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.