Platelet activation dynamics determine thrombus size and structure at arterial but not venous shear

Chris Jones

Platelet response to activating stimuli and pharmaceutical agents varies greatly within the normal population. The majority of data on platelet function comes from endpoint assays, yet platelets function in a dynamic environment and the kinetics of their response is likely to be just as physiologically relevant. To evaluate this, we have developed bespoke real-time flow cytometry assays and an analysis package that enables the measurement of the rate of platelet activation over time. The kinetics of platelet activation we assessed in 143 fasted, healthy, aspirin free donors. A recall of 12 individuals from the initial cohort was used to assess the effect of platelet response kinetics on thrombus formation and structure. The rate of platelet activation varied considerably within the normal population but did not correlate with maximal platelet activation, demonstrating that platelet rate is a separate and novel metric to describe platelet reactivity. The relative rate of platelet response between agonists was strongly correlated, suggesting a central control mechanism regulates the rate of platelet response to all agonists. Furthermore, platelet response kinetics correspond to thrombus size and structure, where faster responders form larger, more densely packed thrombi at arterial, but crucially not venous shear. We have demonstrated that the rate of platelet activation is an important metric in stratifying individual platelet responses. This provides a novel focus for the design and development of anti-platelet therapy, targeting high shear thrombosis without exacerbating bleeding at low shear.

 

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