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Antithrombotic activity of TNF-α
Beatrice Cambien, … , Heather A. Mitchell, Denisa D. Wagner
Beatrice Cambien, … , Heather A. Mitchell, Denisa D. Wagner
Published November 15, 2003
Citation Information: J Clin Invest. 2003;112(10):1589-1596. https://doi.org/10.1172/JCI19284.
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Categories: Article Hematology

Antithrombotic activity of TNF-α

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Abstract

Basic and clinical observations suggest that thrombosis and inflammation are closely related. Here we addressed the role played by TNF-α in thrombus formation and growth in an in vivo mouse model. Using intravital microscopy, we show that systemic administration of TNF-α at doses found in sepsis transiently inhibits thrombus formation and delays arterial occlusion upon vascular injury. These results were reflected in a prolonged bleeding time. Platelets isolated from the TNF-α–treated mice showed a marked decrease in fibrinogen binding and P-selectin expression as well as reduced platelet aggregation in response to various agonists. In contrast, in vitro treatment of platelets with TNF-α did not affect their function. TNF receptor 1– and 2–deficient mice exhibited normal thrombogenesis in the presence of TNF-α. Additionally, the inhibitory effect of TNF-α was lost either after treatment with NG-monomethyl-L-arginine, an inhibitor of NO production, or in mice deficient for iNOS. These results indicate that under inflammatory conditions, when leukocytes need free passage to transmigrate into tissues, TNF-α decreases platelet activation and inhibits thrombi formation. This effect is not exerted directly on platelets but mediated through the rapid generation of NO in the vessel wall.

Authors

Beatrice Cambien, Wolfgang Bergmeier, Simin Saffaripour, Heather A. Mitchell, Denisa D. Wagner

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Figure 3

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Tail bleeding time and plasma clotting time in TNF-α–treated mice. Mice ...
Tail bleeding time and plasma clotting time in TNF-α–treated mice. Mice 12–16 weeks old were infused with PBS or TNF-α. (a) The bleeding time was measured after amputation of a 3-mm portion of the tail. The mice injected with TNF-α (filled circles) exhibited a fourfold prolonged bleeding time compared with control mice (open circles) (P < 0.003). (b) Plasma clotting time was measured in an aggregometer after adding CaCl2 solution. The clotting time was significantly shorter in mice treated with 1 ng/ml of TNF-α (black bar) than in control mice (white bar). P < 0.001, n = 8 mice per group.
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