Biphasic Effect of Thyroid Hormone on Megakaryopoiesis and Platelet Production

Abnormal platelet counts are frequently observed in patients with thyroid dysfunction; however, the direct impact of thyroid hormones on thrombopoiesis remains largely undefined. This study elucidates the dose-response effect of the thyroid hormone triiodothyronine (T) on megakaryocyte (MK) development and thrombopoiesis using both a murine model of hyperthyroidism/hypothyroidism and cultures of human cord blood CD34 cell-derived MKs. After the application of inhibitors to MKs, the examination of total and phosphorylated protein levels of the phosphoinositide 3-kinase (PI3K)/AKT pathway was utilized to assess the specific mechanisms of T action. The use of autophagy dual-staining lentivirus and transmission electron microscopy was employed to evaluate the impact of T on the autophagy flux in MKs. Mouse whole-body irradiation and bone marrow transplantation models are applied to assess the influence of T on the recovery of MKs/platelets . We found that physiological or slightly elevated thyroid hormone levels are essential for sustaining MK development and thrombopoiesis, primarily through the TRα-PI3K/AKT signaling pathway. In contrast, supraphysiological thyroid hormone concentrations induce MK apoptosis via excessive autophagy, thereby reducing platelet production. Here, we present evidence that the thyroid hormone influences MK development and platelet production in a concentration-dependent manner, exhibiting a dualistic role. Our discoveries shed new light on the intricate relationship between thyroid hormones and platelet formation, offering novel perspectives on the pathophysiological consequences of thyroid disorders.