Abstract Number: PB1953
Meeting: ISTH 2020 Congress
Background: Genome wide association studies linked the SLC44A2 rs2288904 (461G>A) polymorphism with venous thrombosis (VT) in humans. It leads to HNA-3a (human neutrophil antigen-3a) or HNA-3b epitope expression by the choline transporter like protein-2 (CTL-2). HNA-3b is associated with a 30% decreased risk of VT. CTL-2 is a ubiquitous transmembrane protein identified as a receptor for Von Willebrand factor (VWF).
Aims: In order to explain the link between CTL-2 and VT development we wanted to determine how CTL-2 expressing either HNA-3a or HNA-3b on neutrophils could modulate their adhesion and activation on VWF under flow.
Methods: Neutrophils homozygous for the HNA-3a- or the HNA-3b-coding allele purified from healthy blood donors were perfused in flow chambers at venous shear rates (100s-1). Different matrices including VWF, and different blocking antibodies were tested. Neutrophil activation under VWF and LPS challenge was evaluated at various cell concentrations in different flow conditions. Neutrophil mobilization was also measured by intravital microscopy in venules from SLC44A2-KO and WT mice after histamine-induced endothelial degranulation and anti-Ly6G staining.
Results: : HNA-3a expression was required for CTL-2-mediated neutrophil adhesion to VWF at 100s-1. This adhesion could occur independently of calcium mobilization and beta-2 integrin engagement. We observed that adhesion of HNA-3a-expressing neutrophils was enhanced when they were preactivated with LPS. Moreover, specific shear conditions could act as a “second hit” on those, increasing their activation and inducing the formation of neutrophil extracellular trap aggregates. In vivo, mice lacking CTL-2 showed a massive reduction in neutrophil rolling in inflamed mesenteric venules.
Conclusions: Our results show that CTL-2/HNA-3a is important in the adhesion and activation process of neutrophils in veins under inflammation and when submitted to specific shears conditions. Neutrophils expressing CTL-2/HNA-3b not being associated with these observations, these results could thus explain the association between the HNA-3b epitope and the reduced risk for VT in humans.
To cite this abstract in AMA style:Zirka G, Robert P, Tilburg J, Maracle C, Legendre P, Alessi MC, Lenting PJ, Morange PE, Thomas GM. CTL-2 is a VWF Receptor Involved in Neutrophil Activation [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/ctl-2-is-a-vwf-receptor-involved-in-neutrophil-activation/. Accessed November 26, 2020.
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