Abstract 159: Effect Of Antiplatelet Agents And Tyrosine Kinase Inhibitors On OxLDL-mediated Platelet Procoagulant Activity

Background & Objective: Oxidized low density lipoprotein (oxLDL) contributes to atherogenesis and cardiovascular disease through interactions with peripheral blood cells, especially platelets. However, the mechanisms by which oxLDL affects platelet activation, and how to best therapeutically target and safely prevent such responses remains unclear. Here, we investigate how oxLDL upregulates glycoprotein VI (GPVI) mediated platelet hemostatic and procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-enhanced platelet activity ex vivo . Methods: Human platelets were treated with oxLDL and GPVI specific agonist, crosslinked collage-related peptide (CRP-XL) and assayed for hemostatic and procoagulant responses in the presence of inhibitors of purinergic receptors (P2Y; ticagrelor, AR-C 66096, MRS2179), cyclooxygenase (COX; aspirin, indomethacin), Bruton’s tyrosine kinase (BTK; ibrutinib), and spleen tyrosine kinase (Syk; fostamatinib/R406). Results: Ex vivo , oxLDL enhanced GPVI-mediated platelet dense granule secretion, alpha granule secretion, integrin activation, thromboxane generation, and platelet aggregation, as well as phosphatidylserine exposure and fibrin generation. Our study further demonstrated that CD36 signaling from oxLDL activation overlaps with the GPVI signaling pathway, in such that the phosphorylation of proteins along the Syk-BTK-PI3K/Akt axis was increased. P2Y antagonists (e.g., ticagrelor), BTK inhibitors (e.g., ibrutinib), and Syk inhibitors (e.g. fostamatinib) reduced oxLDL-mediated platelet responses and procoagulant activity, whereas COX inhibitors (e.g., aspirin) had no significant effect. Conclusion: Together, our results demonstrate that oxLDL enhances ex vivo platelet responses and procoagulant activity downstream of GPVI signaling in a manner that may be reduced by P2Y antagonists and tyrosine kinase inhibitors, but not significantly affected by COX inhibitors.