The prevention and treatment of arterial thrombosis remain a clinical challenge, and a better knowledge of the key molecular pathways may aid in the search for new targets and therapeutic methods to increase protection against ischemia and bleeding events. Collagen-induced platelet aggregation is aided by the chemokine CXCL12, which activates the CXCR4 receptor. In a study, researchers showed that inhibiting CXCR4 inhibits platelet aggregation produced by collagen or human plaque homogenate under static and arterial flow conditions by blocking platelet-secreted CXCL12. CXCL12 initiated a signaling cascade including Bruton’s tyrosine kinase (Btk) that resulted in integrin αIIbβ3 activation, platelet aggregation, and granule release via CXCR4. CXCL12-CCL5 heterodimer interaction can suppress CXCL12-mediated effects, as imitated by CCL5-derived peptides such as [VREY]4. An enhanced form of the peptide, I[VREY]4, binds to CXCL12 on the surface of activated platelets in a complex with CXCR4, limiting Btk activation and reducing platelet CXCL12-dependent arterial thrombosis. I [VREY]4 decreased CXCL12-induced platelet aggregation while not prolonging in vitro bleeding time, in contrast to traditional antiplatelet treatments such as aspirin or P2Y12 inhibition. They showed that platelet-derived CXCL12 was implicated in arterial thrombosis and maybe precisely targeted by peptides with potential anti-atherothrombotic properties.
