Immune cell composition in thrombosis: insights into arterial disease, infection, and tumor metastasis

Luo, Junfu (2025): Immune cell composition in thrombosis: insights into arterial disease, infection, and tumor metastasis. Dissertation, LMU München: Medizinische Fakultät

Abstract

The present thesis, the multifaceted roles of immune cells, especially of CD4+ T cells in atherothrombosis as well as in thrombosis in infection, infection and tumor metastasis have been investigated. The morphological and structural characterization of large thrombi from carotid and femoral arteries highlighted distinct regional differences in fibrin density and immune cell distribution. CD4+ T cells, particularly activated subsets, were predominantly located in fibrin and platelet-rich regions, potentially modulating fibrinolysis through fibrinolysis regulators such as uPA and TAFI. In pulmonary thrombi from COVID-19 patients, CD4+ T cells negatively correlated with the extent of microvascular thrombosis. This correlation was stronger in COVID-19 than in influenza virus infection, highlighting the unique inflammatory and thrombotic interplay in COVID-19 pathophysiology. In chronic arterial thrombosis, neovascularization occurred with microthrombi embedded in microvessels that often contained T helper cells. This could suggest that CD4+ T cells are long-term regulators of thrombosis, potentially contributing to contributing to the maintenance of blood flow through organized thrombotic tissue. In experimental infection with E. coli, CD4+ T cells were found to be engaged in fibrinolysis by means of the binding the fibrinolysis inhibitor (TAFI). CD4+ T cells counteracted TAFI-mediated fibrinolysis inhibition in particular by preventing binding of TAFI to fibrin. Moreover, in a murine model of S. pneumoniae infection, activated Th17 cells were identified as potent attractors of tPA in microvascular thrombosis within liver sinusoids, suggesting a specialized role for this T cell subtype in fibrinolysis during infection. In animal models of pancreatic metastasis, microvascular thrombosis influenced tumor cell extravasation. While rivaroxaban reduced extravasation in poorly pro-coagulant tumor cell lines, it increased extravasation in highly pro-coagulant tumor cell lines, suggesting that under specific conditions, microvascular thrombosis might potentially accelerate early metastasis by influencing vessel permeability. This thesis provides significant insights into the intricate roles of thrombosis and CD4+ T cells across different pathological settings, paving the way for targeted therapeutic strategies in thrombosis and related diseases.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: T cells, Thrombosis, Fibrinolysis
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 15. Juli 2025
• 1. Bericht­erstatter:in: Engelmann, Bernd