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Prothrombotic effects of tumor necrosis factor alpha in vivo are amplified by the absence of TNF-alpha receptor subtype 1 and require TNF-alpha receptor subtype 2

Joachim Pircher12*, Monika Merkle1, Markus Wörnle1, Andrea Ribeiro1, Thomas Czermak2, Yvonn Stampnik2, Hanna Mannell2, Markus Niemeyer3, Volker Vielhauer1 and Florian Krötz4

Author Affiliations

1 Medizinische Klinik und Poliklinik IV, Innenstadt, Ludwig Maximilians University München, Ziemssenstr. 1, 80336 Munich, Germany

2 Walter Brendel Centre of Experimental Medicine, Ludwig Maximilians University München, Marchioninistr. 27, 81377 Munich, Germany

3 Department of Gynecology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, Germany

4 Invasive Cardiology, Clinic Starnberg, Oßwaldstr. 1, 82319 Munich, Germany

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Arthritis Research & Therapy 2012, 14:R225  doi:10.1186/ar4064

Published: 18 October 2012



Elevated serum levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFα) correlate with an increased risk for atherothrombotic events and TNFα is known to induce prothrombotic molecules in endothelial cells. Based on the preexisting evidence for the impact of TNFα in the pathogenesis of autoimmune disorders and their known association with an acquired hypercoagulability, we investigated the effects of TNFα and the role of the TNF receptor subtypes TNFR1 and TNFR2 for arteriolar thrombosis in vivo.


Arteriolar thrombosis and platelet-rolling in vivo were investigated in wildtype, TNFR1-/-, TNFR2-/- and TNFR1-/R2-/- C57BL/6 mice using intravital microscopy in the dorsal skinfold chamber microcirculation model. In vitro, expression of prothrombotic molecules was assessed in human endothelial cells by real-time PCR and flow cytometry.


In wildtype mice, stimulation with TNFα significantly accelerated thrombotic vessel occlusion in vivo upon ferric chloride injury. Arteriolar thrombosis was much more pronounced in TNFR1-/- animals, where TNFα additionally led to increased platelet-endothelium-interaction. TNFα dependent prothrombotic effects were not observed in TNFR2-/- and TNFR1-/R2- mice. In vitro, stimulation of human platelet rich plasma with TNFα did not influence aggregation properties. In human endothelial cells, TNFα induced superoxide production, p-selectin, tissue factor and PAI-1, and suppressed thrombomodulin, resulting in an accelerated endothelial dependent blood clotting in vitro. Additionally, TNFα caused the release of soluble mediators by endothelial cells which induced prothrombotic and suppressed anticoagulant genes comparable to direct TNFα effects.


TNFα accelerates thrombus formation in an in vivo model of arteriolar thrombosis. Its prothrombotic effects in vivo require TNFR2 and are partly compensated by TNFR1. In vitro studies indicate endothelial mechanisms to be responsible for prothrombotic TNFα effects. Our results support a more selective therapeutic approach in anticytokine therapy favouring TNFR2 specific antagonists.