TitleEffect of antiplatelet agents and tyrosine kinase inhibitors on oxLDL-mediated procoagulant platelet activity.
Publication TypeJournal Article
Year of Publication2023
AuthorsZheng TJ, Kohs TCL, Mueller PA, Pang J, Reitsma SE, Parra-Izquierdo I, Melrose AR, Yang L, Choi J, Zientek KD, Sviridov DO, Larson MK, Williams CD, Pamir N, Shatzel JJ, Reddy AP, Kievit P, Remaley AT, Stevens JF, Hinds MT, McCarty OJT, Aslan JE
JournalBlood Adv
Date Published2023 Apr 25
KeywordsAnimals, Hemostatics, Humans, Lipoproteins, LDL, Mice, Platelet Aggregation Inhibitors, Tyrosine Kinase Inhibitors

Low-density lipoprotein (LDL) contributes to atherogenesis and cardiovascular disease through interactions with peripheral blood cells, especially platelets. However, mechanisms by which LDL affects platelet activation and atherothrombosis, and how to best therapeutically target and safely prevent such responses remain unclear. Here, we investigate how oxidized low-density lipoprotein (oxLDL) enhances glycoprotein VI (GPVI)-mediated platelet hemostatic and procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-enhanced platelet procoagulant activity ex vivo. Human platelets were treated with oxLDL and the GPVI-specific agonist, crosslinked collagen-related peptide, and assayed for hemostatic and procoagulant responses in the presence of inhibitors of purinergic receptors (P2YR), cyclooxygenase (COX), and tyrosine kinases. Ex vivo, oxLDL enhanced GPVI-mediated platelet dense granule secretion, α-granule secretion, integrin activation, thromboxane generation and aggregation, as well as procoagulant phosphatidylserine exposure and fibrin generation. Studies of washed human platelets, as well as platelets from mouse and nonhuman primate models of hyperlipidemia, further determined that P2YR antagonists (eg, ticagrelor) and Bruton tyrosine kinase inhibitors (eg, ibrutinib) reduced oxLDL-mediated platelet responses and procoagulant activity, whereas COX inhibitors (eg, aspirin) had no significant effect. Together, our results demonstrate that oxLDL enhances GPVI-mediated platelet procoagulant activity in a manner that may be more effectively reduced by P2YR antagonists and tyrosine kinase inhibitors compared with COX inhibitors.

Alternate JournalBlood Adv
PubMed ID36219587
PubMed Central IDPMC10139943
Grant ListP30 EY010572 / EY / NEI NIH HHS / United States
S10 OD012246 / OD / NIH HHS / United States
R01 HL146549 / HL / NHLBI NIH HHS / United States
R01 HL132985 / HL / NHLBI NIH HHS / United States
P30 CA069533 / CA / NCI NIH HHS / United States
P51 OD011092 / OD / NIH HHS / United States
S10 OD026922 / OD / NIH HHS / United States
F30 HL158079 / HL / NHLBI NIH HHS / United States
S10 RR022589 / RR / NCRR NIH HHS / United States
R01 HL101972 / HL / NHLBI NIH HHS / United States