Broadening the Lens on Inflammation and Immune Dynamics in Venous Thromboembolism

Steven Philip Grover¹Alexander Brill^2*

• ¹Blood Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
• ²University of Birmingham, Birmingham, United Kingdom

Another recurring and crucial player in the field is the vascular endothelium. Beyond serving as a structural barrier, endothelial cells actively participate in immune surveillance and hemostatic regulation. Inflammatory activation of endothelial cells leads to the upregulation of adhesion molecules such as P-selectin and E-selectin, as well as the release of von Willebrand factor, with all these promoting leukocyte and platelet recruitment and facilitating thrombus propagation. Disruption of the endothelial glycocalyx, an early event in thrombus formation, also contributes to these processes by exposing adhesion receptors and altering vascular shear dynamics (7). Recent evidence suggests that preservation of glycocalyx integrity could be a novel therapeutic goal, particularly in patients at high risk for thrombosis.While innate immune drivers have been extensively studied in the context of VTE, the role of adaptive immunity remains relatively underexplored. Emerging data suggest that Th17 cells induce IL-17-mediated endothelial activation and neutrophil recruitment, which may exacerbate thrombotic risk (8,9). Conversely, special regulatory T cells (Tregs) are involved in venous thrombus resolution (10). Interestingly, B cells may be protective against venous thrombosis as their deficiency promotes DVT through elevated neutrophil counts and fibrinogen levels (11). Greater integration of adaptive immune profiling into thrombosis research could reveal new therapeutic angles, particularly in the context of autoimmune and chronic inflammatory conditions.A novel and increasingly relevant perspective not deeply explored in this collection, but deserving mentioning, is the influence of the gut microbiome on thrombotic risk. Metabolites such as trimethylamine-N-oxide (TMAO), produced by gut flora, have been shown to increase platelet reactivity and systemic inflammation (12). In conditions such as obesity, diabetes, and aging, gut dysbiosis is associated with chronic low-grade inflammation, a known risk factor for VTE. Investigating the microbiota-immune-coagulation axis may open new prevention strategies, including dietary modulation or probiotic therapy.In this Research Topic, Alturky et al review evidence in support of the connection between metabolic syndrome and post-thrombotic syndrome identifying key knowledge gaps (13). Lu et al review the key role of monocytes and macrophages in the chronic resolution of venous thrombi (14). Liu et al identify a significant association between platelet derived growth factor and venous thromboembolism using a Mendelian randomization-based approach (15). Cheng et al highlight the potential prothrombotic effects of recombinant human granulocyte colony-stimulating factor treatment in patients with cancer (16). Vincent et al identify an important role for recombinant mast cell chymase as a negative regulator of endogenous fibrinolysis (17).The translational potential of these findings cannot be overstated. As this Research Topic illustrates, targeting inflammatory and immune pathways offers promising avenues for VTE treatment. Statins, for instance, may reduce venous thrombosis burden likely through reducing the inflammatory component in both experimental and clinical studies (18,19). Additionally, inflammatory biomarkers, such as circulating FNA, IL-6, or soluble P-selectin, could serve as tools for risk stratification, especially in cancer-associated thrombosis where individualized treatment remains a challenge (20). A personalized medicine approach, integrating immunological and coagulation profiles, may ultimately yield better outcomes in both prevention and management of VTE.In conclusion, the articles included in this Research Topic advance the understanding of how inflammation and immune responses contribute to venous thromboembolism. By integrating new knowledge in the field, this body of work offers a broader and more nuanced perspective on VTE pathophysiology. These contributions not only enhance our current conceptual models but also provide the foundation for novel therapeutic strategies. Continued interdisciplinary collaboration, for example, modeling of venous thrombosis in silico (21) or in a vessel-on-a-chip devices (22), will be essential to translate these insights from bench to bedside and to fully harness the potential of immunothrombotic research in reducing the burden of VTE.