Work

Selective Inhibition of Integrin β3 Topology Provides a Safer Antithrombotic Strategy

Year: 2026

Type: article

Abstract: Cardiovascular and cerebrovascular diseases, the leading causes of death worldwide, are primarily driven by pathological thrombus formation resulting from uncontrolled platelet aggregation at sites of atherosclerotic plaque rupture. Current antiplatelet drugs are designed either to indirectly inhibit intracellular signaling pathways that activate integrin αIIbβ3 or to directly block the binding of the activated integrin to fibrinogen. However, because this interaction is also essential for normal hemostasis, these drugs inevitably increase the risk of serious spontaneous bleeding. In this study, we aimed to develop a safer strategy to prevent thrombosis without impairing hemostasis. Building on our previous findings that the transmembrane domain (TMD) of integrin β3 undergoes distinct topological changes during force- vs. agonist-dependent activation, we targeted the β-tail domain of integrin β3 as an epitope for an antibody that selectively blocks force-induced changes. This antibody specifically inhibits force-dependent αIIbβ3 activation, a key driver of platelet aggregation at atherosclerotic lesions, and suppresses platelet aggregation in ex vivo and in vivo models without inducing bleeding. From these results, we conclude that this approach offers a promising therapeutic strategy to prevent thrombosis while minimizing bleeding risk, addressing a major limitation of current antiplatelet therapy.

Source: Advanced Science

DOI: 10.1002/advs.202522086