THE RECIPROCAL RELATIONSHIP OF THROMBOPOIETIN (C-MPL LIGAND) TO CHANGES IN THE PLATELET MASS DURING BUSULFAN-INDUCED THROMBOCYTOPENIA IN THE RABBIT

Thrombopoietin (c-Mpl ligand) has recently been purified and is consid ered to be the humoral regulator of platelet production. To see whethe r this molecule possessed the physiologic characteristics necessary to mediate the feedback loop between blood platelets and the bone marrow megakaryocytes, we determined the relationship between blood levels o f thrombopoietin and changes in the circulating platelet mass. We deve loped a model of nonimmune thrombocytopenia in rabbits by the subcutan eous administration of busulfan. Compared with pretreatment plasma, pl asma taken from all thrombocytopenic rabbits at their platelet nadir c ontained increased amounts of thrombopoietin. All of this activity was neutralized by soluble c-Mpl receptor. We subsequently measured the l evel of thrombopoietin in the circulation over the entire time course after the administration of busulfan. As the platelet mass declined, l evels of thrombopoietin increased inversely and proportionally and pea ked during the platelet nadir, With return of the platelet mass toward normal, thrombopoietin levels decreased accordingly. When platelets w ere transfused into thrombocytopenic rabbits near the time of their pl atelet count nadir, the elevated levels of thrombopoietin decreased. I n addition, platelets were observed to remove thrombopoietin from thro mbocytopenic plasma in vitro. These results confirm that thrombopoieti n is the humoral mediator of megakaryocytopoiesis and suggest that the platelet mass may directly play a role in regulating the circulating levels of this factor, (C) 1995 by The American Society of Hematology.