Identification of a rheology dependent platelet aggregation mechanism

Abstract

There is a growing body of evidence suggesting that the dynamics of platelet aggregation are regulated by shear (rheology) dependent platelet aggregation mechanisms that operate alongside traditional soluble agonist dependent aggregation mechanisms. Rheology-dependent platelet aggregation requires the biomechanical adhesive and signalling function of GPIb and integrin αIIbβ3, with the contribution of each receptor to the initiation of aggregation dependent on local hemodynamic conditions. In contrast, soluble agonists amplify and potentiate platelet activation and play a major role in stabilising formed aggregates. Unravelling the dynamics of platelet aggregation and thrombus formation in vivo therefore requires consideration of the co-operative interplay between soluble agonist and rheology-dependent platelet aggregation mechanisms. This thesis focuses on the role of hemodynamics (rheology) in platelet activation and aggregation. Chapter 3 describes the characterisation of the dynamic behaviour of platelet aggregation in vivo. In Chapter 4 it is established that platelet aggregation is greatly enhanced by acute changes in blood flow conditions. A novel rheology dependent platelet aggregation mechanism is identified that operates in the presence of shear microgradients. In chapter 5 I further characterise rheology dependent platelet aggregation and establish the relative role of soluble agonists in this process. Chapter 6 describes a novel and highly localised platelet morphological shape change that forms the basis of a mechano-sensory mechanism that allows platelets to respond to local hemodynamic conditions. This mechanism, involving membrane tether restructuring, increases the ability of discoid platelets to aggregate within low or decelerating shear zones in the blood flow.