CBE PhD Dissertation Defense | “The effects of platelet signaling inhibitors on clot development under flow”

Abstract: 

“Syk and Src family kinases (SFK) inhibitors interfere with signaling from GPVI, α2β1, αIIbβ3, and GPIb-IX-V to reduce thrombotic risk or induce bleeding episodes. Collagen-mediated clustering of platelet GPVI results in phosphorylation of SFKs such as Lyn and Fyn, and active Lyn is constitutively bound to GPVI to allow rapid signaling. During clotting under flow, the generation of fibrin can have diverse influences on platelet signaling by sequestering thrombin and potentially activating GPVI signaling within the clot interior. These inhibitors tackle the thrombus formation at earlier stages since the platelets reach the activation surface. Direct inhibition of GPVI was used to compare the difference between inhibition of subsequent pathways. Using microfluidics, the effects of these inhibitors can be explored under defined hemodynamic flows and procoagulant surface triggers. Additionally, the drug may be present in the blood at desired time of clotting by perfusion switching to drug-treated blood. This experimental design allows exploration of platelet response at different stages of clotting through the measurement of drug potency to modulate clotting on different procoagulant surface conditions.“