Impact of a novel variant of the beta isoform of the TBXA2R gene associated with a hemorrhagic disorder on platelet and endothelial function

Inherited bleeding disorders are genetic diseases that manifest with a tendency to bleed, which may be life-threatening and may significantly worsen quality of life. Thromboxane is a molecule that acts as a platelet agonist interacting with its receptor on the surface of platelets and activates them, in this way allowing them to arrest bleeding. The thromboxane receptor defect is a very rare and poorly studied inherited bleeding disorder caused by mutations in the TBXA2R gene. Its diagnosis requires complex laboratory tests and it is still unclear whether being carrier of a TBXA2R mutation is sufficient to generate a bleeding disorder or additional genetic alterations are required. There are two subtypes of the thromboxane receptor, TPα and TPβ, and it is not yet clear whether platelets possess both and which are the relative functions of the two. Finally, the thromboxane receptor is present also in endothelial cells, the cells paving the inner side of our blood vessels, but nobody has ever studied whether mutations in the thromboxane receptor can also damage these cells. Starting from the study of a family affected by this rare genetic disease, our project aims to enhance knowledge on the thromboxane receptor defect by improving its diagnosis, clarifying the role of concomitant genetic mutations which can contribute to bleeding, and determining whether the TPβ subtype of the receptor is expressed in platelets and what is its function. In addition, we will also investigate whether mutations in the thromboxane receptor may impact endothelial cells, contributing to patient bleeding.