CX3CR1/CX3CL1 Axis Mediates Platelet-Leukocyte Adhesion to Arterial Endothelium in Younger Patients with a History of Idiopathic Deep Vein Thrombosis

Abstract

Mechanisms linking deep vein thrombosis (DVT) and subclinical atherosclerosis and risk of cardiovascular events are poorly understood. The aim of this study was to investigate the potential impact of CX₃CR1/CX₃CL1 axis in DVT-associated endothelial dysfunction. The study included 22 patients (age: 37.5 ± 8.2 years) with a history of idiopathic DVT and without known cardiovascular risk factors and 23 aged-matched control subjects (age: 34 ± 7.8 years). Flow cytometry was used to evaluate peripheral markers of platelet activation, leukocyte immunophenotypes and CX₃CR1/CX₃CL1 expression in both groups. A flow chamber assay was employed to measure leukocyte arrest under dynamic conditions. Platelet activation and the percentage of circulating CX₃CR1-expressing platelets, CX₃CR1-expressing platelet-bound monocytes and CD8⁺ lymphocytes were higher in patients with DVT than in controls. Additionally, patients with DVT had increased plasma levels of CX₃CL1, soluble P-selectin and platelet factor 4/CXCL4. Interestingly, this correlated with enhanced platelet-leukocyte interaction and leukocyte adhesion to TNFα-stimulated arterial endothelial cells, which was partly dependent on endothelial CX₃CL1 upregulation and increased CX₃CR1 expression on platelets, monocytes and lymphocytes. In conclusion, increased CX₃CR1 expression on circulating platelets may constitute a prognostic marker for long-term adverse cardiovascular events in patients with DVT. Blockade of CX₃CL1/CX₃CR1 axis may represent a new therapeutic strategy for the prevention of cardiovascular comorbidities associated with DVT.