Antithrombotic activity of TNF-α
Beatrice Cambien, Wolfgang Bergmeier, Simin Saffaripour, Heather A. Mitchell, Denisa D. Wagner
Beatrice Cambien, Wolfgang Bergmeier, Simin Saffaripour, Heather A. Mitchell, Denisa D. Wagner
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Article Hematology

Antithrombotic activity of TNF-α

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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Effect of in vivo and in vitro treatments with TNF-α on platelet functio...
Effect of in vivo and in vitro treatments with TNF-α on platelet function. PBS (white bars) or TNF-α (black bars) were administered for 30 minutes either to whole blood samples (a, c, and e) or by intravenous injection into mice (b, d, and f). PRP was prepared, and platelets were tested for aggregation in response to 2 μM ADP (e and f). To study platelet activation by flow cytometry, platelets were washed, activated for 5 minutes with thrombin (0.1 U/ml) or CRP (2 μg/ml), and incubated for 10 minutes at 37°C with FITC-conjugated Ab’s against human fibrinogen (a and b) or a FITC-conjugated mAb against P-selectin (c and d). (g and h) Shown are representative results of TNF-α systemic administration on fibrinogen binding and platelet aggregation. n = 6 mice per group. *P < 0.05; **P < 0.005. MFI, mean fluorescence intensity.