Abstract Number: OC 52.3
Meeting: ISTH 2021 Congress
Background: Platelets and neutrophils are the first cells to appear at sites of an arterial thrombus and both contribute to the pathology of thrombotic events. Platelet-neutrophil interactions involve multiple receptor-ligand interactions, but it remains unknown how these arise and are regulated at the site of a growing thrombus.
Aims: To unravel the mechanisms of neutrophil-platelet interactions in the setting of arterial thrombosis.
Methods: In vitro thrombus formation was induced by perfusion of human whole blood over collagen at an arterial shear rate. Human neutrophil adhesion, movement, Ca2+-fluxes, activation markers and neutrophil extracellular traps (NETs) were assessed by confocal microscopy, as well as the activation status of the platelet thrombi. Integrin αIIbβ3 involvement in neutrophil recruitment was assessed with Glanzmann thrombasthenia blood or by integrin inhibition.
Results: Platelets in thrombi were found to attract neutrophils at high-shear upon flow disturbance. The neutrophil adhesion was mediated through P-selectin and other receptors, but negatively regulated by integrin αIIbβ3. Absence or inhibition of the integrin increased neutrophil recruitment to a platelet thrombus. Thrombus-adhered neutrophils stained positively for activation markers including CD11b and reactive oxygen species. In spite of this activation, the cells did not form NETs. Of the thrombus-interacting neutrophils, >65% displayed repetitive intracellular Ca2+ spiking, which related to their movement pattern around thrombi. Suppressing platelet activation by post-treatment of the thrombus with a prostacyclin analogue profoundly reduced the Ca2+ spiking in neutrophils, pointing to continuous release of neutrophil-activating substances by platelets. Inhibition of platelet-derived chemokines (CXCL7 or CCL5) suppressed the Ca2+ fluxes, and affected their movement patterns. Furthermore, incubation of isolated neutrophils with CXCL7, CCL5 or platelet releasate re-introduced these Ca2+ fluxes.
Conclusions: Neutrophil adhesion and activation at a thrombus is antagonistically regulated by several platelet receptors including integrins and a continuous release of chemokines from platelets.
To cite this abstract in AMA style:Schönichen C, Nagy M, LN Brouns S, Montague S, Ní Ainle F, Knoops K, R Koenen R, Soehnlein O, P Watson S, WM Heemskerk J. Platelet Chemokines and Integrins Antagonistically Steer Neutrophil Activation in Arterial Thrombus Formation [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/platelet-chemokines-and-integrins-antagonistically-steer-neutrophil-activation-in-arterial-thrombus-formation/. Accessed March 4, 2024.
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