Inhibition of prothrombotic effect of thrombopoietin with ticlopidine ameliorates survival after total body irradiation
Mouthon M-A., Gaugler M-H., Vandamme M, Gourmelon P., Wagemaker G. and Van der Meeren A.
18th congress of the international society on thromboses and haemostasis, Paris, 6-12/07/2001
Thrombopoietin stimulates platelet activation in the presence of platelet agonists. On the other hand, irradiation induces the release of platelet agonists. Thus, we have determined the effects of thrombopoietin on platelet activation and thrombosis formation in irradiated C57BL6/J mice and whether the use of ticlopidine, an anti-platelet drug, could reduce thrombopoietin-induced platelet activation and promote long term survival. Platelet counts decreased subsequently to 9 Gy total body irradiation because platelet production is reduced to virtually none after such an irradiation dose. However, platelet counts decreased more rapidly in mice receiving 0.3 µg thrombopoietin 2h after irradiation suggesting that thrombopoietin enhanced platelet adhesion and aggregation to the endothelium. Accordingly, platelet activation, as determined by P-selectin expression on platelets, was higher in thrombopoietin-treated mice as compared to placebo group, regardless an ex vivo stimulation with agonists. Moreover, immunohistochemistry studies and injection of 125I-fibrinogen showed that thrombopoietin induced an higher fibrin deposition into tissues. Pretreatment of mice with ticlopidine dramatically reduced platelet activation and alleviated the platelet consumption induced by thrombopoietin. The combination of ticlopidine with thrombopoietin almost fully promoted 180-day survival whereas only 30% of the mice treated with thrombopoietin alone survived. In summary, thrombopoietin increases platelet reactivity in irradiated mice which, in turn, promotes thrombosis. The use of ticlopidine is efficient to counteract this adverse effect of thrombopoietin and our results suggest that platelet thrombi are involved in long term mortality of thrombopoietin-treated irradiated mice.