Olfactory Receptors and Dysregulated Platelet Activity in Abdominal Aortic Aneurysms
ISTH Academy. Cameron S. Jul 10, 2019; 273752; OC 78.5 Topic: Platelet Antagonists & Novel Therapeutics
Scott Cameron
Scott Cameron
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OC 78.5

Olfactory Receptors and Dysregulated Platelet Activity in Abdominal Aortic Aneurysms

S. Cameron1,2, D. Mix3, A. Mohan4, J. Ashton5, M. Balys5, S. Ture6, K. Krauel7, M. Rondina8, M. Mastrangelo6, A. Doyle3, M. Stoner3, C. Morrell6
1University of Rochester Medical Center, Internal Medicine, Rochester, United States, 2University of Rochester Medical Center, Cardiac Surgery, Rochester, United States, 3University of Rochester Medical Center, Vascular Surgery, Rochester, United States, 4University of Rochester Medical Center, Aab CVRI, Rochester, United States, 5University of Rochester Medical Center, Department of Micobiology and Immunology, Rochester, United States, 6University of Rochester Medical Center, Aab AVRI, Rochester, United States, 7University of Utah School of Medicine, Internal Medicine, Salt Lake City, United States, 8University of Utah, Salt Lake City, United States

Main Topic: Platelets and Megakaryocytes
Category: Platelet Antagonists & Novel Therapeutics

Background: AAA growth and rupture are associated with platelet activation and thrombus in aneurysmal segments. We hypothesized that specific mechanical signals activate platelets and contribute to AAA progression and rupture.
Aims: Using platelets isolated from humans with AAA and relevant murine models of AAA, we investigated whether the platelet phenotype changes.
Methods: Platelets were isolated from human control and AAA patients and mice, and activation was assessed by flow cytometry. A screen for transcripts in AAA patient platelets compared to healthy platelets was assessed by mRNA-seq, and validated by qPCR and Western blotting. Blood flow was simulated ex vivo using a cone/flow system. Clonal cell lines of platelet olfactory receptors (OR) were created for a ligand screen. OR activity was assessed by downstream cAMP Response Element [CRE] function by luciferase activity, and cAMP binding Protein (CREB) activity by phospo-antibody. A murine AAA model mimicking the human condition of AAA with luminal thrombus prior to rupture was used.
Results: Human platelets from AAA patients were reactive through thromboxane and PAR receptors. Platelets from patients with AAA expressed increased OR2L13 mRNA and surface protein compared to healthy platelets. Platelets in a murine AAA model were markedly reactive early in AAA progression but became less reactive coincident with increased platelet OR2L13 expression. An ex vivo system to recapitulate steady (laminar) or disturbed (turbulent) blood flow (S-flow and D-flow, respectively) showed OR2L13 is redirected to the platelet membrane >10-fold under D-flow conditions. Human and murine platelet activation in response to agonists was attenuated by OR2L13 ligands.
Conclusions: D-flow, such as in AAA segments, activates platelets which secrete enzymes capable of remodeling aorta. Platelets from patients with AAA and mice with AAA express increased OR2L13, and platelet activation is reduced by OR2L13 ligands. Platelet OR2L13 expression may be protective in response to D-flow in AAA.

[AAA and Platelet Olfactory 2L13]

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