The platelets found in blood are membrane-wrapped cell fragments generated by a specialized population of megakaryocytes. As such, platelets can contain most of the molecules and structures that are present inside a cell, and exhibit behavior and surface features that reflect their parent cell’s state. The primary purpose of platelets is to induce coagulation of blood and formation of a clot, or thrombus, where needed, such as following injury. With age, there is a tendency for clotting to be maladaptively triggered, particularly around areas of damage and dysfunction in blood vessel walls, such as where atherosclerotic plaques have developed. But even without atherosclerosis and other damage to the innner endothelial layer of blood vessels, there are still other changes to platelets themselves that make inappropriate clotting more likely.
This is the background that led to the development of widely used anti-thrombotic drugs that suppress the enhanced tendency towards clotting. Unfortunately, these drugs act on the same regulatory systems that are employed during useful, necessary clotting, such as following injury. Bleeding is a problematic side-effect. This is a common story in attempts to intervene in problems that occur with age, with chronic inflammation providing another example. The obvious paths to suppress unwanted behavior in system run awry turn out to also suppress desired behavior in that system. As biotechnology and the capabilities of the life science community advance, however, we start to see the first signs of improvement, of the ability to begin to manipulate these complex systems more adroitly, finding ways to suppress the unwanted outcomes with lesser effects on the desired outcomes.
Researchers discover a new therapeutic target to prevent thrombi with a lower bleeding risk
Antiplatelet drugs are one of the main tools used to prevent thrombus formation in people who have had a heart attack or stroke or who have cardiovascular diseases with a high thrombotic risk. These treatments work by reducing platelets’ ability to aggregate and form clots that can obstruct the arteries. However, their use also increases the risk of bleeding, a common complication that limits their use in certain patients and remains one of the major challenges in cardiology today.
Now, a study dentifies a new protein involved in platelet activation that could help advance toward safer antithrombotic therapies. The work shows for the first time that the LRP5 protein, known for its role in the WNT signaling pathway, is directly involved in platelet aggregation and in arterial thrombus formation. “We have observed that both the genetic deletion of LRP5 and its pharmacological inhibition very significantly reduce platelet activation and thrombus formation in preclinical models, but with a much lower bleeding impact than that of classic antiplatelet agents such as aspirin or clopidogrel.”
LRP5, a WNT signalling pathway receptor, and platelet activation
Human platelets, as well as platelets isolated from wild-type (Wt) and Lrp5-deficient (Lrp5-/-) mice, were challenged with ADP, collagen, LRP5-specific inhibitors, and standard platelet inhibitor drugs. Both platelet aggregation and flow-dependent platelet deposition on collagen-coated surfaces were significantly lower in Lrp5-/- than in Wt mice. In vivo carotid artery occlusion time measured by real-time blood flow monitoring was significantly prolonged in Lrp5-/- mice. Human platelets express high levels of LRP5 and flow-mediated human platelet deposition and aggregation was highly reduced by LRP5 inhibition. Under the experimental conditions tested, LRP5 deletion did not significantly affect coagulation nor induce bleeding.
These findings reveal for the first time that LRP5 plays a critical role in platelet adhesion and thrombus formation. Genetic deletion and biochemical inhibition of LRP5 markedly impair platelet aggregation and thrombosis in preclinical models, without major effects on haemostasis. Although further research is needed to evaluate its clinical applicability, LRP5 appears as a novel and actionable target to modulate platelet reactivity and thrombosis.
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