Ticlopidine inhibits the prothrombotic effects of thrombopoietin and ameliorates survival after supralethal total body irradiation.
Thrombopoietin modulates the response of platelets to several agonists and, on the other hand, those agonists can be released following irradiation. Thus, we have determined the effects of thrombopoietin, on its own and in combination with ticlopidine, an anti-platelet drug, on platelet activation, thrombosis formation and survival of irradiated C57BL6/J mice. Administration of thrombopoietin 2 h after 9 Gy total body irradiation increased the 125I-fibrin deposition in mouse tissues and accelerated platelet consumption as revealed by an enhanced drop in platelet counts. Additionally, the number of activated platelets, i.e. those expressing P-selectin on their membrane, was higher in thrombopoietin-treated mice as compared to the placebo group, regardless ex vivo stimulation with agonists. These effects of thrombopoietin on platelet activation and consumption were reduced when mice were pretreated with ticlopidine. The combination of ticlopidine with thrombopoietin almost fully promoted 180-day survival, reaching the same efficacy as bone marrow transplantation, while only 30% of the mice treated with thrombopoietin alone survived. In summary, thrombopoietin induces long term-mortality of irradiated mice probably through platelet-mediated thrombosis and thus, ticlopidine efficiently counteracts these adverse effects of thrombopoietin.
Mouthon
Marc-André
MA
Département de Protection de la Santé de l'Homme et de Dosimétrie, Institut de Protection et de Sûreté Nucléaire, Fontenay-aux-Roses, France. marc-andre.mouthon@ipsn.fr
Gaugler
Marie-Hélène
MH
Vandamme
Marie
M
Gourmelon
Patrick
P
Wagemaker
Gerard
G
Van der Meeren
Anne
A
D000818:Animals; D016026:Bone Marrow Transplantation; D004353:Drug Evaluation, Preclinical; D005342:Fibrinolysis / Q000187:drug effects / Q000528:radiation effects; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D015539:Platelet Activation / Q000187:drug effects / Q000528:radiation effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010976:Platelet Count; D058919:Purinergic P2 Receptor Antagonists; D011832:Radiation Injuries / Q000097:blood / Q000188:drug therapy*; D011837:Radiation-Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D058925:Receptors, Purinergic P2Y12; D013926:Thrombopoietin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D013927:Thrombosis / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D013988:Ticlopidine / Q000494:pharmacology* / Q000627:therapeutic use; D014916:Whole-Body Irradiation / Q000009:adverse effects
D005343:Fibrinolytic Agents; D008565:Membrane Proteins; C548577:P2ry12 protein, mouse; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D011837:Radiation-Protective Agents; D058925:Receptors, Purinergic P2Y12; D013926:Thrombopoietin; D013988:Ticlopidine