minutes, LRP5-deficient mice did not completely occlude the vessel during the 30-minute experiment. Furthermore, the researchers observed that the deposition of platelets and fibrinogen on blood vessel walls was reduced and the antithrombotic effects associated with LRP5 inhibition were enhanced.
“What we are seeing is that LRP5 is involved in a central mechanism of platelet activation and communication,” explains Dr. Maria Borrell Pages. “Inhibiting this protein alters important processes required to stabilize and amplify blood clot formation.”
Similar results were obtained in experiments conducted using human blood. Pharmacological inhibition of LRP5 reduced both platelet aggregation and thrombus formation under high-flow conditions, reproducing the behavior observed in animal models.
Furthermore, the effect on bleeding was clearly lower than that observed with conventional antiplatelet drugs. In animal models, bleeding times were much shorter than those recorded after treatment with acetylsalicylic acid or clopidogrel, reinforcing the potential of LRP5 as a new therapeutic target for developing safer antithrombotic strategies.
Direct interaction with P2Y12 receptors
Another most important finding of this study was the identification of a direct interaction between LRP5 and the platelet P2Y12 receptor, one of the main therapeutic targets for antiplatelet drugs currently used in patients at cardiovascular risk. Drugs such as clopidogrel, prasugrel, and ticagrelor work precisely by blocking this receptor, preventing platelet activation and aggregation.
Experiments conducted by the IR Sant Pau and CIBERCV teams showed that LRP5 helps regulate P2Y12 function during platelet activation. The researchers observed that when LRP5 is blocked or absent, P2Y12 loses some of its ability to transmit signals that activate platelets to aggregate, thereby significantly reducing clot formation.
Additionally, LRP5-deficient platelets showed changes in the release of molecules stored within granules, a process necessary to amplify clot formation. The researchers detected decreased release of serotonin and proteins associated with platelet activation, as well as changes in the phosphorylation of VASP, a functional marker closely related to P2Y12 activity.
“This shows that LRP5 functions as an important regulator of platelet response,” explains Dr. Maria Borrell Pages. “Rather than directly blocking the classical clotting mechanism, we modulate the processes that help amplify and stabilize blood clot formation,” the researchers said, adding that the discovery opens new avenues in the study of thrombosis. “The possibility of acting not only on classical receptors, but also on regulatory proteins involved in platelet activation, could help in the development of more selective treatments that may be safer in the future.”
Aiming for safer antithrombotic therapy
The authors emphasize that this study is still in the preclinical stage and further research is needed to translate these findings into clinical practice. LRP5 is involved in multiple physiological functions, including cardiovascular, neurological, and bone metabolic processes, which means that future therapeutic development should explore selective strategies that specifically target platelets.
Still, this study positions LRP5 as a new potential therapeutic target for thrombosis and provides a new approach to try to reduce bleeding risk, one of the major problems associated with current antiplatelet therapy. In clinical practice, many patients at high cardiovascular risk require long-term treatment to prevent new thrombotic events, but increased bleeding risk may limit its use and treatment intensity.
The possibility of delaying thrombus formation without significantly altering physiological hemostasis is indeed one of the main goals of current cardiovascular research. The relevance of this approach was highlighted by: european heart journal itself. Publication of this study was accompanied by an independent editorial article focused on the development of new antithrombotic strategies that can reduce the bleeding risks associated with traditional treatments.
“Our study opens new avenues to explore the possibility of more selective and safer antithrombotic treatments,” concludes Dr. Maria Borrell Pages. “Although we are still in the experimental phase, identifying the regulatory mechanisms of platelet activation, such as LRP5, may help us develop more precise treatments in the future.”
sauce:
Institut de Recerca Sant Pau
Reference magazines:
Lucero, A. others. (2025) LRP5, WNT signaling pathway receptor, and platelet activation; European Heart Journal. DOI: 10.1093/eurheartj/ehaf772. https://academic.oup.com/eurheartj/article-abstract/47/16/1964/8272826
