Investigating platelet receptor shedding mechanisms in physiological and pathophysiological conditions

Platelets respond to vascular cues such as extracellular matrix exposure, bacterial and viral invasion, and alterations to fluid shear rates and shear stress, enabling platelets to play a pivota ‘early responder’ role to vascular injuries. They adhere to an injured endothelium through specific adhesion/signalling receptors, including GPVI and GPIb-IX-V. Platelet adhesion unleashes a cascade of platelet signalling and activation responses, resulting in degranulation, and aggregation, all of which are essential for the formation of blood clots. However, to prevent excessive activation, platelets employ a mechanism to downregulate the presence of receptors on their surface. One intriguing mechanism for this downregulation involves the metalloproteolytic shedding of the active, ligand-binding portion of platelet receptor proteins.

Our research laboratory is dedicated to the in-depth exploration of the intricate interplay among platelet receptors, metalloproteases, and the surrounding plasma microenvironment, all of which contribute to receptor shedding, a normal haemostatic process that can lead to clotting and bleeding outcomes in patients with prothrombotic or bleeding phenotypes. We have a range of discovery research projects which explore how other platelet proteins such as amyloid precursor protein (APP) and Trem-like transcript-1 (TLT-1) undergo controlled autologous proteolysis under pathophysiologicial conditions.

Figure 1:Hicks et al; The molecular basis of immune-based platelet disorders. Clin Sci (Lond) 13 November 2020; 134 (21): 2807–2822.

 

Figure 2: SEM imaging of human platelets activated through Collagen-GPVI receptor interaction in plasma. Image was acquired at 1000KX magnification.