Thyroid-stimulating hormone enhances platelet activation and arterial thrombosis

Thyroid-stimulating hormone (TSH), elevated in conditions like subclinical hypothyroidism, has been clinically linked to a higher risk of morbidity and mortality in patients with coronary artery disease (CAD). Here, we aim to investigate the effects of TSH on CAD-associated platelet activation and arterial thrombosis, along with the underlying mechanisms.

Clinical study demonstrated that higher TSH levels are associated with an increased risk of major adverse cardiovascular events in CAD patients. In vitro human and mouse platelet function studies found that TSH potentiates agonist-induced platelet aggregation, dense granule adenosine triphosphate release, integrin alpha-IIb beta-3 activation, P-selectin release from α-granules, platelet spreading, and clot retraction. Furthermore, in vivo animal studies demonstrated that TSH enhances thrombosis, whole blood thrombus formation, and middle cerebral artery occlusion-induced brain injury. Mechanistic studies revealed that platelets express the TSH receptor (TSHR). TSH binds to platelet TSHR and activates both the Gs/cAMP/PKA and Gq/Ca2+/PKC/MAPK signaling pathways. Activation of the Gq pathway is more pronounced than that of the Gs pathway, thereby potentiating platelet activation. Finally, our in vivo work showed that TSH aggravates microvascular obstruction and promotes myocardial infarction expansion in a mouse myocardial ischeamia/reperfusion injury model.

TSH augments platelet activation and in vivo thrombus formation through engagement of platelet TSHR, subsequently activating downstream signaling cascades involving Gs/cAMP/PKA and Gq/Ca2+/PKC/MAPK pathways.