Abstract Number: PB0044
Meeting: ISTH 2020 Congress
Background: Atherosclerosis not only results from lipid accumulation within the arterial wall but is also a chronic inflammatory disease. Aberrant leukocyte recruitment plays a pivotal role in atherogenesis; we posit that platelets promote leukocyte adhesion during inflammation and encourage inappropriate leukocyte recruitment in atherosclerosis. We hypothesize that selective targeting of kinase pathways of platelet activation may reduce inflammation associated with atherogenesis.
Aims: Investigate the effects of TEC kinase inhibition with the BTK inhibitor, ibrutinib. on endothelial inflammation and platelet-endothelial interactions in a non-human primate atherosclerosis model.
Methods: Two obese rhesus macaques on a high-fat diet for 2 years with detectable carotid intimal thickening were administered ibrutinib orally (10mg/kg/d) for 1 week. We performed in vivo molecular imaging of VCAM-1 and platelet GPIbα as surrogates for endothelial inflammation and platelet activation, respectively. Whole blood was collected on days 0, 2, and 7 for flow cytometry studies. Platelet aggregation in response to the GPVI-agonist CRP was measured using aggregometry. Complete blood counts, lipid levels, and hemostatic assessments were recorded.
Results: After 7 days of ibrutinib administration, molecular imaging of the bilateral carotid arteries showed dramatically decreased carotid signal for both VCAM-1 and GPIbα compared to vehicle. Flow cytometry showed reduced systemic platelet activation and secretion in response to CRP following ibrutinib administration, while platelet aggregation in response to CRP was abrogated compared to baseline. Ibrutinib had no measurable effect on complete blood counts; lipid levels; or prothrombin time and activated partial thromboplastin times.
Conclusions: In a non-human primate model of early atherosclerosis, BTK inhibition reduced endothelial inflammation and platelet activation and endothelial interaction in vivo, and decreased platelet activation and GPVI-mediated aggregation in vitro. These finding suggest that BTK may play a role in driving platelet-mediated inflammation contributing to atherogenesis. Targeting BTK may confer beneficial effects on both the inflammatory and thrombotic contributors to atherosclerosis.
To cite this abstract in AMA style:Kohs T, Olson S, Xie A, Hodovan J, Muller M, McArthur C, Johnson J, Wallisch M, Lorentz C, Verbout N, Kievit P, Aslan J, McCarty O, Lindner J, Shatzel J. Effect of BTK Inhibition on Platelet-mediated Inflammation in an Obese Rhesus Macaque Model of Early Atherosclerosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/effect-of-btk-inhibition-on-platelet-mediated-inflammation-in-an-obese-rhesus-macaque-model-of-early-atherosclerosis/. Accessed November 28, 2023.
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